Next Article in Journal
An Effective MM/GBSA Protocol for Absolute Binding Free Energy Calculations: A Case Study on SARS-CoV-2 Spike Protein and the Human ACE2 Receptor
Next Article in Special Issue
Visual pH Sensors: From a Chemical Perspective to New Bioengineered Materials
Previous Article in Journal
Impact of the Type of Crosslinking Agents on the Properties of Modified Sodium Alginate/Poly(vinyl Alcohol) Hydrogels
Previous Article in Special Issue
Intrinsically Disordered Proteins as Regulators of Transient Biological Processes and as Untapped Drug Targets
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

1
Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran 1477893855, Iran
2
Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran 1417466191, Iran
3
Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
4
Student Research Committee, Iran University of Medical Sciences, Tehran 1449614535, Iran
5
Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
6
Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul 34956, Turkey
7
Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey
8
Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
*
Author to whom correspondence should be addressed.
Submission received: 24 March 2021 / Revised: 8 April 2021 / Accepted: 9 April 2021 / Published: 19 April 2021
(This article belongs to the Special Issue Feature Review Papers in Chemical Biology)

Abstract

:
The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

1. Introduction

The field of cancer chemotherapy is suffering from a number of challenges; drug resistance is the most significant. In respect to the benefits of chemotherapy in the treatment of cancer patients, factors responsible for mediating chemoresistance should be identified in further studies, in order to prevent drug resistance [1,2,3,4,5,6,7]. Cisplatin (CP) is a platinum-containing drug that was first discovered in 1965 and became famous due to its great antimicrobial activity. More experiments demonstrated that platinum-containing agents can possess anti-cancer activity [8,9,10,11,12,13]. As an electrophilic reagent, platinum can interact with nucleophilic residues of nucleobases, including guanine and adenosine by forming covalent bonds. Due to the presence of nucleophilic residues on a wide variety of cellular components, platinum-containing compounds can interact with ribosomes, spliceosomes, RNA and proteins [14,15,16,17]. The major pathway for suppressing cancer progression by CP is inducing DNA damage by forming adducts with DNA, resulting in apoptosis and cell cycle arrest [18]. More efforts in revealing anti-tumor activity of CP revealed that CP has the capacity of internalization in organelles, such as endoplasmic reticulum (ER), mitochondrion, lysosomes, and nucleus. This demonstrates that, in addition to DNA damage, CP can induce cell death by impairing homeostasis of vital organelles, such as ER and mitochondrion [19,20]. However, this impact may negatively affect anti-tumor activity of CP. It has been reported that in spite of impairing homeostasis of proteins and organelles in cytoplasm upon CP accumulation, pro-survival mechanisms, such as autophagy, unfolded protein response (UPR) and other protective processes may be activated [21,22,23]. These mechanisms may induce cancer cells resistance to CP chemotherapy.
Upon administration, CP immediately emerges in blood circulation. A high amount of CP (up to 98%) can be found in status of connected to plasma proteins, such as human serum albumin (HAS) [24,25]. Each HAS can bind to five CP molecules. One of the problems in patients receiving CP is the emergence of zinc imbalance. This is due to binding capacity of HAS-CP to histidine residues that are involved in transportation of Zn2+ ions in cells [26,27]. The penetration of CP into cells is performed via passive diffusion [28].
The benefits of using CP in cancer chemotherapy became absent as a result of chemoresistance. Cancer cells no longer become responsive to CP chemotherapy and can upregulate molecular pathways to induce drug resistance [29,30,31]. A wide variety of factors are considered as key players in mediating CP resistance. Drug transporters participate in triggering CP resistance. ATP7A and ATP7B are copper transporters that can bind to cysteine residue of CP to diminish its internalization in cells, leading to chemoresistance [32]. It has been reported that enhanced activity and expression of P-glycoprotein (P-gp) can also stimulate CP resistance [33]. On the other hand, in CP-resistant cancer cells, pro-apoptotic factors, such as BCL2 associated X (BAX) undergo down-regulation, while an increase occurs in the expression of anti-apoptotic factors, such as Bcl-2 to trigger CP resistance [34,35]. It seems that glutathione peroxidase 4 (GPX4) upregulation prevents ferroptosis in cancer cells to mediate CP resistance [31]. In this case, the inhibition of these antioxidant agents can predispose cancer cells to CP chemotherapy. In head and neck cancer cells, down-regulating glutaredoxin 5 stimulates ferroptosis, leading to CP sensitivity [36]. Transcriptional activation of RAD51 by CtBP1 results in CP resistance [37]. Noteworthy, it appears that CP administration can significantly promote metastasis and invasion of cancer cells by inducing macrophages [38]. The experiments have also tried to target molecular pathways involved in CP resistance via anti-tumor agents. For instance, propofol and hederagenin are among anti-tumor agents that can promote CP sensitivity of cancer cells by down-regulating Wnt signaling and suppressing autophagy [2,39].
As mentioned earlier, the impact of CP on intracellular organelles might pave the way for CP resistance. In the present review, our aim is to reveal the role of reactive oxygen species (ROS) in mediating/suppressing CP resistance. This review focuses on molecular pathways to relate ROS generation with efficacy of CP chemotherapy in cancer therapy. Future experiments can focus on targeting molecular pathways involved in this review articles and we have provided some examples in this case.

2. ROS: Dual Role in Cancer Progression/Inhibition

2.1. Basics

Reactive species have gained much attention in the field of biology and medicine, and to date, different kinds of reactive species have been recognized, based on their source, being either oxygen, nitrogen or sulfur [40,41,42]. ROS are derived from oxygen through some reactions such as reduction-oxidation reactions or electronic excitation [43]. There are four major types of ROS, including superoxide, hydrogen peroxide, peroxyl radical and lipid peroxidase [44,45,46]. As chemically active free radicals, ROS play a remarkable role in tissue homeostasis. The production of ROS occurs in mitochondrion and this is performed during mitochondrial respiration and inducing the partial reduction of oxygen [45,47,48]. In addition to mitochondria, other cellular organelles, such as ER and peroxisomes can participate in ROS formation [49,50]. It has been reported that ROS can interact with proteins, lipids and genetic materials in cells [51,52]. The imbalance in the generation of ROS can lead to the emergence of oxidative stress with the dual role of being beneficial or harmful. The physiological functions of cells, such as aging, inflammation and immune responses are governed by ROS [53,54,55]. Therefore, the presence of ROS is vital for normal function of cells. However, increased levels of ROS production can result in the development of pathological events, including neurodegenerative diseases, diabetes and cancer [56,57,58].
ROS participate in redox signaling and in this case, their low level generated by mitochondrial respiration or nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase (NOX) is required [59]. In redox signaling, ROS regulate a variety of molecules, including protein kinases and transcription factors to monitor proliferation, differentiation, migration and cytokine production. The opposite term of redox signaling is redox modulation that ROS action does not rely on first messenger (extracellular stimuli) and ROS induce changes in characteristics of redox-sensitive molecules, such as nucleic acid and metabolic enzymes [60]. One of the most well-known pathways that ROS participate is apoptosis induction. Enhanced generation of ROS disrupts mitochondrial homeostasis, and this leads to the upregulation of apoptotic factors, such as Bax and Bid, and down-regulation of anti-apoptotic factors, such as Bcl-2. Then, the release of cytochrome C (cyt C) from mitochondrion occur, leading to activation of caspase cascade and apoptotic cell death. Furthermore, ROS can impair ER homeostasis to stimulate apoptosis [61].

2.2. ROS Role in Cancer

In the previous section, we have summarized the role of ROS production, their role in physiological conditions and related pathways. In this section, an overview of the ROS role in cancer progression/inhibition is provided to shed some light on its targeting pathways in cancer therapy. The molecular pathways that are regulated by ROS are of importance in cancer therapy [62,63,64]. Increased ROS generation leads to the activation of p38 and extracellular signal-regulated kinase (ERK), which subsequently stimulates cell death and cell cycle arrest at S and G2/M phases [65]. Organelles are vital targets of ROS in cancer cells. Upon ROS overgeneration, ER stress occurs, and related molecular pathways, including glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) undergo upregulation that trigger anti-tumor activity [66]. Previously, it was mentioned that an increase in ROS generation impairs mitochondrial homeostasis. It has been reported that by triggering mitochondrial damage, ROS promotes the expression level of FOXO3a in mediating its nuclear translocation. In the nucleus, FOXO3a enhances expression level of tumor-suppressing factors, such as Bim caspase-3 and phosphatase and tensin homolog (PTEN) to induce apoptosis in cancer cells [67]. This study clearly demonstrates that by regulating mitochondria, ROS can induce apoptosis. In addition to apoptotic cell death, ROS overgeneration can stimulate ferroptosis in decreasing proliferation and viability of cancer cells [68]. Autophagy is another programmed cell death (PCD) mechanism that can be stimulated by ROS levels in cancer therapy [69,70]. In lung cancer cells, increased ROS generation leads to stimulation of mitogen-activated protein kinase (MAPK) that in turn, induces ERK and c-Jun N-terminal kinase (JNK) pathways. Then, autophagic cell death occurs that remarkably diminishes proliferation and growth of lung cancer cells [71]. Therefore, elevating ROS generation is the most important pathway that anti-tumor agents follow in cancer elimination [72]. One of the forms of autophagy is mitophagy that degrades damaged mitochondrion [73]. ROS overgeneration leads to mitochondrial injury and provides the conditions for mitophagy, resulting in a decrease in cancer cell viability [74]. Noteably, in respect to the role of ROS in reducing cancer cell viability, it has been reported that cancer stem cells (CSCs) preserve ROS generation at low levels to obtain chemoresistance [75]. Therefore, using agents that enhance ROS generation is improtant in providing chemosensitivity. Overall, studies are in agreement with anti-tumor activity of ROS and their capacity in regulating various molecular pathways [76,77,78,79,80]. However, there are controversies about the role of ROS in cancer cells. Although previous statements demonstrate the role of ROS as anti-tumor agents, there are experiments showing the tumorigenesis role of ROS. Immune system plays a significant role in cancer therapy. In impairing anti-tumor activity of immune system, cancer-associated fibroblasts (CAFs) enhance ROS generation to provide polarization of monocytes to myeloid-derived suppressor cell (MDSC) [81]. It appears that hepatitis B virus (HBV) can enhance ROS generation in hepatocellular carcinoma. Enhanced ROS production leads to IQGAP1 and Rac1 interaction that overexpressed Rac1 induces Src/FAK signaling via phosphorylation to promote migration and invasion of cancer cells, and stimulate anoikis resistance [82]. These studies demonstrate the dual role of ROS in cancer. In the next sections, a mechanistic discussion of ROS role in CP sensitivity/resistance is provided [83].

3. ROS, Cisplatin Chemotherapy and Related Molecular Pathways

Cisplatin Sensitivity

The Krüppel-like factor 4 (KLF4) is a zinc finger-containing transcription factor capable of regulating different biological activities such as differentiation and tumorigenesis. The interaction partner and cell type determine role of KLF4 as a tumor-suppressing or tumor-promoting factor [84]. The overexpression of KLF4 is in favor of enhancing CP-mediated apoptosis in cancer cells [85]. In CP resistant-cancer cells, KLF4 and ROS undergo down-regulation that are responsible for increased cell viability [86]. As their levels decrease simultaneously, KLF4 upregulation may promote ROS levels in enhancing CP sensitivity of cancer cells.
MicroRNAs (miRNAs) are regulators of different biological processes in cells, such as proliferation, migration, differentiation, apoptosis and autophagy [87]. In addition to physiological roles, miRNAs also play a significant role in pathological events via regulating various molecular pathways [88]. MiRNA-124 is a new emerging miRNA in cancer chemotherapy that its upregulation down-regulates oncogenic signal transducer and activator of transcription 3 (STAT3) pathway to promote CP sensitivity [89]. Furthermore, it can be considered as a biomarker for determining response to CP chemotherapy, so that gastric cancer patients with low levels of miRNA-124 have poor response to CP chemotherapy [90]. Noteworthy, miRNA-124 can regulate ROS levels in affecting CP response of cancer cells. In this way, miRNA-124 decreases SIRT1 expression to increase ROS levels that subsequently, stimulate JNK phosphorylation, leading to increased CP sensitivity of hepatocellular carcinoma cells [91]. The same phenomenon occurs by miRNA-519d in colorectal cancer cells. MiRNA-519d is a critical regulator of cancer response to CP chemotherapy. MiRNA-519d can reduce expression level of XIAP to potentiate CP cytotoxicity against cancer cells [92]. Furthermore, miRNA-519d impedes CP resistance by inducing apoptosis through MCL-1-dependent mitochondrial pathway [93]. In colorectal cancer cells, miRNA-519d down-regulates the expression level of tripartite motif 32 (TRIM32) to enhance ROS levels, leading to mitochondrial dysfunction and increased CP sensitivity [94]. Investigating the expression level demonstrates that miRNAs with tumor-suppressing role undergo down-regulation in CP resistant-cancer cells. Such phenomenon is obvious in cervical cancer in which miRNA-497 shows low expression, while an increase occurs in expression profile of transketolase (TKT) (upregulation in 81.1% of samples). By reducing TKT expression, miRNA-497 promotes ROS levels, while induces GSH depletion, leading to cancer cell death and CP sensitivity [95].
Recent experiments have focused on revealing role of sirtuin-2 (SIRT2) in cancer and providing rationale for its therapeutic targeting [96]. SIRT2 can suppress migration and invasion of cancer cells via isocitrate dehydrogenase 1 (IDH1) deacetylation [97]. Furthermore, SIRT2 can inhibit proliferation and colony-formation capacity of cancer cells [98]. In ovarian cancer cells, enhancing SIRT2 expression paves the way for CP sensitivity. CP administration significantly increases ROS levels to induce SIRT2 expression, resulting in ovarian cancer suppression [78].
One of the targets in cancer therapy is ER, so that inducing ER stress enhances efficacy of chemotherapy in cancer eradication [99]. Triggering ER stress and activating UPR are followed by CP in cancer treatment [100]. In ovarian cancer cells, CP enhances ROS levels to induce ER stress. Then, UPR activates that overcomes drug resistance [101]. It seems that ROS levels can be considered as a biomarker for predicting response of cancer cells to chemotherapy. For this purpose, Sun and colleagues have developed a scoring system, based on ROS, for predicting cancer patients’ response to CP chemotherapy. In this system, there are 25 scores in which scores 0–12 demonstrate low score groups, while scores 13–25 show high score groups. As ROS overgeneration enhances CP sensitivity and apoptosis induction, by enhancing ROS levels, patients are included in high score groups, which have high overall survival and good prognosis [102]. This score can be used in clinical course. Furthermore, down-regulating molecular pathways modulating ROS can pave the way for CP sensitivity. The human paraoxonase (PON) family has three distinct members including PON1, PON2 and PON3. PON1 and PON3 are expressed in the liver, while PON2 demonstrates expression in various tissues and intracellular accumulation upon translation [103]. It has been reported that PON2 possesses antioxidant activity in different tissues, such as the intestine and nervous system [104,105,106]. The overexpression of PON2 is correlated with CP resistance. In order to increase CP sensitivity of melanoma cells, silencing PON2 promotes ROS levels, resulting in decreased viability and proliferation [107]. Figure 1 and Table 1 demonstrate an overview of molecular pathways involved in CP sensitivity via ROS regulation.

4. Cisplatin Resistance

Inhibiting the expression of molecular pathways that reduce ROS levels and confer CP resistance is important in effective cancer chemotherapy. That is the reason why experiments have focused on the identification of such pathways and disrupting their expression. In head and neck cancers, ROS inhibition is associated with CP resistance. Enhancing ROS levels mediates ferroptosis and cell death. Nuclear factor erythroid 2-related factor 2 (Nrf2) is suggested to diminish ROS levels upon CP chemotherapy of head and neck cancer cells. Nrf2 signaling inhibition promotes ROS levels, potentiating ferroptosis and providing CP sensitivity [115].
It seems that ROS can provide metabolic reprograming to enhance resistance of non-small cell lung cancer (NSCLC) cells to CP. In this way, exposing NSCLC cells to CP is associated with an increase in mitochondrial function, PPAR-gamma coactivator-1α (PGC-1α) and mitochondrial. Simultaneously, glycolysis down-regulation occurs, but this does not affect cell cycle progression of cancer cells. These metabolic changes are mediated via ROS, so that ROS can promote PGC-1α expression and mitochondrial mass that are in favor of CP resistance. The inhibition of PGC-1α or suppressing oxidative phosphorylation enhance CP sensitivity of NSCLC cells [116]. This experiment highlights the fact that we should consider metabolic reprogramming resulted from ROS and take strategies for overcoming this condition. The stimulation of factors involved in reducing ROS levels can promote CP resistance of NSCLC cells. Nrf2 participates in regulating redox balance and its activation is correlated with a decrease in ROS levels, and protecting cells against cell death [117,118]. Furthermore, Nrf2 activation can diminish ROS levels and prevent ferroptosis in cancer cells [119]. However, Nrf2 activation can diminish ROS levels in favor of inhibition of cell death in cancer cells and providing chemoresistance [98,120]. Such association has been examined in triggering CP resistance. It has been reported that polarity protein Scribble enhances CP sensitivity of NSCLC cells. However, in vitro and in vivo experiments have shown down-regulation of this factor in CP resistant-NSCLC cells. Upon Scribble down-regulation, proteasomal degradation of NADPH oxidase 2 (Nox2) occurs that subsequently, ROS levels decrease. On the other hand, Nrf2 signaling activation results from Scribble down-regulation that can also participate in decreasing ROS levels. These impacts together lead to the development of CP resistance in NSCLC cells and a reduction in CP-mediated apoptosis [121]. This experiment has potential application in clinical studies, since CP poses increasing challenges in the treatment of cancer patients, and if such signaling networks are affected in clinical course, we can prevent chemotherapy failure.
ROS inhibition can activate molecular pathways involved in cancer progression and phosphoinositide 3-kinase (PI3K)/protein kinase-B (Akt) is one of them. It has been reported that activation of PI3K/Akt axis not only promotes proliferation and metastasis of cancer cells [122,123,124,125], but also triggers chemoresistance [126,127,128,129]. Therefore, it is important to reveal the role of this molecular pathway in CP resistance of cancer cells and providing prospects for its targeting. In CP-resistant NSCLC cells, glutathione peroxidase 1 (GPX1) remarkably diminishes ROS levels to stimulate Akt signaling, as a tumor-promoting factor for CP resistance. The investigation of molecular pathways demonstrates that master transcription factor nuclear factor-kappaB (NF-κB) functions as upstream mediator of GPX1 in CP resistance, so that NF-kB inhibition leads to CP sensitivity of NSCLC cells [89]. GPX2 is also involved in CP resistance via reducing ROS levels, paving the way for failure of CP in lung cancer chemotherapy [130].
To be more specific about mechanisms involved in CP resistance, the significant role of drug transporters in this process should be considered and how they interact with ROS overgeneration. The enhanced activity of ATP-binding cassette (ABC) transporters such as multidrug resistance protein 1 (ABCB1) is suggested to induce CP resistance [111,131]. Importantly, revealing molecular pathways, regulating ABCB1 expression and activity, is of importance for providing a platform for next targeting in cancer treatment and enhancing CP sensitivity. It has been reported that EF hand domain-containing protein 2 (EFHD2) as a calcium-binding protein enhances production of NOX4 to promote ROS generation. Subsequently, ROS generation function as upstream mediator of ABCB1 to enhance its expression, resulting in CP resistance [132].
In the tumor microenvironment of cancer cells, some changes can occur to ensure progression and proliferation. The pyruvate kinase isoenzyme type M2 (PKM2) is a regulator of Warburg impact in cancer cells and can enhance glycolysis in cancer cells via catalyzing synthesis of pyruvate from phosphoenolpyruvate (PEP). Increasing evidence demonstrate the therapeutic potential of targeting PKM2 in cancer and enhancing CP sensitivity [133,134,135,136]. Exosomal transfer of PKM2 in hypoxic condition results in the generation of reductive metabolites that counter CP-mediated ROS production, preventing apoptosis and DNA damage and providing condition for CP resistance [137].
Thioredoxin (TRX1) is a disulfide-reducing dithiol enzyme and as an antioxidant enzyme plays a vital role in reduction of enzymes [138]. Recently, attention has been directed towards the role of TRX1 in cancer, particularly drug resistance. It has been reported that TRX inhibition inhibits drug resistance and viability of cancer cells via suppressing Akt phosphorylation and promoting caspase-3 expression [139]. Anti-tumor compounds, such as isodeoxyelephantopin are capable of down-regulating TRX1 and stimulating ROS-induced JNK signaling, leading to enhanced CP sensitivity [140]. Down-regulating TRX1 is suggested to promote dependency of cancer cells on oxidative metabolism. Furthermore, TRX1 down-regulation enhances ROS generation in cancer cells to increase their CP sensitivity [141].
One of the important aspects is the regulation of CP sensitivity by miRNAs [142]. Furthermore, miRNAs can modulate ROS levels in cells [143,144]. Therefore, understanding the role of miRNAs in regulating ROS levels in CP chemotherapy is significant. MiRNA-140 is a tumor-suppressing factor that enhances CP sensitivity of cancer cells via down-regulating Wnt signaling [97]. In increasing CP sensitivity, miRNA-140 down-regulates SIRT1 expression to promote ROS levels. Then, ROS induces JNK phosphorylation to increase CP-mediated apoptosis [113]. As more experiments are performed, different molecular pathways are revealed that mediate CP resistance of thoracic cancers. The tumor necrosis factor receptor-associated protein 1 (TRAP1) is a new therapeutic target in cancer. This mitochondrial heat shock protein can be found in other locations of cells such as nucleus, cytoplasm and endoplasmic reticulum [145,146]. It seems that upregulation of TRAP1 triggers drug resistance of cancer cells and prevents apoptosis [147]. The CP resistant-lung cancer cells demonstrate high expression level of TRAP1 and apoptosis inhibition. Silencing TRAP1 is associated with increase in capacity of CP in cancer elimination by enhancing ROS levels and mediating mitochondrial dysfunction [148].
In the introduction section, it was mentioned that ROS can induce apoptosis via triggering mitochondrial dysfunction. Furthermore, it was described that enhanced ROS overgeneration can enhance tumorigenesis. Such an association between ROS and mitochondrial dysfunction in enhancing gastric cancer progression has been evaluated. The eukaryotic initiation factor 2α (eIF2α)-ATF4 axis is a regulator of stress response and can provide conditions in favor of cell survival upon stressful conditions and preventing apoptosis [149,150]. There are different contributors of elF2a including dsRNA-activated protein kinase R (PKR), heme-regulated inhibitor eIF2α kinase (HRI), protein kinase R-like endoplasmic reticulum kinase (PERK), and general control nonderepressible-2 (GCN2) that are stimulated in various stress conditions [149]. When mitochondrial dysfunction occurs, GCN2 or PERK can enhance elF2α expression [151,152]. Exposing gastric cancer cells to CP increases expression level of SLC7A11 (×CT). It seems that mitochondrial dysfunction is responsible for enhanced ×CT and GSH expressions. Studies of the molecular pathways demonstrate that GCN2 can stimulate eIF2α/ATF4 axis to induce mitochondrial dysfunction, leading to enhanced ×CT and ROS levels, as well as triggering CP resistance [153]. Another experiment also reveals role of ×CT in CP resistance. However, in this study, upstream mediator of salubrinal plays an important. Salubrinal enhances expression level of ×CT to increase GSH expression, and silencing ×CT is associated with inability of salubrinal in triggering CP resistance, showing that ×CT is vital for this process. Furthermore, as ×CT enhances GSH expression, they may involve in reducing ROS levels and triggering CP resistance [154].
Noteworthy, molecular pathways that protect cancer cells against oxidative stress damage, can lead to CP resistance. Peroxiredoxin 2 (PRDX2) is a supporter of cells against oxidative damage via reducing ROS and H2O2 levels [155]. In gastric cancer cells, PRDX2 in cooperation with NF-kB-p65 subunit diminish ROS levels to suppress DNA damage and cell death, leading to CP resistance [156]. It seems that ROS participate in mechanisms that suppress CP-mediated apoptosis and mediate chemoresistance [157].
Recent years, much emphasis has been directed towards role of tumor microenvironment in cancer progression. Low levels of angiogenesis and high proliferation of cancer cells induce hypoxic conditions in the tumor microenvironment that are accompanied by an increase in expression level of hypoxia inducible factor-1α (HIF-1α) providing the conditions for cancer growth [158,159,160]. On the other hand, in response to different changes in the tumor microenvironment, alterations in structures and dynamics of mitochondria occur. The dynamin-related protein 1 (Drp1) is involved in mitochondrion dynamics and its phosphorylation level determines its activation or inhibition. For instance, Drp1 phosphorylation at serine 616 in results in its activation and mitochondrial fission, while phosphorylation at serine 637 prevents Drp1 activation and subsequent mitochondrial fission [161,162,163]. A recent study has clearly shed some light on the associations between mitochondria, hypoxia and CP resistance. In hypoxic conditions, an increase occurs in levels of ROS in ovarian cancer cells that subsequently, down-regulate the expression level of Drp1 (serine 637), resulting in mitochondrial fission and CP resistance. Furthermore, Mitofusins 1 and 2 (Mfn1 and 2) involving in mitochondrion dynamics are suppressed by hypoxia-mediated ROS to induce mitochondrial fission and CP resistance [164].
It is worth mentioning that ROS can associate metabolism and metastasis of cancer cells. Then, this relationship can be extended to even affect result of immunotherapy. Therefore, it is of great importance to understand ROS interaction with mechanisms involved in cancer metastasis and its association immune factors. Such relationships have been investigated in CP chemotherapy. It has been reported that high levels of ROS change the metabolic profile of lung cancer cells. This metabolism alteration leads to the reliance of lung cancer cells to mitochondrial oxidative metabolism than glucose. More investigations demonstrate that this metabolic alteration significantly enhances migration and invasion of lung cancer cells via EMT induction. Besides, EMT participates in triggering programmed death ligand-1 (PD-L1) upregulation that provides immune evasion of cancer cells [165]. This study clearly demonstrates that ROS, proliferation, metastasis and the response of cancer cells to chemotherapy and immunotherapy are in close relationship with each other, and ROS play the central and key role.
One of the pathways CP follow in cancer suppression is inducing DNA damage and preventing cancer progression. However, activation of signaling networks involved in DNA damage repair can provide CP resistance of cancer cells. Such phenomenon in ovarian cancer cells that can be targeted in next studies for triggering CP sensitivity. Dual oxidase 1 (DUOX1) is a carcinogenesis factor via increasing hydrogen peroxide levels [166]. Besides, DUOX1 can enhance ROS level to inhibit cell differentiation [167]. On the other hand, ataxia telangiectasia and Rad3-related protein (ATR) is a serine/threonine protein kinase modulating DNA damage [168]. It has been reported that ATR can induce Checkpoint kinase 1 (Chk1) to trigger DNA damage repair [169,170]. In ovarian cancer cells, DUOXA1 significantly elevates the production of ROS in stimulating ATR/Chk1 axis, leading to CP resistance. The in vitro and in vivo experiments have confirmed role of DUOXA1-mediated ROS overgeneration in CP resistance, and for overcoming poor prognosis in patients, targeting this pathway is of importance [171].
In previous sections, we discussed how Nrf2 signaling can participate in CP resistance. Another experiment also demonstrates role of Nrf2 signaling in CP resistance with an emphasis on upstream mediator of signaling. Increasing evidence shows tumor-promoting role of sirtuin-5 (SIRT5) in different cancers [172,173,174]. There is a dual relationship between SIRT5 and Nrf2 signaling in CP chemotherapy, so that SIRT5 can regulate Nrf2 signaling in reducing nephrotoxicity of CP [173]. In ovarian cancer cells, overexpression of SIRT5 is associated with CP resistance and prevents CP-mediated proliferation inhibition and DNA damage via reducing ROS levels. In this way, SIRT5 stimulates Nrf2 signaling and its downstream target heme oxygenase-1 (HO-1) to reduce ROS levels [175]. In fact, SIRT5/Nrf2 axis results in a reduction in ROS levels, and silencing SIRT5 or Nrf2 provides the way for CP sensitivity via ROS overgeneration. Another experiment also confirms how Nrf2 regulation by an upstream mediator can lead to CP resistance. In ovarian cancer cells with high expression level of p62, cancer cells are resistance to anti-tumor activity of CP. The investigation of molecular pathways demonstrates that p62 induces Nrf2 signaling via Keap1 down-regulation, resulting in reinforcement of antioxidant defense system and protection of cancer cells against inhibitory impact of CP [176]. It has been reported that ROS can function as upstream mediator of tumor-promoting factors in CP resistance. Previously, we described the role of PGC-1α in CP resistance. In ovarian cancer cells, mitochondrial dysfunction enhances ROS levels to stimulate PGC-1α expression, leading to CP resistance [177]. As more experiments are performed, more signaling networks involved in CP resistance of ovarian cancer cells are revealed [178]. Figure 2 and Table 2 provide a summary of ROS and related molecular pathways in CP resistance.

5. Therapeutic Targeting

In respect of the fact that molecular pathways involved in CP resistance and their regulatory impact on ROS levels and signaling have been identified, experiments have focused on using anti-tumor compounds, which are mostly phytochemicals. In the section, we provide a mechanistic discussion around using these compounds and their signaling targets. Plant derived-natural compounds have opened a new gate in cancer therapy due to their multitargeting capacity [193,194,195,196]. Melatonin is a hormone of pineal gland that is synthesized in other organs with higher concentrations [197]. Recent studies have shown different biological and therapeutic activities of melatonin that anti-tumor activity is among them. Noteworthy, melatonin can be considered as a potent chemosensitizer agent [198]. In this way, melatonin can also enhance anti-tumor activity of CP. For instance, it has been reported that melatonin can activate caspase-3/7 cleavage and induce cell cycle arrest in potentiating cytotoxicity of CP against lung cancer cells [199]. Importantly, ROS plays a key role in mediating anti-tumor activity of melatonin and its capacity in promoting CP sensitivity. By enhancing ROS levels, melatonin activates intrinsic pathway of apoptosis, resulting in enhanced CP sensitivity of cervical cancer cells [200]. In addition to apoptosis, melatonin can affect other pathway of programmed cell death, known as autophagy. Generally, autophagy is a “self-digestion” mechanism and its induction is of importance in cancer therapy [201,202]. Increasing evidence demonstrate the close relationship between autophagy and ROS, so that ROS overgeneration can stimulate autophagy [203,204]. By enhancing ROS levels, melatonin simultaneously induces autophagy and apoptosis [205]. A similar strategy is followed by withaferin-A in enhancing CP sensitivity of oral cancer cells via enhancing ROS levels and triggering both apoptosis and autophagy [206]. However, one hint should be considered that autophagy may stimulate chemoresistance [207], and when investigating dual relationship between autophagy and ROS, this aspect of autophagy should be highlighted and considered.
Emodin is a plant derived-natural compound with high anti-tumor activity [208,209]. This potent anti-tumor agent can suppress cancer metastasis via inhibiting epithelial-to-mesenchymal transition (EMT) [204]. The anti-tumor activity of emodin is dose-dependent and can affect different molecular pathways, such as miRNA-34a and vascular endothelial growth factor receptor (VEGFR) [210]. In enhancing CP sensitivity of endometrial cancer cells, emodin targets ROS levels. In this way, emodin diminishes ROS levels to induce apoptosis and suppress tumor growth (both in vitro and in vivo) [211]. Another experiment also confirms the role of emodin in increasing ROS levels, and potentiating the anti-tumor activity of CP against bladder cancer cells [212]. In fact, several signaling networks are affected by anti-tumor compounds in triggering CP sensitivity that enhancing ROS levels is one of them [213].
Previously, it was shown that Nrf2 signaling activation is in favor of CP resistance via reducing ROS levels. Noteworthy, anti-tumor compounds targeting Nrf2 signaling and enhancing CP sensitivity have been discovered. Exposing head and neck cancer cells to wogonin, as a flavonoid compound, significantly reduces expression level of Nrf2, leading to CP sensitivity through increasing ROS accumulation [214]. Another experiment also reveals the down-regulation of Nrf2 upon CP and a novel polyphenol, known as (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23), to enhance ROS accumulation, resulting in cell death and increased CP sensitivity [215]. However, we still have a long way in regulating Nrf2 signaling, since this study has just examined the expression level of Nrf2. What about anti-tumor compounds targeting Keap1 or nuclear translocation of Nrf2? Future experiments will appropriately respond to this question.
Allicin is another naturally occurring compound with the capacity to suppress cancer proliferation, increase radio-sensitivity, and down-regulate NF-κB signaling [216]. Allicin is extensively applied with other chemotherapeutic agents. For instance, allicin can promote chemosensitivity of cancer cells via apoptosis induction, enhancing miRNA-486-3p level and reducing cancer cell viability [217,218]. A newly conducted experiment has obviously demonstrated the role of allicin in CP sensitivity of lung cancer cells. In this way, allicin increases ROS levels to induce both autophagy and apoptosis, and trigger cell cycle arrest (S/G2-M phase) [219]. By increasing ROS levels, a decrease occurs in intracellular level of GSH that is in favor of apoptosis induction via caspase-3 and -7 stimulation [220]. Previously, it was discussed that Akt phosphorylation and activation can promote cancer progression and induce chemoresistance [221,222]. Interestingly, ROS can function as an upstream mediator of Akt signaling [223,224]. Piperlongumine as an anti-tumor agent, promotes ROS levels and accumulation in lung cancer cells to suppress Akt signaling, leading to CP sensitivity [225]. Another aspect is related to impact of anti-tumor compounds on CP-mediated DNA damage, so that by increasing ROS levels, anti-tumor compounds enhance p53 phosphorylation to induce DNA damage and cell death [226]. The importance is efficacy of this combination in enhancing anti-tumor activity of CP in vivo, so that the combination of CP and shikonin effectively suppresses tumor growth in colon cancer (HCT116 xenograft tumor) [227]. Therefore, the next step can be translating these findings to clinical application for enhancing the overall survival of cancer patients and preventing chemotherapy failure.
Clarithromycin (CAM) is a well-known antibiotic that was first applied in 2005. CAM can affect both apoptosis and autophagy by enhancing cytotoxicity of 5-fluorouracil as a chemotherapeutic agent against colorectal cancer cells [228]. A similar phenomenon occurs during CP chemotherapy. In this way, CAM significantly enhances ROS levels to impair ovarian cancer growth in vitro and in vivo, leading to CP sensitivity [229]. However, the story is not always so simple. The dual role of ROS as a pro-survival and pro-death mechanism was extensively discussed in the introduction section. AXL is a receptor tyrosine kinase with a role in cancer that has been suggested to be tumor-promoting. In increasing metastasis of breast cancer cells and providing their immune evasion, AXL and Mertk cooperate together [230]. It has been reported that the overexpression of AXL can induce mitogen-activated protein kinase (MAPK) and triggering therapy resistance [231]. In ovarian cancer cells, decreasing AXL expression is correlated with CP sensitivity by suppressing glycolysis [232]. A combination of CP and pemetrexed can sufficiently stimulate cell death in mesothelioma cells via enhancing ROS levels. However, ROS signaling activates AXL, which diminishes cytotoxicity against cancer cells. In providing effective cancer chemotherapy, it is better co-administer a AXL blocker such as BGB324 with CP and pemetrexed [233]. This study reminds us that although anti-tumor compounds enhance ROS production in providing CP sensitivity, it should be noted that ROS can activate downstream targets with tumor-promoting roles such as AXL.
It is worth mentioning that CP can promote ROS levels in mediating cell death in cancer cells. However, when an anti-tumor agent, such as vitamin D is co-administered with CP, its potential in enhancing ROS levels enhances [234]. Furthermore, a combination of CP with other anti-tumor compounds provide conditions for suppressing molecular pathways that can enhance cancer progression. For instance, plumbagin and CP induce JNK signaling, while they inhibit Akt/mTOR signaling to enhance ROS levels, leading to apoptosis, autophagy and decreased viability of tongue squamous cell carcinoma cells [235]. NF-κB signaling pathway is a molecular pathway where overexpression paves the way for chemoresistance of cancer cells [206,236]. Triptolide promotes intracellular accumulation of ROS to inhibit NF-κB signaling and down-regulate Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP) as anti-apoptotic factors, increasing CP sensitivity of ovarian cancer cells [237]. Reducing glycolysis (Warburg effect) and impairing mitochondrial function are induced by ascorbate in increasing CP sensitivity of osteosarcoma cells (Figure 3) [238]. Overall, the following points can be concluded about using anti-tumor compounds, which are mostly phytochemicals and have roles in enhancing CP sensitivity of cancer cells:
  • Anti-tumor compounds significantly promote intracellular accumulation of ROS to mediate intrinsic pathway of apoptosis via mitochondrial dysfunction [239,240,241,242,243,244,245,246,247,248,249,250],
  • Molecular pathways responsible for cancer progression and mediating CP resistance are suppressed by anti-tumor compounds upon increasing ROS levels [251,252,253,254],
  • Most of the anti-tumor compounds applied with CP in cancer chemotherapy are plant derived-natural products, and one of their drawbacks is their poor bioavailability that can be overcome using nanoparticles. This aspect is discussed in next section (Table 3 and Table 4).

6. Gene Therapy

In relation to the fact that molecular pathways, responsible for CP resistance, have been identified, genetic tools can be employed in providing CP sensitivity. This strategy can be specified by targeting molecular pathways that regulate ROS in CP chemotherapy. Although a few experiments have evaluated role of gene therapy in affecting ROS and CP sensitivity, this section provides a mechanistic discussion with future prospects to show how genetic tools can be utilized for affecting ROS and CP sensitivity.
Previously, it was mentioned that HIF-1α is activated in hypoxic conditions and can promote cancer progression [294,295,296,297,298,299]. As there is a close relationship between HIF-1α and cancer metabolism, targeting this molecular pathway is of importance in CP sensitivity. Among genetic tools, small interfering RNA (siRNA) has shown high potential in promoting CP sensitivity via down-regulating tumor-promoting factors [296,300,301]. In this case, HIF-1α down-regulation by siRNA leads to a change in cancer metabolism from aerobic glycolysis to mitochondrial oxidative phosphorylation. Then, ROS overgeneration occurs, resulting in apoptosis and increased CP sensitivity. This experiment obviously demonstrates impact of siRNA on ROS-related molecular pathways and their role in CP chemotherapy. Furthermore, in order to promote the potential of siRNA in gene silencing, its delivery by attenuated Salmonella has been performed [302]. In addition to HIF-1α, Nrf2 signaling role in CP resistance has been discussed before [303]. It seems that down-regulating Nrf2 expression by siRNA paves the way for CP sensitivity via inhibiting HO-1, subsequent increase in ROS generation and promoting CP-mediated cell death [304]. Future experiments can focus on developing nanoparticles for siRNA delivery, affecting molecular pathways regulating ROS and promoting CP sensitivity. More experiments are needed to target factors regulating ROS levels in CP chemotherapy, paving the way for cancer elimination. Furthermore, other kinds of genetic tools, such as CRISPR/Cas9 system and short-hairpin RNA (shRNA) can be utilized in this case.

7. Nanotherapeutics

In the previous section, a mechanistic discussion of the role of molecular pathways regulating ROS levels in CP resistance/sensitivity was provided. Then, it was shown that anti-tumor compounds can affect ROS levels in mediating CP sensitivity. However, these therapies suffer from poor bioavailability and provide a platform for their targeted delivery is important in increasing their efficacy in triggering CP sensitivity. Furthermore, upstream mediators of ROS can be targeted by genetic tools, such as siRNA. However, siRNA should first circulate in blood and then move to the tumor site. It may be degraded by enzymes, while circulating in blood, and also, its efficacy increases by targeted delivery thereby promoting its intracellular accumulation [305,306]. In this section, we demonstrate how nanocarriers can be helpful in regulating ROS levels and providing CP sensitivity.
Nanoscale delivery systems can significantly promote intracellular accumulation of drugs in cells via mediating endocytosis [307,308]. Another benefit of using nanocarriers is providing simultaneous chemotherapy and phototherapy in cancer eradication [309,310]. Such a strategy has been applied for CP delivery and preventing drug resistance. In this case, mesoporous silica nanoparticles (MSNs) have been developed for CP delivery. In order to provide phototherapy capacity of MSNs, their surface modification by chlorin e6 (Ce6) was performed. The nanocarriers demonstrated good properties such as particle size of 100 nm and zeta potential of 18.2 mV. These nanoparticles penetrate into cancer cells through endocytosis to promote intracellular accumulation of CP. Exposure to 660 nm light irradiation induces phototherapy effect and significantly promote ROS production in lung cancer cells, leading to enhanced efficacy of CP in cancer elimination [311]. Another experiment also demonstrates the role of photodynamic therapy in increasing ROS levels, and sensitizing cancer cells to apoptosis that are of importance in promoting their CP sensitivity [312]. Overall, irradiation and photo-excitation are vital for promoting ROS levels and activating pro-apoptotic factors, such as p38 MAPK to increase CP sensitivity of cancer cells [313]. It is worth mentioning that nanoparticles can also mediate co-delivery of CP with other anti-tumor compounds. Metformin is a potent anti-tumor compound that suppresses mammalian target of rapamycin (mTOR) via AMP-activated protein kinase (AMPK) upregulation, leading to CP sensitivity of cancer cells [314]. For enhancing the efficacy of metformin and CP in cancer chemotherapy, nanoplatforms have been developed [315]. It is worth mentioning that metformin- and CP-loaded nanoparticles can affect ROS. In this way, exposing colorectal cancer cells to CP- and metformin-loaded nanocubosomes is associated with an increase in ROS levels, that subsequently, enhance NADPH oxidase, while decreasing lactate dehydrogenase (LDH), leading to caspase-3 cleavage and chemosensitivity [316].
Curcumin is also a plant derived-natural compound with diverse therapeutic effects that anti-tumor activity is among them [317,318,319,320,321]. Curcumin is extensively applied with CP in suppressing progression of cancer cells and providing their chemosensitivity via targeting molecular pathways and mechanisms such as apoptosis, metastasis, KLF4 and SOX2 [322,323]. Loading CP and curcumin on liposomal nanocarriers increases their potential in enhancing ROS levels and suppressing hepatocellular carcinoma progression [324]. Another experiment also reveals role of curcumin-loaded nanoparticles in increasing ROS levels in oral cancer cells and sensitizing them to CP-mediated cell death [325]. In fact, the field of materials science can direct us towards using agents capable of promoting ROS levels and reversing CP resistance. Such a strategy has been utilized recently by Sun and colleagues. In this way, they synthesized nanogel by conjugating chitosan to diallyl disulfide, and then, its grafting with valproate. The interesting point is that valproate induces 18-fold increase in p53 expression, and simultaneously, diallyl disulfide triggers 8-fold increase in ROS levels, leading to CP sensitivity. Furthermore, in vivo experiment also confirmed role of this nanogel in reducing tumor growth inhibition and CP sensitivity [326]. A newly conducted experiment demonstrates that tocotrienols-, caffeic acid- and CP-loaded nanoemulsions can enhance ROS production up to 16.9%, and 30.2% in lung and liver cancers, respectively [327], that are importance in mediating cell death and preventing cell cycle progression.
Notably, carbon nanomaterials, such as graphene possess carcinogenesis impact [296]. Applying such carriers for CP delivery may exert reverse effect and promote drug resistance of cancer cells. It has been reported that CP-loaded multiwalled carbon nanotubes significantly diminish ROS levels and induce failure of CP in mediating apoptosis in breast cancer cells, leading to development of drug resistance [328]. Therefore, this aspect should be considered while synthesizing nanocarriers for CP delivery and suppressing cancer progression.
Overall, studies are in line with the fact that using nanoparticles is of importance in increasing ROS levels and sensitizing cancer cells to CP chemotherapy. Furthermore, nanocarriers can undergo surface modification to enhance their selectivity towards cancer cells. Finally, nanoparticles can provide phototherapy in promoting ROS generation, resulting in an increase in efficacy of CP in cancer chemotherapy (Figure 4) [298,329,330,331].

8. Conclusions and Remarks

In the present review, a comprehensive discussion of ROS role in CP resistance/sensitivity was provided. Due to frequent application of CP, cancer cells have obtained resistance to this chemotherapeutic agent, and if an effective cancer chemotherapy is performed, molecular pathways and mechanisms responsible for CP resistance should be identified so they can be targeted through novel therapeutics. The exact role of ROS in cancer cells has not been completely determined, and it may act as a pro-survival or pro-death mechanism. This context-dependent role of ROS has resulted in much attention in revealing its role in CP resistance/sensitivity. Upstream mediators of ROS can affect response of cancer cells to CP chemotherapy, and noteworthy, downstream targets also play a significant role, as shown in this review. The important hint is that experiments have used therapeutic agents in targeting ROS and providing CP sensitivity. In this case, both genetic and pharmacological interventions have been performed. Anti-tumor compounds that are mostly phytochemicals, enhance ROS levels to mediate mitochondrial dysfunction and cell death. It should be noted that ROS can activate both autophagy and apoptosis. In contrast to apoptosis, autophagy can promote the progression of cancer cells [332]. Therefore, if autophagy activation occurs following pharmacological intervention and enhancing ROS levels in CP chemotherapy, the exact role of autophagy should be determined, and if autophagy functions as a pro-survival mechanism, autophagy inhibitors, such as chloroquine can be utilized.
Another important aspect is using gene therapy to influence levels and CP chemotherapy. Similar to pharmacological intervention, genetic tools can also promote CP sensitivity via regulating ROS levels. However, the drawbacks of these strategies should also be considered. For instance, anti-tumor compounds suffer from poor bioavailability. Genetic tools, such as siRNA may undergo degradation while circulating in blood and it has an off-targeting feature. To overcome the aforementioned disadvantages, scientists have focused on developing nanoarchitectures. These nanocarriers provide targeted delivery, co-delivery with other anti-tumor agents and genetic tools, increased intracellular accumulation in cancer cells and promote ROS generation that are important in CP sensitivity. Although pre-clinical studies have investigated ROS and CP chemotherapy, future experiments can focus on developing novel therapies for targeting ROS in the treatment of cancer patients. Furthermore, if nanoparticle application is applied in this field, a biocompatibility profile should be considered.

Author Contributions

Conceptualization, M.A., A.Z. (Ali Zarrabi) and K.-s.A.; Writing, H.S., K.H., A.Z. (Amirhossein Zabolian), H.S., S.M.R.T., A.R., S.S. and S.O.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2018R1D1A1B07042969).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

CP: cisplatin; ER, endoplasmic reticulum; UPR, unfolded protein response; HAS, human serum albumin; P-gp, P-glycoprotein; GPX4, glutathione peroxidase 4; ROS, reactive oxygen species; NOX, NADPH oxidase; cyt C, cytochrome C; ERK, extracellular signal-regulated kinase; GRP78, glucose regulated protein 78; CHOP, C/EBP homologous protein; PTEN, phosphatase and tensin homolog; PCD, programmed cell death; JNK, c-Jun N-terminal kinase; CSCs, cancer stem cells; CAFs, cancer-associated fibroblasts; MDSC, myeloid-derived suppressor cell; HBV, hepatitis B virus; KLF4, krupple-like factor 4; miRNAs, microRNAs; STAT3, signal transducer and activator of transcription 3; TRIM32, tripartite motif 32; TKT, transketolase; SIRT2, sirtuin-2; IDH1, isocitrate dehydrogenase 1; PON, paraoxonase; Nrf2, nuclear factor erythroid 2-related factor 2; NSCLC, non-small cell lung cancer; PGC-1α, PPAR-gamma co-activator-1α; Nox2, NADPH oxidase 2; PI3K, phosphoinositide 3-kinase; Akt, protein kinase-B; GPX1, glutathione peroxidase 1; NF-κB, nuclear factor-kappaB; ABC, ATP-binding cassette; ABCB1, multidrug resistance protein 1; EFHD2, EF hand domain-containing protein 2; PKM2, pyruvate kinase isoenzyme type M2; PEP, phosphoenolpyruvate; TRX1, thioredoxin; TRAP1, tumor necrosis factor receptor-associated protein 1; elF2α, eukaryotic initiation factor 2α; PKR, protein kinase R; HRI, heme-regulated inhibitor; PERK, protein kinase R-like endoplasmic reticulum kinase; GCN2, general control nonderepressible-2; PRDX2, peroxiredoxin 2; HIF-1α, hypoxia inducible factor-1α; Drp1, dynamin-related protein 1; Mfn, mitofusin; PD-L1, programmed death ligand-1; DUOX1, dual oxidase 1; ATR, ataxia telangiectasia and Rad3-related protein; ChK1, Checkpoint kinase 1; SIRT5, sirtuin-5; HO-1, heme oxygenase-1; EMT, epithelial-to-mesenchymal transition; VEGFR, vascular endothelial growth factor receptor; CAM, clatrithromycin; MAPK, mitogen-activated protein kinase; XIAP, X-linked inhibitor of apoptosis protein; siRNA, small interfering RNA; shRNA, short-hairpin RNA; MSNs, mesoporous silica nanoparticles; mTOR, mammalian target of rapamycin; AMPK, AMP-activated protein kinase; LDH, lactate dehydrogenase.

References

  1. Talib, W.H. A ketogenic diet combined with melatonin overcomes cisplatin and vincristine drug resistance in breast carcinoma syngraft. Nutrition 2020, 72, 110659. [Google Scholar] [CrossRef] [PubMed]
  2. Huang, Y.; Lei, L.; Liu, Y. Propofol Improves Sensitivity of Lung Cancer Cells to Cisplatin and Its Mechanism. Med. Sci. Monit. 2020, 26, e919786. [Google Scholar] [CrossRef] [Green Version]
  3. Yu, W.; Chen, Y.; Putluri, N.; Coarfa, C.; Robertson, M.J.; Putluri, V.; Stossi, F.; Dubrulle, J.; Mancini, M.A.; Pang, J.C.; et al. Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress. Cancers 2020, 12, 1670. [Google Scholar] [CrossRef]
  4. Manu, K.A.; Shanmugam, M.K.; Ramachandran, L.; Li, F.; Siveen, K.S.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Arfuso, F.; Kumar, A.P.; et al. Isorhamnetin augments the anti-tumor effect of capecitabine through the negative regulation of NF-κB signaling cascade in gastric cancer. Cancer Lett. 2015, 363, 28–36. [Google Scholar] [CrossRef]
  5. Manu, K.A.; Shanmugam, M.K.; Li, F.; Chen, L.; Siveen, K.S.; Ahn, K.S.; Kumar, A.P.; Sethi, G. Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products. J. Mol. Med. 2014, 92, 267–276. [Google Scholar] [CrossRef] [Green Version]
  6. Ashrafizaveh, S.; Ashrafizadeh, M.; Zarrabi, A.; Husmandi, K.; Zabolian, A.; Shahinozzaman, M.; Aref, A.R.; Hamblin, M.R.; Nabavi, N.; Crea, F. Long non-coding RNA in the doxorubicin resistance of cancer cells. Cancer Lett. 2021, 508, 104–114. [Google Scholar] [CrossRef] [PubMed]
  7. Mirzaei, S.; Zarrabi, A.; Hashemi, F.; Zabolian, A.; Saleki, H.; Ranjbar, A.; Seyed Saleh, S.H.; Bagherian, M.; Sharifzadeh, S.o.; Hushmandi, K.; et al. Regulation of Nuclear Factor-KappaB (NF-κB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis? Cancer Lett. 2021. [Google Scholar] [CrossRef] [PubMed]
  8. Yan, X.-Y.; Qu, X.-Z.; Xu, L.; Yu, S.-H.; Tian, R.; Zhong, X.-R.; Sun, L.-K.; Su, J. Insight into the role of p62 in the cisplatin resistant mechanisms of ovarian cancer. Cancer Cell Int. 2020, 20, 1–11. [Google Scholar] [CrossRef] [PubMed]
  9. Rosenberg, B.; Vancamp, L.; Krigas, T. Inhibition of Cell Division in Escherichia Coli by Electrolysis Products from a Platinum Electrode. Nature 1965, 205, 698–699. [Google Scholar] [CrossRef] [PubMed]
  10. Peng, H.; Jin, H.; Zhuo, H.; Huang, H. Enhanced antitumor efficacy of cisplatin for treating ovarian cancer in vitro and in vivo via transferrin binding. Oncotarget 2017, 8, 45597–45611. [Google Scholar] [CrossRef] [Green Version]
  11. Wang, W.; Shanmugam, M.K.; Xiang, P.; Yam, T.Y.A.; Kumar, V.; Chew, W.S.; Chang, J.K.; Ali, M.Z.B.; Reolo, M.J.Y.; Peh, Y.X.; et al. Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment. Cancers 2020, 12, 211. [Google Scholar] [CrossRef] [Green Version]
  12. Ashrafizadeh, M.; Zarrabi, A.; Hushmandi, K.; Kalantari, M.; Mohammadinejad, R.; Javaheri, T.; Sethi, G. Association of the epithelial–mesenchymal transition (EMT) with cisplatin resistance. Int. J. Mol. Sci. 2020, 21, 4002. [Google Scholar] [CrossRef]
  13. Mirzaei, S.; Mohammadi, A.T.; Gholami, M.H.; Hashemi, F.; Zarrabi, A.; Zabolian, A.; Hushmandi, K.; Makvandi, P.; Samec, M.; Liskova, A. Nrf2 signaling pathway in cisplatin chemotherapy: Potential involvement in organ protection and chemoresistance. Pharmacol. Res. 2021, 167, 105575. [Google Scholar] [CrossRef] [PubMed]
  14. Melnikov, S.V.; Söll, D.; Steitz, T.A.; Polikanov, Y.S. Insights into RNA binding by the anticancer drug cisplatin from the crystal structure of cisplatin-modified ribosome. Nucleic Acids Res. 2016, 44, 4978–4987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Russo Krauss, I.; Ferraro, G.; Merlino, A. Cisplatin-Protein Interactions: Unexpected Drug Binding to N-Terminal Amine and Lysine Side Chains. Inorg Chem. 2016, 55, 7814–7816. [Google Scholar] [CrossRef] [PubMed]
  16. Ashrafizadeh, M.; Hushmandi, K.; Hashemi, M.; Akbari, M.E.; Kubatka, P.; Raei, M.; Koklesova, L.; Shahinozzaman, M.; Mohammadinejad, R.; Najafi, M.; et al. Role of microRNA/Epithelial-to-Mesenchymal Transition Axis in the Metastasis of Bladder Cancer. Biomolecules 2020, 10, 1159. [Google Scholar] [CrossRef] [PubMed]
  17. Yuan, X.; Zhang, W.; He, Y.; Yuan, J.; Song, D.; Chen, H.; Qin, W.; Qian, X.; Yu, H.; Guo, Z. Proteomic analysis of cisplatin- and oxaliplatin-induced phosphorylation in proteins bound to Pt-DNA adducts. Metallomics 2020, 12, 1834–1840. [Google Scholar] [CrossRef]
  18. Gatti, L.; Cassinelli, G.; Zaffaroni, N.; Lanzi, C.; Perego, P. New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants. Drug Resist. Update 2015, 20, 1–11. [Google Scholar] [CrossRef]
  19. Gąsiorkiewicz, B.M.; Koczurkiewicz-Adamczyk, P.; Piska, K.; Pękala, E. Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer. Investig. New Drugs 2020, 39, 1–26. [Google Scholar] [CrossRef] [PubMed]
  20. Türkeş, C.; Arslan, M.; Demir, Y.; Cocaj, L.; Nixha, A.R.; Beydemir, Ş. Synthesis, biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorganic Chem. 2019, 89, 103004. [Google Scholar] [CrossRef] [PubMed]
  21. Galluzzi, L.; Vitale, I.; Michels, J.; Brenner, C.; Szabadkai, G.; Harel-Bellan, A.; Castedo, M.; Kroemer, G. Systems biology of cisplatin resistance: Past, present and future. Cell Death Dis 2014, 5, e1257. [Google Scholar] [CrossRef] [Green Version]
  22. Thakur, B.; Ray, P. Cisplatin triggers cancer stem cell enrichment in platinum-resistant cells through NF-κB-TNFα-PIK3CA loop. J. Exp. Clin. Cancer Res. 2017, 36, 164. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Shen, D.W.; Pouliot, L.M.; Hall, M.D.; Gottesman, M.M. Cisplatin resistance: A cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharm. Rev. 2012, 64, 706–721. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Makovec, T. Cisplatin and beyond: Molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol. Oncol. 2019, 53, 148–158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Dabrowiak, J.C. Metals in Medicine; John Wiley & Sons: Hoboken, NJ, USA, 2017. [Google Scholar]
  26. Sooriyaarachchi, M.; Narendran, A.; Gailer, J. Comparative hydrolysis and plasma protein binding of cis-platin and carboplatin in human plasma in vitro. Metallomics 2011, 3, 49–55. [Google Scholar] [CrossRef]
  27. Handing, K.B.; Shabalin, I.G.; Kassaar, O.; Khazaipoul, S.; Blindauer, C.A.; Stewart, A.J.; Chruszcz, M.; Minor, W. Circulatory zinc transport is controlled by distinct interdomain sites on mammalian albumins. Chem. Sci. 2016, 7, 6635–6648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Martinčič, A.; Cemazar, M.; Sersa, G.; Kovač, V.; Milačič, R.; Ščančar, J. A novel method for speciation of Pt in human serum incubated with cisplatin, oxaliplatin and carboplatin by conjoint liquid chromatography on monolithic disks with UV and ICP-MS detection. Talanta 2013, 116, 141–148. [Google Scholar] [CrossRef]
  29. Peng, L.; Sang, H.; Wei, S.; Li, Y.; Jin, D.; Zhu, X.; Li, X.; Dang, Y.; Zhang, G. circCUL2 regulates gastric cancer malignant transformation and cisplatin resistance by modulating autophagy activation via miR-142-3p/ROCK2. Mol. Cancer 2020, 19, 156. [Google Scholar] [CrossRef]
  30. Shriwas, O.; Priyadarshini, M.; Samal, S.K.; Rath, R.; Panda, S.; Das Majumdar, S.K.; Muduly, D.K.; Botlagunta, M.; Dash, R. DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m(6)A-demethylation of FOXM1 and NANOG. Apoptosis 2020, 25, 233–246. [Google Scholar] [CrossRef]
  31. Zhang, X.; Gu, G.; Li, X.; Zhang, C. Lidocaine alleviates cisplatin resistance and inhibits migration of MGC-803/DDP cells through decreasing miR-10b. Cell Cycle 2020, 19, 2530–2537. [Google Scholar] [CrossRef]
  32. Ferreira, C.R.; Gahl, W.A. Disorders of metal metabolism. Transl. Sci. Rare Dis. 2017, 2, 101–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Xu, Z.; Sun, Y.; Wang, D.; Sun, H.; Liu, X. SNHG16 promotes tumorigenesis and cisplatin resistance by regulating miR-338-3p/PLK4 pathway in neuroblastoma cells. Cancer Cell Int. 2020, 20, 236. [Google Scholar] [CrossRef] [PubMed]
  34. Jia, T.; Ming, S.X.; Cao, Q.Q.; Xu, F.L. Combined treatment with acetazolamide and cisplatin enhances the chemosensitivity of human head and neck squamous cell carcinoma TU868 cells. Arch. Oral Biol. 2020, 119, 104905. [Google Scholar] [CrossRef]
  35. Wang, Z.; Sun, W.; Sun, X.; Wang, Y.; Zhou, M. Kaempferol ameliorates Cisplatin induced nephrotoxicity by modulating oxidative stress, inflammation and apoptosis via ERK and NF-κB pathways. Amb Express 2020, 10, 58. [Google Scholar] [CrossRef] [PubMed]
  36. Lee, J.; You, J.H.; Shin, D.; Roh, J.L. Inhibition of Glutaredoxin 5 predisposes Cisplatin-resistant Head and Neck Cancer Cells to Ferroptosis. Theranostics 2020, 10, 7775–7786. [Google Scholar] [CrossRef]
  37. Deng, Y.; Guo, W.; Xu, N.; Li, F.; Li, J. CtBP1 transactivates RAD51 and confers cisplatin resistance to breast cancer cells. Mol. Carcinog. 2020, 59, 512–519. [Google Scholar] [CrossRef]
  38. Liu, W.; Wang, W.; Wang, X.; Xu, C.; Zhang, N.; Di, W. Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis. Cancer Lett. 2020, 472, 59–69. [Google Scholar] [CrossRef]
  39. Zhang, X.; Sui, S.; Wang, L.; Li, H.; Zhang, L.; Xu, S.; Zheng, X. Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. J. Cell Physiol. 2020, 235, 3425–3437. [Google Scholar] [CrossRef]
  40. Sies, H.; Jones, D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 2020, 21, 363–383. [Google Scholar] [CrossRef] [PubMed]
  41. Kirtonia, A.; Sethi, G.; Garg, M. The multifaceted role of reactive oxygen species in tumorigenesis. Cell. Mol. Life Sci. 2020, 77, 4459–4483. [Google Scholar] [CrossRef] [PubMed]
  42. Liu, L.; Ahn, K.S.; Shanmugam, M.K.; Wang, H.; Shen, H.; Arfuso, F.; Chinnathambi, A.; Alharbi, S.A.; Chang, Y.; Sethi, G.; et al. Oleuropein induces apoptosis via abrogating NF-κB activation cascade in estrogen receptor-negative breast cancer cells. J. Cell. Biochem. 2019, 120, 4504–4513. [Google Scholar] [CrossRef] [PubMed]
  43. Kim, C.; Lee, S.G.; Yang, W.M.; Arfuso, F.; Um, J.Y.; Kumar, A.P.; Bian, J.; Sethi, G.; Ahn, K.S. Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model. Cancer Lett. 2018, 431, 123–141. [Google Scholar] [CrossRef]
  44. Harris, I.S.; DeNicola, G.M. The complex interplay between antioxidants and ROS in cancer. Trends Cell Biol. 2020. [Google Scholar] [CrossRef] [PubMed]
  45. Dai, X.; Wang, L.; Deivasigamni, A.; Looi, C.Y.; Karthikeyan, C.; Trivedi, P.; Chinnathambi, A.; Alharbi, S.A.; Arfuso, F.; Dharmarajan, A.; et al. A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma. Oncotarget 2017, 8, 12831–12842. [Google Scholar] [CrossRef] [Green Version]
  46. Zhang, J.; Ahn, K.S.; Kim, C.; Shanmugam, M.K.; Siveen, K.S.; Arfuso, F.; Samym, R.P.; Deivasigamanim, A.; Lim, L.H.; Wang, L.; et al. Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model. Antioxid. Redox Signal. 2016, 24, 575–589. [Google Scholar] [CrossRef]
  47. Jaune-Pons, E.; Vasseur, S. Role of amino acids in regulation of ROS balance in cancer. Arch. Biochem. Biophys. 2020, 108438. [Google Scholar] [CrossRef]
  48. Lee, M.; Hirpara, J.L.; Eu, J.Q.; Sethi, G.; Wang, L.; Goh, B.C.; Wong, A.L. Targeting STAT3 and oxidative phosphorylation in oncogene-addicted tumors. Redox Biol. 2019, 25, 101073. [Google Scholar] [CrossRef] [PubMed]
  49. Zisook, S.; Shear, K.; Kendler, K.S. Validity of the bereavement exclusion criterion for the diagnosis of major depressive episode. World Psychiatry 2007, 6, 102. [Google Scholar]
  50. Del Río, L.A.; López-Huertas, E. ROS generation in peroxisomes and its role in cell signaling. Plant. Cell Physiol. 2016, 57, 1364–1376. [Google Scholar] [CrossRef] [PubMed]
  51. Cui, Q.; Wang, J.-Q.; Assaraf, Y.G.; Ren, L.; Gupta, P.; Wei, L.; Ashby Jr, C.R.; Yang, D.-H.; Chen, Z.-S. Modulating ROS to overcome multidrug resistance in cancer. Drug Resist. Updates 2018, 41, 1–25. [Google Scholar] [CrossRef]
  52. Yadav, S.K.; Adhikary, B.; Chand, S.; Maity, B.; Bandyopadhyay, S.K.; Chattopadhyay, S. Molecular mechanism of indomethacin-induced gastropathy. Free Radic. Biol. Med. 2012, 52, 1175–1187. [Google Scholar] [CrossRef] [PubMed]
  53. Banoth, B.; Cassel, S.L. Mitochondria in innate immune signaling. Transl. Res. 2018, 202, 52–68. [Google Scholar] [CrossRef] [PubMed]
  54. Shankar, S.; Mahadevan, A.; Satishchandra, P.; Uday Kumar, R.; Yasha, T.; Santosh, V.; Chandramuki, A.; Ravi, V.; Nath, A. Neuropathology of HIV/AIDS with an overview of the Indian scene. Indian J. Med. Res. 2005, 121, 468–488. [Google Scholar] [PubMed]
  55. Giorgi, C.; Marchi, S.; Simoes, I.C.; Ren, Z.; Morciano, G.; Perrone, M.; Patalas-Krawczyk, P.; Borchard, S.; Jędrak, P.; Pierzynowska, K. Mitochondria and reactive oxygen species in aging and age-related diseases. Int. Rev. Cell Mol. Biol. 2018, 340, 209–344. [Google Scholar]
  56. Butterfield, D.A.; Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci. 2019, 20, 148–160. [Google Scholar] [CrossRef]
  57. Gerber, P.A.; Rutter, G.A. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid. Redox Signal. 2017, 26, 501–518. [Google Scholar] [CrossRef] [Green Version]
  58. Liu, Z.; Ren, Z.; Zhang, J.; Chuang, C.-C.; Kandaswamy, E.; Zhou, T.; Zuo, L. Role of ROS and nutritional antioxidants in human diseases. Front. Physiol. 2018, 9, 477. [Google Scholar] [CrossRef] [Green Version]
  59. Chatterjee, R.; Chatterjee, J. ROS and oncogenesis with special reference to EMT and stemness. Eur. J. Cell Biol. 2020, 99, 151073. [Google Scholar] [CrossRef]
  60. Li, R.; Prasad, V.; Huang, B. Gaussian mixture model-based ensemble Kalman filtering for state and parameter estimation for a PMMA process. Processes 2016, 4, 9. [Google Scholar] [CrossRef] [Green Version]
  61. Ballard, J.W.O.; Towarnicki, S.G. Mitochondria, the gut microbiome and ROS. Cell Signal. 2020, 75, 109737. [Google Scholar] [CrossRef] [PubMed]
  62. Aggarwal, V.; Tuli, H.S.; Varol, A.; Thakral, F.; Yerer, M.B.; Sak, K.; Varol, M.; Jain, A.; Khan, M.A.; Sethi, G. Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements. Biomolecules 2019, 9, 735. [Google Scholar] [CrossRef] [Green Version]
  63. Lee, J.H.; Kim, C.; Lee, S.G.; Sethi, G.; Ahn, K.S. Ophiopogonin D, a Steroidal Glycoside Abrogates STAT3 Signaling Cascade and Exhibits Anti-Cancer Activity by Causing GSH/GSSG Imbalance in Lung Carcinoma. Cancers 2018, 10, 427. [Google Scholar] [CrossRef] [Green Version]
  64. Sinha, N.; Panda, P.K.; Naik, P.P.; Das, D.N.; Mukhopadhyay, S.; Maiti, T.K.; Shanmugam, M.K.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; et al. Abrus agglutinin promotes irreparable DNA damage by triggering ROS generation followed by ATM-p73 mediated apoptosis in oral squamous cell carcinoma. Mol. Carcinog 2017, 56, 2400–2413. [Google Scholar] [CrossRef]
  65. Hao, Y.; Huang, Y.; Chen, J.; Li, J.; Yuan, Y.; Wang, M.; Han, L.; Xin, X.; Wang, H.; Lin, D.; et al. Exopolysaccharide from Cryptococcus heimaeyensis S20 induces autophagic cell death in non-small cell lung cancer cells via ROS/p38 and ROS/ERK signalling. Cell Prolif 2020, 53, e12869. [Google Scholar] [CrossRef]
  66. Celesia, A.; Morana, O.; Fiore, T.; Pellerito, C.; D’Anneo, A.; Lauricella, M.; Carlisi, D.; De Blasio, A.; Calvaruso, G.; Giuliano, M.; et al. ROS-Dependent ER Stress and Autophagy Mediate the Anti-Tumor Effects of Tributyltin (IV) Ferulate in Colon Cancer Cells. Int. J. Mol. Sci. 2020, 21, 8135. [Google Scholar] [CrossRef]
  67. Nasimian, A.; Farzaneh, P.; Tamanoi, F.; Bathaie, S.Z. Cytosolic and mitochondrial ROS production resulted in apoptosis induction in breast cancer cells treated with Crocin: The role of FOXO3a, PTEN and AKT signaling. Biochem. Pharm. 2020, 177, 113999. [Google Scholar] [CrossRef]
  68. Shen, L.D.; Qi, W.H.; Bai, J.J.; Zuo, C.Y.; Bai, D.L.; Gao, W.D.; Zong, X.L.; Hao, T.T.; Ma, Y.; Cao, G.C. Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation. Anat. Rec. 2021, 304, 313–322. [Google Scholar] [CrossRef]
  69. Deng, S.; Shanmugam, M.K.; Kumar, A.P.; Yap, C.T.; Sethi, G.; Bishayee, A. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer 2019, 125, 1228–1246. [Google Scholar] [CrossRef] [PubMed]
  70. Patra, S.; Mishra, S.R.; Behera, B.P.; Mahapatra, K.K.; Panigrahi, D.P.; Bhol, C.S.; Praharaj, P.P.; Sethi, G.; Patra, S.K.; Bhutia, S.K. Autophagy-modulating phytochemicals in cancer therapeutics: Current evidences and future perspectives. Semin. Cancer Biol. 2020. [Google Scholar] [CrossRef] [PubMed]
  71. Fan, J.; Ren, D.; Wang, J.; Liu, X.; Zhang, H.; Wu, M.; Yang, G. Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo. Cell Death Dis. 2020, 11, 126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Wang, W.; Dong, X.; Liu, Y.; Ni, B.; Sai, N.; You, L.; Sun, M.; Yao, Y.; Qu, C.; Yin, X.; et al. Itraconazole exerts anti-liver cancer potential through the Wnt, PI3K/AKT/mTOR, and ROS pathways. Biomed. Pharm. 2020, 131, 110661. [Google Scholar] [CrossRef]
  73. Praharaj, P.P.; Naik, P.P.; Panigrahi, D.P.; Bhol, C.S.; Mahapatra, K.K.; Patra, S.; Sethi, G.; Bhutia, S.K. Intricate role of mitochondrial lipid in mitophagy and mitochondrial apoptosis: Its implication in cancer therapeutics. Cell. Mol. Life Sci. 2019, 76, 1641–1652. [Google Scholar] [CrossRef]
  74. Chuang, K.C.; Chang, C.R.; Chang, S.H.; Huang, S.W.; Chuang, S.M.; Li, Z.Y.; Wang, S.T.; Kao, J.K.; Chen, Y.J.; Shieh, J.J. Imiquimod-induced ROS production disrupts the balance of mitochondrial dynamics and increases mitophagy in skin cancer cells. J. Derm. Sci. 2020, 98, 152–162. [Google Scholar] [CrossRef]
  75. Choi, H.J.; Jhe, Y.L.; Kim, J.; Lim, J.Y.; Lee, J.E.; Shin, M.K.; Cheong, J.H. FoxM1-dependent and fatty acid oxidation-mediated ROS modulation is a cell-intrinsic drug resistance mechanism in cancer stem-like cells. Redox Biol. 2020, 36, 101589. [Google Scholar] [CrossRef] [PubMed]
  76. Wang, F.; Wu, H.; Fan, M.; Yu, R.; Zhang, Y.; Liu, J.; Zhou, X.; Cai, Y.; Huang, S.; Hu, Z.; et al. Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells. FASEB J. 2020, 34, 4266–4282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Swetha, K.L.; Sharma, S.; Chowdhury, R.; Roy, A. Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy. Pharm. Rep. 2020, 72, 1749–1765. [Google Scholar] [CrossRef]
  78. Wang, H.; Zhao, L.; Wu, J.; Hong, J.; Wang, S. Propofol induces ROS-mediated intrinsic apoptosis and migration in triple-negative breast cancer cells. Oncol. Lett. 2020, 20, 810–816. [Google Scholar] [CrossRef] [PubMed]
  79. Oh, H.N.; Lee, M.H.; Kim, E.; Kwak, A.W.; Yoon, G.; Cho, S.S.; Liu, K.; Chae, J.I.; Shim, J.H. Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET. Biomolecules 2020, 10, 297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Zhu, Q.; Guo, Y.; Chen, S.; Fu, D.; Li, Y.; Li, Z.; Ni, C. Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells. OncoTargets Ther. 2020, 13, 2807–2817. [Google Scholar] [CrossRef] [Green Version]
  81. Xiang, H.; Ramil, C.P.; Hai, J.; Zhang, C.; Wang, H.; Watkins, A.A.; Afshar, R.; Georgiev, P.; Sze, M.A.; Song, X.S.; et al. Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing ROS-Generating Monocytic MDSCs in Lung Squamous Cell Carcinoma. Cancer Immunol Res. 2020, 8, 436–450. [Google Scholar] [CrossRef] [Green Version]
  82. Mo, C.F.; Li, J.; Yang, S.X.; Guo, H.J.; Liu, Y.; Luo, X.Y.; Wang, Y.T.; Li, M.H.; Li, J.Y.; Zou, Q. IQGAP1 promotes anoikis resistance and metastasis through Rac1-dependent ROS accumulation and activation of Src/FAK signalling in hepatocellular carcinoma. Br. J. Cancer 2020, 123, 1154–1163. [Google Scholar] [CrossRef]
  83. Nguyen, D.J.M.; Theodoropoulos, G.; Li, Y.Y.; Wu, C.; Sha, W.; Feun, L.G.; Lampidis, T.J.; Savaraj, N.; Wangpaichitr, M. Targeting the Kynurenine Pathway for the Treatment of Cisplatin-Resistant Lung Cancer. Mol. Cancer Res. 2020, 18, 105–117. [Google Scholar] [CrossRef] [Green Version]
  84. Rowland, B.D.; Peeper, D.S. KLF4, p21 and context-dependent opposing forces in cancer. Nat. Rev. Cancer 2006, 6, 11–23. [Google Scholar] [CrossRef]
  85. Zhang, L.; Li, X.; Chao, Y.; He, R.; Liu, J.; Yuan, Y.; Zhao, W.; Han, C.; Song, X. KLF4, a miR-32-5p targeted gene, promotes cisplatin-induced apoptosis by upregulating BIK expression in prostate cancer. Cell Commun. Signal. 2018, 16, 53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Yadav, S.S.; Kumar, M.; Varshney, A.; Yadava, P.K. KLF4 sensitizes the colon cancer cell HCT-15 to cisplatin by altering the expression of HMGB1 and hTERT. Life Sci. 2019, 220, 169–176. [Google Scholar] [CrossRef] [PubMed]
  87. Sailo, B.L.; Banik, K.; Girisa, S.; Bordoloi, D.; Fan, L.; Halim, C.E.; Wang, H.; Kumar, A.P.; Zheng, D.; Mao, X.; et al. FBXW7 in Cancer: What Has Been Unraveled Thus Far? Cancers 2019, 11, 246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Abadi, A.J.; Zarrabi, A.; Gholami, M.H.; Mirzaei, S.; Hashemi, F.; Zabolian, A.; Entezari, M.; Hushmandi, K.; Ashrafizadeh, M.; Khan, H. Small in Size, but Large in Action: MicroRNAs as Potential Modulators of PTEN in Breast and Lung Cancers. Biomolecules 2021, 11, 304. [Google Scholar] [CrossRef] [PubMed]
  89. Qi, M.M.; Ge, F.; Chen, X.J.; Tang, C.; Ma, J. MiR-124 changes the sensitivity of lung cancer cells to cisplatin through targeting STAT3. Eur. Rev. Med. Pharm. Sci. 2019, 23, 5242–5250. [Google Scholar] [CrossRef]
  90. Jin, L.; Zhang, Z. Serum miR-3180-3p and miR-124-3p may Function as Noninvasive Biomarkers of Cisplatin Resistance in Gastric Cancer. Clin. Lab. 2020, 66. [Google Scholar] [CrossRef]
  91. Xu, Y.; Lai, Y.; Weng, H.; Tan, L.; Li, Y.; Chen, G.; Luo, X.; Ye, Y. MiR-124 sensitizes cisplatin-induced cytotoxicity against CD133(+) hepatocellular carcinoma cells by targeting SIRT1/ROS/JNK pathway. Aging 2019, 11, 2551–2564. [Google Scholar] [CrossRef]
  92. Pang, Y.; Mao, H.; Shen, L.; Zhao, Z.; Liu, R.; Liu, P. MiR-519d represses ovarian cancer cell proliferation and enhances cisplatin-mediated cytotoxicity in vitro by targeting XIAP. OncoTargets Ther. 2014, 7, 587–597. [Google Scholar] [CrossRef] [Green Version]
  93. Xie, Q.; Wang, S.; Zhao, Y.; Zhang, Z.; Qin, C.; Yang, X. MiR-519d impedes cisplatin-resistance in breast cancer stem cells by down-regulating the expression of MCL-1. Oncotarget 2017, 8, 22003–22013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Su, X.; Wang, B.; Wang, Y.; Wang, B. Inhibition of TRIM32 Induced by miR-519d Increases the Sensitivity of Colorectal Cancer Cells to Cisplatin. OncoTargets Ther. 2020, 13, 277–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Yang, H.; Wu, X.L.; Wu, K.H.; Zhang, R.; Ju, L.L.; Ji, Y.; Zhang, Y.W.; Xue, S.L.; Zhang, Y.X.; Yang, Y.F.; et al. MicroRNA-497 regulates cisplatin chemosensitivity of cervical cancer by targeting transketolase. Am. J. Cancer Res. 2016, 6, 2690–2699. [Google Scholar]
  96. Chen, G.; Huang, P.; Hu, C. The role of SIRT2 in cancer: A novel therapeutic target. Int. J. Cancer 2020, 147, 3297–3304. [Google Scholar] [CrossRef] [PubMed]
  97. Wu, S.; Wang, H.; Pan, Y.; Yang, X.; Wu, D. miR-140-3p enhances cisplatin sensitivity and attenuates stem cell-like properties through repressing Wnt/β-catenin signaling in lung adenocarcinoma cells. Exp. Med. 2020, 20, 1664–1674. [Google Scholar] [CrossRef] [PubMed]
  98. Du, F.; Li, Z.; Zhang, G.; Shaoyan, S.; Geng, D.; Tao, Z.; Qiu, K.; Liu, S.; Zhou, Y.; Zhang, Y.; et al. SIRT2, a direct target of miR-212-5p, suppresses the proliferation and metastasis of colorectal cancer cells. J. Cell Mol. Med. 2020, 24, 9985–9998. [Google Scholar] [CrossRef]
  99. Cho, H.Y.; Thomas, S.; Golden, E.B.; Gaffney, K.J.; Hofman, F.M.; Chen, T.C.; Louie, S.G.; Petasis, N.A.; Schönthal, A.H. Enhanced killing of chemo-resistant breast cancer cells via controlled aggravation of ER stress. Cancer Lett. 2009, 282, 87–97. [Google Scholar] [CrossRef]
  100. Shin, S.Y.; Lee, J.M.; Lee, M.S.; Koh, D.; Jung, H.; Lim, Y.; Lee, Y.H. Targeting cancer cells via the reactive oxygen species-mediated unfolded protein response with a novel synthetic polyphenol conjugate. Clin. Cancer Res. 2014, 20, 4302–4313. [Google Scholar] [CrossRef] [Green Version]
  101. Jung, E.; Koh, D.; Lim, Y.; Shin, S.Y.; Lee, Y.H. Overcoming multidrug resistance by activating unfolded protein response of the endoplasmic reticulum in cisplatin-resistant A2780/CisR ovarian cancer cells. BMB Rep. 2020, 53, 88–93. [Google Scholar] [CrossRef] [Green Version]
  102. Sun, C.; Guo, E.; Zhou, B.; Shan, W.; Huang, J.; Weng, D.; Wu, P.; Wang, C.; Wang, S.; Zhang, W.; et al. A reactive oxygen species scoring system predicts cisplatin sensitivity and prognosis in ovarian cancer patients. BMC Cancer 2019, 19, 1061. [Google Scholar] [CrossRef] [PubMed]
  103. She, Z.G.; Chen, H.Z.; Yan, Y.; Li, H.; Liu, D.P. The human paraoxonase gene cluster as a target in the treatment of atherosclerosis. Antioxid. Redox Signal. 2012, 16, 597–632. [Google Scholar] [CrossRef] [PubMed]
  104. Ng, C.J.; Wadleigh, D.J.; Gangopadhyay, A.; Hama, S.; Grijalva, V.R.; Navab, M.; Fogelman, A.M.; Reddy, S.T. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J. Biol. Chem. 2001, 276, 44444–44449. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Précourt, L.P.; Marcil, V.; Ntimbane, T.; Taha, R.; Lavoie, J.C.; Delvin, E.; Seidman, E.G.; Beaulieu, J.F.; Levy, E. Antioxidative properties of paraoxonase 2 in intestinal epithelial cells. Am. J. Physiol. Gastrointest Liver Physiol. 2012, 303, G623–G634. [Google Scholar] [CrossRef] [Green Version]
  106. Giordano, G.; Cole, T.B.; Furlong, C.E.; Costa, L.G. Paraoxonase 2 (PON2) in the mouse central nervous system: A neuroprotective role? Toxicol. Appl. Pharm. 2011, 256, 369–378. [Google Scholar] [CrossRef] [Green Version]
  107. Campagna, R.; Bacchetti, T.; Salvolini, E.; Pozzi, V.; Molinelli, E.; Brisigotti, V.; Sartini, D.; Campanati, A.; Ferretti, G.; Offidani, A.; et al. Paraoxonase-2 Silencing Enhances Sensitivity of A375 Melanoma Cells to Treatment with Cisplatin. Antioxidants 2020, 9, 1238. [Google Scholar] [CrossRef] [PubMed]
  108. Liu, Q.; Wang, K. The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin. Cell Biol. Int. 2019, 43, 1245–1256. [Google Scholar] [CrossRef]
  109. Koyama, T.; Suzuki, H.; Imakiire, A.; Yanase, N.; Hata, K.; Mizuguchi, J. Id3-mediated enhancement of cisplatin-induced apoptosis in a sarcoma cell line MG-63. Anticancer Res. 2004, 24, 1519–1524. [Google Scholar]
  110. Narita, N.; Ito, Y.; Takabayashi, T.; Okamoto, M.; Imoto, Y.; Ogi, K.; Tokunaga, T.; Matsumoto, H.; Fujieda, S. Suppression of SESN1 reduces cisplatin and hyperthermia resistance through increasing reactive oxygen species (ROS) in human maxillary cancer cells. Int. J. Hyperth. 2018, 35, 269–278. [Google Scholar] [CrossRef]
  111. Xue, D.F.; Pan, S.T.; Huang, G.; Qiu, J.X. ROS enhances the cytotoxicity of cisplatin by inducing apoptosis and autophagy in tongue squamous cell carcinoma cells. Int. J. Biochem. Cell Biol. 2020, 122, 105732. [Google Scholar] [CrossRef]
  112. Kleih, M.; Böpple, K.; Dong, M.; Gaißler, A.; Heine, S.; Olayioye, M.A.; Aulitzky, W.E.; Essmann, F. Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells. Cell Death Dis. 2019, 10, 851. [Google Scholar] [CrossRef] [Green Version]
  113. Lin, Z.; Pan, J.; Chen, L.; Wang, X.; Chen, Y. MiR-140 Resensitizes Cisplatin-Resistant NSCLC Cells to Cisplatin Treatment Through the SIRT1/ROS/JNK Pathway. OncoTargets Ther. 2020, 13, 8149–8160. [Google Scholar] [CrossRef]
  114. Ciccarone, F.; De Falco, P.; Ciriolo, M.R. Aconitase 2 sensitizes MCF-7 cells to cisplatin eliciting p53-mediated apoptosis in a ROS-dependent manner. Biochem. Pharm. 2020, 180, 114202. [Google Scholar] [CrossRef]
  115. Roh, J.L.; Kim, E.H.; Jang, H.; Shin, D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017, 11, 254–262. [Google Scholar] [CrossRef]
  116. Cruz-Bermúdez, A.; Laza-Briviesca, R.; Vicente-Blanco, R.J.; García-Grande, A.; Coronado, M.J.; Laine-Menéndez, S.; Palacios-Zambrano, S.; Moreno-Villa, M.R.; Ruiz-Valdepeñas, A.M.; Lendinez, C.; et al. Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition. Free Radic. Biol. Med. 2019, 135, 167–181. [Google Scholar] [CrossRef] [PubMed]
  117. He, F.; Antonucci, L.; Karin, M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis 2020, 41, 405–416. [Google Scholar] [CrossRef] [PubMed]
  118. Song, X.; Long, D. Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases. Front. Neurosci. 2020, 14, 267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Shin, D.; Kim, E.H.; Lee, J.; Roh, J.L. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic. Biol. Med. 2018, 129, 454–462. [Google Scholar] [CrossRef]
  120. Luo, P.; Wu, S.; Ji, K.; Yuan, X.; Li, H.; Chen, J.; Tian, Y.; Qiu, Y.; Zhong, X. LncRNA MIR4435-2HG mediates cisplatin resistance in HCT116 cells by regulating Nrf2 and HO-1. PLoS ONE 2020, 15, e0223035. [Google Scholar] [CrossRef] [PubMed]
  121. Wang, N.; Song, L.; Xu, Y.; Zhang, L.; Wu, Y.; Guo, J.; Ji, W.; Li, L.; Zhao, J.; Zhang, X.; et al. Loss of Scribble confers cisplatin resistance during NSCLC chemotherapy via Nox2/ROS and Nrf2/PD-L1 signaling. EBioMedicine 2019, 47, 65–77. [Google Scholar] [CrossRef] [Green Version]
  122. Shorning, B.Y.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int. J. Mol. Sci. 2020, 21, 4507. [Google Scholar] [CrossRef]
  123. Fattahi, S.; Amjadi-Moheb, F.; Tabaripour, R.; Ashrafi, G.H.; Akhavan-Niaki, H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci. 2020, 262, 118513. [Google Scholar] [CrossRef] [PubMed]
  124. Lee, J.H.; Chinnathambi, A.; Alharbi, S.A.; Shair, O.H.M.; Sethi, G.; Ahn, K.S. Farnesol abrogates epithelial to mesenchymal transition process through regulating Akt/mTOR pathway. Pharm. Res. 2019, 150, 104504. [Google Scholar] [CrossRef]
  125. Lee, J.H.; Kim, C.; Um, J.Y.; Sethi, G.; Ahn, K.S. Casticin-Induced Inhibition of Cell Growth and Survival Are Mediated through the Dual Modulation of Akt/mTOR Signaling Cascade. Cancers 2019, 11, 254. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Wei, X.; Xu, L.; Jeddo, S.F.; Li, K.; Li, X.; Li, J. MARK2 enhances cisplatin resistance via PI3K/AKT/NF-κB signaling pathway in osteosarcoma cells. Am. J. Transl. Res. 2020, 12, 1807–1823. [Google Scholar] [PubMed]
  127. Cao, W.Q.; Zhai, X.Q.; Ma, J.W.; Fu, X.Q.; Zhao, B.S.; Zhang, P.; Fu, X.Y. Natural borneol sensitizes human glioma cells to cisplatin-induced apoptosis by triggering ROS-mediated oxidative damage and regulation of MAPKs and PI3K/AKT pathway. Pharm. Biol. 2020, 58, 72–79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Ong, P.S.; Wang, L.Z.; Dai, X.; Tseng, S.H.; Loo, S.J.; Sethi, G. Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives. Front. Pharmacol. 2016, 7, 395. [Google Scholar] [CrossRef]
  129. Mohan, C.D.; Srinivasa, V.; Rangappa, S.; Mervin, L.; Mohan, S.; Paricharak, S.; Baday, S.; Li, F.; Shanmugam, M.K.; Chinnathambi, A.; et al. Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway. PLoS ONE 2016, 11, e0153155. [Google Scholar] [CrossRef] [Green Version]
  130. Du, H.; Chen, B.; Jiao, N.L.; Liu, Y.H.; Sun, S.Y.; Zhang, Y.W. Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma. Oxid. Med. Cell Longev. 2020, 2020, 7370157. [Google Scholar] [CrossRef]
  131. Zhang, S.; Wang, Y. Deoxyshikonin inhibits cisplatin resistance of non-small-cell lung cancer cells by repressing Akt-mediated ABCB1 expression and function. J. Biochem. Mol. Toxicol. 2020, 34, e22560. [Google Scholar] [CrossRef] [PubMed]
  132. Fan, C.C.; Tsai, S.T.; Lin, C.Y.; Chang, L.C.; Yang, J.C.; Chen, G.Y.; Sher, Y.P.; Wang, S.C.; Hsiao, M.; Chang, W.C. EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis. Redox Biol. 2020, 34, 101571. [Google Scholar] [CrossRef]
  133. Wang, Y.; Hao, F.; Nan, Y.; Qu, L.; Na, W.; Jia, C.; Chen, X. PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis. Int. J. Biol. Sci. 2018, 14, 1883–1891. [Google Scholar] [CrossRef] [Green Version]
  134. Martin, S.P.; Fako, V.; Dang, H.; Dominguez, D.A.; Khatib, S.; Ma, L.; Wang, H.; Zheng, W.; Wang, X.W. PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2020, 39, 99. [Google Scholar] [CrossRef] [PubMed]
  135. Shang, D.; Wu, J.; Guo, L.; Xu, Y.; Liu, L.; Lu, J. Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2. Int. J. Oncol. 2017, 50, 1848–1856. [Google Scholar] [CrossRef]
  136. Li, W.; Qiu, Y.; Hao, J.; Zhao, C.; Deng, X.; Shu, G. Dauricine upregulates the chemosensitivity of hepatocellular carcinoma cells: Role of repressing glycolysis via miR-199a:HK2/PKM2 modulation. Food Chem. Toxicol. 2018, 121, 156–165. [Google Scholar] [CrossRef] [PubMed]
  137. Wang, D.; Zhao, C.; Xu, F.; Zhang, A.; Jin, M.; Zhang, K.; Liu, L.; Hua, Q.; Zhao, J.; Liu, J.; et al. Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2. Theranostics 2021, 11, 2860–2875. [Google Scholar] [CrossRef]
  138. Powis, G.; Kirkpatrick, D.L. Thioredoxin signaling as a target for cancer therapy. Curr. Opin. Pharm. 2007, 7, 392–397. [Google Scholar] [CrossRef] [PubMed]
  139. Haas, B.; Schütte, L.; Wos-Maganga, M.; Weickhardt, S.; Timmer, M.; Eckstein, N. Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. Int. J. Mol. Sci. 2018, 19, 2874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Hong, L.; Chen, J.; Wu, F.; Wu, F.; Shen, X.; Zheng, P.; Shao, R.; Lu, K.; Liu, Z.; Chen, D.; et al. Isodeoxyelephantopin Inactivates Thioredoxin Reductase 1 and Activates ROS-Mediated JNK Signaling Pathway to Exacerbate Cisplatin Effectiveness in Human Colon Cancer Cells. Front. Cell Dev. Biol. 2020, 8, 580517. [Google Scholar] [CrossRef]
  141. Wangpaichitr, M.; Sullivan, E.J.; Theodoropoulos, G.; Wu, C.; You, M.; Feun, L.G.; Lampidis, T.J.; Kuo, M.T.; Savaraj, N. The relationship of thioredoxin-1 and cisplatin resistance: Its impact on ROS and oxidative metabolism in lung cancer cells. Mol. Cancer 2012, 11, 604–615. [Google Scholar] [CrossRef] [Green Version]
  142. Ashrafizadeh, M.; Zarrabi, A.; Hushmandi, K.; Hashemi, F.; Moghadam, E.R.; Owrang, M.; Hashemi, F.; Makvandi, P.; Goharrizi, M.A.S.B.; Najafi, M.; et al. Lung cancer cells and their sensitivity/resistance to cisplatin chemotherapy: Role of microRNAs and upstream mediators. Cell. Signal. 2021, 78, 109871. [Google Scholar] [CrossRef]
  143. Shang, J.; Wang, L.; Tan, L.; Pan, R.; Wu, D.; Xia, Y.; Xu, P. MiR-27a-3p overexpression mitigates inflammation and apoptosis of lipopolysaccharides-induced alveolar epithelial cells by targeting FOXO3 and suppressing the activation of NAPDH/ROS. Biochem. Biophys. Res. Commun. 2020, 533, 723–731. [Google Scholar] [CrossRef]
  144. Zhang, Y.; Xiao, Y.; Ma, Y.; Liang, N.; Liang, Y.; Lu, C.; Xiao, F. ROS-mediated miR-21-5p regulates the proliferation and apoptosis of Cr(VI)-exposed L02 hepatocytes via targeting PDCD4. Ecotoxicol. Environ. Saf. 2020, 191, 110160. [Google Scholar] [CrossRef] [PubMed]
  145. Maddalena, F.; Sisinni, L.; Lettini, G.; Condelli, V.; Matassa, D.S.; Piscazzi, A.; Amoroso, M.R.; La Torre, G.; Esposito, F.; Landriscina, M. Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Mol. Oncol. 2013, 7, 895–906. [Google Scholar] [CrossRef] [PubMed]
  146. Cechetto, J.D.; Gupta, R.S. Immunoelectron microscopy provides evidence that tumor necrosis factor receptor-associated protein 1 (TRAP-1) is a mitochondrial protein which also localizes at specific extramitochondrial sites. Exp. Cell Res. 2000, 260, 30–39. [Google Scholar] [CrossRef] [PubMed]
  147. Agorreta, J.; Hu, J.; Liu, D.; Delia, D.; Turley, H.; Ferguson, D.J.; Iborra, F.; Pajares, M.J.; Larrayoz, M.; Zudaire, I. TRAP1 regulates proliferation, mitochondrial function, and has prognostic significance in NSCLC. Mol. Cancer Res. 2014, 12, 660–669. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Zhang, X.; Dong, Y.; Gao, M.; Hao, M.; Ren, H.; Guo, L.; Guo, H. Knockdown of TRAP1 promotes cisplatin-induced apoptosis by promoting the ROS-dependent mitochondrial dysfunction in lung cancer cells. Mol. Cell Biochem. 2021, 476, 1075–1082. [Google Scholar] [CrossRef]
  149. Wek, R.C.; Jiang, H.Y.; Anthony, T.G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 2006, 34, 7–11. [Google Scholar] [CrossRef]
  150. Harding, H.P.; Zhang, Y.; Zeng, H.; Novoa, I.; Lu, P.D.; Calfon, M.; Sadri, N.; Yun, C.; Popko, B.; Paules, R.; et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 2003, 11, 619–633. [Google Scholar] [CrossRef]
  151. Martínez-Reyes, I.; Sánchez-Aragó, M.; Cuezva, J.M. AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells. Biochem. J. 2012, 444, 249–259. [Google Scholar] [CrossRef]
  152. Rouschop, K.M.; Dubois, L.J.; Keulers, T.G.; van den Beucken, T.; Lambin, P.; Bussink, J.; van der Kogel, A.J.; Koritzinsky, M.; Wouters, B.G. PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc. Natl. Acad. Sci. USA 2013, 110, 4622–4627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Wang, S.F.; Chen, M.S.; Chou, Y.C.; Ueng, Y.F.; Yin, P.H.; Yeh, T.S.; Lee, H.C. Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway. Oncotarget 2016, 7, 74132–74151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Wang, S.F.; Wung, C.H.; Chen, M.S.; Chen, C.F.; Yin, P.H.; Yeh, T.S.; Chang, Y.L.; Chou, Y.C.; Hung, H.H.; Lee, H.C. Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis. Int. J. Mol. Sci. 2018, 19, 3389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. De Franceschi, L.; Bertoldi, M.; De Falco, L.; Franco, S.S.; Ronzoni, L.; Turrini, F.; Colancecco, A.; Camaschella, C.; Cappellini, M.D.; Iolascon, A. Oxidative stress modulates heme synthesis and induces peroxiredoxin-2 as a novel cytoprotective response in β-thalassemic erythropoiesis. Haematologica 2011, 96, 1595. [Google Scholar] [CrossRef] [Green Version]
  156. Wang, S.; Chen, Z.; Zhu, S.; Lu, H.; Peng, D.; Soutto, M.; Naz, H.; Peek, R., Jr.; Xu, H.; Zaika, A.; et al. PRDX2 protects against oxidative stress induced by H. pylori and promotes resistance to cisplatin in gastric cancer. Redox Biol. 2020, 28, 101319. [Google Scholar] [CrossRef] [PubMed]
  157. Lin, X.M.; Li, S.; Zhou, C.; Li, R.Z.; Wang, H.; Luo, W.; Huang, Y.S.; Chen, L.K.; Cai, J.L.; Wang, T.X.; et al. Cisplatin induces chemoresistance through the PTGS2-mediated anti-apoptosis in gastric cancer. Int. J. Biochem. Cell Biol. 2019, 116, 105610. [Google Scholar] [CrossRef] [PubMed]
  158. Carreau, A.; Hafny-Rahbi, B.E.; Matejuk, A.; Grillon, C.; Kieda, C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J. Cell. Mol. Med. 2011, 15, 1239–1253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  159. Eales, K.; Hollinshead, K.; Tennant, D. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis 2016, 5, e190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Ma, Z.; Wang, L.Z.; Cheng, J.T.; Lam, W.S.T.; Ma, X.; Xiang, X.; Wong, A.L.; Goh, B.C.; Gong, Q.; Sethi, G.; et al. Targeting Hypoxia-Inducible Factor-1-Mediated Metastasis for Cancer Therapy. Antioxid. Redox Signal. 2021. [Google Scholar] [CrossRef]
  161. Taguchi, N.; Ishihara, N.; Jofuku, A.; Oka, T.; Mihara, K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J. Biol. Chem. 2007, 282, 11521–11529. [Google Scholar] [CrossRef] [Green Version]
  162. Archer, S.L. Mitochondrial dynamics—Mitochondrial fission and fusion in human diseases. N. Engl. J. Med. 2013, 369, 2236–2251. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Itoh, K.; Nakamura, K.; Iijima, M.; Sesaki, H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 2013, 23, 64–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Han, Y.; Kim, B.; Cho, U.; Park, I.S.; Kim, S.I.; Dhanasekaran, D.N.; Tsang, B.K.; Song, Y.S. Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene 2019, 38, 7089–7105. [Google Scholar] [CrossRef]
  165. Wangpaichitr, M.; Kandemir, H.; Li, Y.Y.; Wu, C.; Nguyen, D.; Feun, L.G.; Kuo, M.T.; Savaraj, N. Relationship of Metabolic Alterations and PD-L1 Expression in Cisplatin Resistant Lung Cancer. Cell Dev. Biol. 2017, 6. [Google Scholar] [CrossRef]
  166. Ohye, H.; Sugawara, M. Dual oxidase, hydrogen peroxide and thyroid diseases. Exp. Biol. Med. 2010, 235, 424–433. [Google Scholar] [CrossRef]
  167. Sandiford, S.D.; Kennedy, K.A.; Xie, X.; Pickering, J.G.; Li, S.S. Dual oxidase maturation factor 1 (DUOXA1) overexpression increases reactive oxygen species production and inhibits murine muscle satellite cell differentiation. Cell Commun. Signal. 2014, 12, 5. [Google Scholar] [CrossRef] [Green Version]
  168. Pichierri, P.; Rosselli, F. The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. EMBO J. 2004, 23, 1178–1187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Flynn, R.L.; Zou, L. ATR: A master conductor of cellular responses to DNA replication stress. Trends Biochem. Sci. 2011, 36, 133–140. [Google Scholar] [CrossRef] [Green Version]
  170. Zhang, Y.; Hunter, T. Roles of Chk1 in cell biology and cancer therapy. Int. J. Cancer 2014, 134, 1013–1023. [Google Scholar] [CrossRef] [Green Version]
  171. Meng, Y.; Chen, C.W.; Yung, M.M.H.; Sun, W.; Sun, J.; Li, Z.; Li, J.; Li, Z.; Zhou, W.; Liu, S.S.; et al. DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer. Cancer Lett. 2018, 428, 104–116. [Google Scholar] [CrossRef] [Green Version]
  172. Greene, K.S.; Lukey, M.J.; Wang, X.; Blank, B.; Druso, J.E.; Lin, M.J.; Stalnecker, C.A.; Zhang, C.; Negrón Abril, Y.; Erickson, J.W.; et al. SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc. Natl. Acad. Sci. USA 2019, 116, 26625–26632. [Google Scholar] [CrossRef]
  173. Shi, L.; Yan, H.; An, S.; Shen, M.; Jia, W.; Zhang, R.; Zhao, L.; Huang, G.; Liu, J. SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol. Oncol. 2019, 13, 358–375. [Google Scholar] [CrossRef]
  174. Yang, X.; Wang, Z.; Li, X.; Liu, B.; Liu, M.; Liu, L.; Chen, S.; Ren, M.; Wang, Y.; Yu, M.; et al. SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation. Cancer Res. 2018, 78, 372–386. [Google Scholar] [CrossRef] [Green Version]
  175. Sun, X.; Wang, S.; Gai, J.; Guan, J.; Li, J.; Li, Y.; Zhao, J.; Zhao, C.; Fu, L.; Li, Q. SIRT5 Promotes Cisplatin Resistance in Ovarian Cancer by Suppressing DNA Damage in a ROS-Dependent Manner via Regulation of the Nrf2/HO-1 Pathway. Front. Oncol. 2019, 9, 754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Xia, M.; Yu, H.; Gu, S.; Xu, Y.; Su, J.; Li, H.; Kang, J.; Cui, M. p62/SQSTM1 is involved in cisplatin resistance in human ovarian cancer cells via the Keap1-Nrf2-ARE system. Int. J. Oncol. 2014, 45, 2341–2348. [Google Scholar] [CrossRef]
  177. Shen, L.; Zhou, L.; Xia, M.; Lin, N.; Ma, J.; Dong, D.; Sun, L. PGC1α regulates mitochondrial oxidative phosphorylation involved in cisplatin resistance in ovarian cancer cells via nucleo-mitochondrial transcriptional feedback. Exp. Cell Res. 2021, 398, 112369. [Google Scholar] [CrossRef]
  178. Chen, J.; Adikari, M.; Pallai, R.; Parekh, H.K.; Simpkins, H. Dihydrodiol dehydrogenases regulate the generation of reactive oxygen species and the development of cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharm. 2008, 61, 979–987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Shigeta, K.; Hasegawa, M.; Kikuchi, E.; Yasumizu, Y.; Kosaka, T.; Mizuno, R.; Mikami, S.; Miyajima, A.; Kufe, D.; Oya, M. Role of the MUC1-C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma. Cancer Sci. 2020, 111, 3639–3652. [Google Scholar] [CrossRef]
  180. Guo, Y.; Jia, Y.; Wang, S.; Liu, N.; Gao, D.; Zhang, L.; Lin, Z.; Wang, S.; Kong, F.; Peng, C.; et al. Downregulation of MUTYH contributes to cisplatin-resistance of esophageal squamous cell carcinoma cells by promoting Twist-mediated EMT. Oncol. Rep. 2019, 42, 2716–2727. [Google Scholar] [CrossRef] [PubMed]
  181. Xiong, P.; Li, Y.X.; Tang, Y.T.; Chen, H.G. Proteomic analyses of Sirt1-mediated cisplatin resistance in OSCC cell line. Protein J. 2011, 30, 499–508. [Google Scholar] [CrossRef]
  182. Shirato, A.; Kikugawa, T.; Miura, N.; Tanji, N.; Takemori, N.; Higashiyama, S.; Yokoyama, M. Cisplatin resistance by induction of aldo-keto reductase family 1 member C2 in human bladder cancer cells. Oncol. Lett. 2014, 7, 674–678. [Google Scholar] [CrossRef] [Green Version]
  183. Hour, T.C.; Lai, Y.L.; Kuan, C.I.; Chou, C.K.; Wang, J.M.; Tu, H.Y.; Hu, H.T.; Lin, C.S.; Wu, W.J.; Pu, Y.S.; et al. Transcriptional up-regulation of SOD1 by CEBPD: A potential target for cisplatin resistant human urothelial carcinoma cells. Biochem. Pharm. 2010, 80, 325–334. [Google Scholar] [CrossRef] [Green Version]
  184. Zhang, Z.; Yu, L.; Dai, G.; Xia, K.; Liu, G.; Song, Q.; Tao, C.; Gao, T.; Guo, W. Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells. Sci. Rep. 2017, 7, 7070. [Google Scholar] [CrossRef] [Green Version]
  185. Liu, Y.; Zhang, Z.; Li, Q.; Zhang, L.; Cheng, Y.; Zhong, Z. Mitochondrial APE1 promotes cisplatin resistance by downregulating ROS in osteosarcoma. Oncol. Rep. 2020, 44, 499–508. [Google Scholar] [CrossRef]
  186. Pan, C.; Jin, L.; Wang, X.; Li, Y.; Chun, J.; Boese, A.C.; Li, D.; Kang, H.B.; Zhang, G.; Zhou, L.; et al. Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance. J. Clin. Investig. 2019, 129, 2431–2445. [Google Scholar] [CrossRef] [PubMed]
  187. Geoghegan, F.; Buckland, R.J.; Rogers, E.T.; Khalifa, K.; O’Connor, E.B.; Rooney, M.F.; Behnam-Motlagh, P.; Nilsson, T.K.; Grankvist, K.; Porter, R.K. Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells. Oncotarget 2017, 8, 94711–94725. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  188. Zheng, X.L.; Yang, J.J.; Wang, Y.Y.; Li, Q.; Song, Y.P.; Su, M.; Li, J.K.; Zhang, L.; Li, Z.P.; Zhou, B.; et al. RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells. Acta Pharmacol. Sin. 2020, 41, 1223–1233. [Google Scholar] [CrossRef] [PubMed]
  189. Muscella, A.; Vetrugno, C.; Antonaci, G.; Cossa, L.G.; Marsigliante, S. PKC-δ/PKC-α activity balance regulates the lethal effects of cisplatin. Biochem. Pharm. 2015, 98, 29–40. [Google Scholar] [CrossRef]
  190. Songserm, T.; Pongrakhananon, V.; Chanvorachote, P. Sub-toxic cisplatin mediates anoikis resistance through hydrogen peroxide-induced caveolin-1 up-regulation in non-small cell lung cancer cells. Anticancer Res. 2012, 32, 1659–1669. [Google Scholar] [PubMed]
  191. Su, J.; Xu, Y.; Zhou, L.; Yu, H.M.; Kang, J.S.; Liu, N.; Quan, C.S.; Sun, L.K. Suppression of chloride channel 3 expression facilitates sensitivity of human glioma U251 cells to cisplatin through concomitant inhibition of Akt and autophagy. Anat. Rec. 2013, 296, 595–603. [Google Scholar] [CrossRef]
  192. Kim, C.W.; Lu, J.N.; Go, S.I.; Jung, J.H.; Yi, S.M.; Jeong, J.H.; Hah, Y.S.; Han, M.S.; Park, J.W.; Lee, W.S.; et al. p53 restoration can overcome cisplatin resistance through inhibition of Akt as well as induction of Bax. Int. J. Oncol. 2013, 43, 1495–1502. [Google Scholar] [CrossRef]
  193. Brockmueller, A.; Sameri, S.; Liskova, A.; Zhai, K.; Varghese, E.; Samuel, S.M.; Büsselberg, D.; Kubatka, P.; Shakibaei, M. Resveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism. Cancers 2021, 13, 188. [Google Scholar] [CrossRef]
  194. Samec, M.; Liskova, A.; Koklesova, L.; Samuel, S.M.; Zhai, K.; Buhrmann, C.; Varghese, E.; Abotaleb, M.; Qaradakhi, T.; Zulli, A. Flavonoids against the Warburg phenotype—Concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism. EPMA J. 2020, 1–22. [Google Scholar] [CrossRef] [PubMed]
  195. Zhai, K.; Brockmüller, A.; Kubatka, P.; Shakibaei, M.; Büsselberg, D. Curcumin’s Beneficial Effects on Neuroblastoma: Mechanisms, Challenges, and Potential Solutions. Biomolecules 2020, 10, 1469. [Google Scholar] [CrossRef] [PubMed]
  196. Kubatka, P.; Kello, M.; Kajo, K.; Samec, M.; Liskova, A.; Jasek, K.; Koklesova, L.; Kuruc, T.; Adamkov, M.; Smejkal, K. Rhus coriaria L.(Sumac) Demonstrates Oncostatic Activity in the Therapeutic and Preventive Model of Breast Carcinoma. Int. J. Mol. Sci. 2021, 22, 183. [Google Scholar] [CrossRef] [PubMed]
  197. Acuña-Castroviejo, D.; Escames, G.; Venegas, C.; Díaz-Casado, M.E.; Lima-Cabello, E.; López, L.C.; Rosales-Corral, S.; Tan, D.X.; Reiter, R.J. Extrapineal melatonin: Sources, regulation, and potential functions. Cell. Mol. Life Sci. 2014, 71, 2997–3025. [Google Scholar] [CrossRef]
  198. Jadid, M.F.S.; Aghaei, E.; Taheri, E.; Seyyedsani, N.; Chavoshi, R.; Abbasi, S.; Khorrami, A.; Goleij, P.; Hajazimian, S.; Taefehshokr, S.; et al. Melatonin increases the anticancer potential of doxorubicin in Caco-2 colorectal cancer cells. Env. Toxicol. 2021. [Google Scholar] [CrossRef]
  199. Plaimee, P.; Weerapreeyakul, N.; Barusrux, S.; Johns, N.P. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif. 2015, 48, 67–77. [Google Scholar] [CrossRef]
  200. Pariente, R.; Pariente, J.A.; Rodríguez, A.B.; Espino, J. Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: Effects on oxidative stress and DNA fragmentation. J. Pineal Res. 2016, 60, 55–64. [Google Scholar] [CrossRef]
  201. Long, J.; He, Q.; Yin, Y.; Lei, X.; Li, Z.; Zhu, W. The effect of miRNA and autophagy on colorectal cancer. Cell Prolif. 2020, 53, e12900. [Google Scholar] [CrossRef]
  202. Li, J.; Chen, X.; Kang, R.; Zeh, H.; Klionsky, D.J.; Tang, D. Regulation and function of autophagy in pancreatic cancer. Autophagy 2020, 1–22. [Google Scholar] [CrossRef]
  203. Li, K.; Deng, Y.; Deng, G.; Chen, P.; Wang, Y.; Wu, H.; Ji, Z.; Yao, Z.; Zhang, X.; Yu, B.; et al. High cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells. Stem Cell Res. 2020, 11, 131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  204. You, L.; Chen, J.; Liu, W.; Xiang, Q.; Luo, Z.; Wang, W.; Xu, W.; Wu, K.; Zhang, Q.; Liu, Y.; et al. Enterovirus 71 induces neural cell apoptosis and autophagy through promoting ACOX1 downregulation and ROS generation. Virulence 2020, 11, 537–553. [Google Scholar] [CrossRef]
  205. Fernandez-Gil, B.I.; Guerra-Librero, A.; Shen, Y.Q.; Florido, J.; Martínez-Ruiz, L.; García-López, S.; Adan, C.; Rodríguez-Santana, C.; Acuña-Castroviejo, D.; Quiñones-Hinojosa, A.; et al. Melatonin Enhances Cisplatin and Radiation Cytotoxicity in Head and Neck Squamous Cell Carcinoma by Stimulating Mitochondrial ROS Generation, Apoptosis, and Autophagy. Oxid. Med. Cell Longev. 2019, 2019, 7187128. [Google Scholar] [CrossRef] [Green Version]
  206. Yin, X.; Yang, G.; Ma, D.; Su, Z. Inhibition of cancer cell growth in cisplatin-resistant human oral cancer cells by withaferin-A is mediated via both apoptosis and autophagic cell death, endogenous ROS production, G2/M phase cell cycle arrest and by targeting MAPK/RAS/RAF signalling pathway. J. Buon 2020, 25, 332–337. [Google Scholar] [PubMed]
  207. Jin, Y.; Huang, R.; Xia, Y.; Huang, C.; Qiu, F.; Pu, J.; He, X.; Zhao, X. Long Noncoding RNA KIF9-AS1 Regulates Transforming Growth Factor-β and Autophagy Signaling to Enhance Renal Cell Carcinoma Chemoresistance via microRNA-497-5p. DNA Cell Biol. 2020, 39, 1096–1103. [Google Scholar] [CrossRef] [PubMed]
  208. Manu, K.A.; Shanmugam, M.K.; Ong, T.H.; Subramaniam, A.; Siveen, K.S.; Perumal, E.; Samy, R.P.; Bist, P.; Lim, L.H.; Kumar, A.P.; et al. Emodin suppresses migration and invasion through the modulation of CXCR4 expression in an orthotopic model of human hepatocellular carcinoma. PLoS ONE 2013, 8, e57015. [Google Scholar] [CrossRef] [Green Version]
  209. Subramaniam, A.; Loo, S.Y.; Rajendran, P.; Manu, K.A.; Perumal, E.; Li, F.; Shanmugam, M.K.; Siveen, K.S.; Park, J.I.; Ahn, K.S.; et al. An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins. Apoptosis 2013, 18, 1175–1187. [Google Scholar] [CrossRef] [Green Version]
  210. Bai, J.; Wu, J.; Tang, R.; Sun, C.; Ji, J.; Yin, Z.; Ma, G.; Yang, W. Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR(2) and miR-34a. Investig. New Drugs 2020, 38, 229–245. [Google Scholar] [CrossRef]
  211. Ding, N.; Zhang, H.; Su, S.; Ding, Y.; Yu, X.; Tang, Y.; Wang, Q.; Liu, P. Emodin Enhances the Chemosensitivity of Endometrial Cancer by Inhibiting ROS-Mediated Cisplatin-resistance. Anticancer Agents Med. Chem. 2018, 18, 1054–1063. [Google Scholar] [CrossRef]
  212. Li, X.; Wang, H.; Wang, J.; Chen, Y.; Yin, X.; Shi, G.; Li, H.; Hu, Z.; Liang, X. Emodin enhances cisplatin-induced cytotoxicity in human bladder cancer cells through ROS elevation and MRP1 downregulation. BMC Cancer 2016, 16, 578. [Google Scholar] [CrossRef] [Green Version]
  213. Zhu, B.; Ren, C.; Du, K.; Zhu, H.; Ai, Y.; Kang, F.; Luo, Y.; Liu, W.; Wang, L.; Xu, Y.; et al. Olean-28,13b-olide 2 plays a role in cisplatin-mediated apoptosis and reverses cisplatin resistance in human lung cancer through multiple signaling pathways. Biochem. Pharm. 2019, 170, 113642. [Google Scholar] [CrossRef]
  214. Kim, E.H.; Jang, H.; Shin, D.; Baek, S.H.; Roh, J.L. Targeting Nrf2 with wogonin overcomes cisplatin resistance in head and neck cancer. Apoptosis 2016, 21, 1265–1278. [Google Scholar] [CrossRef]
  215. Kim, E.H.; Jang, H.; Roh, J.L. A Novel Polyphenol Conjugate Sensitizes Cisplatin-Resistant Head and Neck Cancer Cells to Cisplatin via Nrf2 Inhibition. Mol. Cancer 2016, 15, 2620–2629. [Google Scholar] [CrossRef]
  216. Huang, W.L.; Wu, S.F.; Xu, S.T.; Ma, Y.C.; Wang, R.; Jin, S.; Zhou, S. Allicin enhances the radiosensitivity of colorectal cancer cells via inhibition of NF-κB signaling pathway. J. Food Sci. 2020, 85, 1924–1931. [Google Scholar] [CrossRef] [PubMed]
  217. Wu, H.; Li, X.; Zhang, T.; Zhang, G.; Chen, J.; Chen, L.; He, M.; Hao, B.; Wang, C. Overexpression miR-486-3p Promoted by Allicin Enhances Temozolomide Sensitivity in Glioblastoma Via Targeting MGMT. Neuromol. Med. 2020, 22, 359–369. [Google Scholar] [CrossRef] [Green Version]
  218. Țigu, A.B.; Toma, V.A.; Moț, A.C.; Jurj, A.; Moldovan, C.S.; Fischer-Fodor, E.; Berindan-Neagoe, I.; Pârvu, M. The Synergistic Antitumor Effect of 5-Fluorouracil Combined with Allicin against Lung and Colorectal Carcinoma Cells. Molecules 2020, 25, 1947. [Google Scholar] [CrossRef] [PubMed]
  219. Pandey, N.; Tyagi, G.; Kaur, P.; Pradhan, S.; Rajam, M.V.; Srivastava, T. Allicin Overcomes Hypoxia Mediated Cisplatin Resistance in Lung Cancer Cells through ROS Mediated Cell Death Pathway and by Suppressing Hypoxia Inducible Factors. Cell Physiol. Biochem. 2020, 54, 748–766. [Google Scholar] [CrossRef] [PubMed]
  220. Kośmider, A.; Czepielewska, E.; Kuraś, M.; Gulewicz, K.; Pietrzak, W.; Nowak, R.; Nowicka, G. Uncaria tomentosa Leaves Decoction Modulates Differently ROS Production in Cancer and Normal Cells, and Effects Cisplatin Cytotoxicity. Molecules 2017, 22, 620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  221. Yang, H.; Zhu, J.; Wang, G.; Liu, H.; Zhou, Y.; Qian, J. STK35 Is Ubiquitinated by NEDD4L and Promotes Glycolysis and Inhibits Apoptosis Through Regulating the AKT Signaling Pathway, Influencing Chemoresistance of Colorectal Cancer. Front. Cell Dev. Biol. 2020, 8, 582695. [Google Scholar] [CrossRef] [PubMed]
  222. Gao, J.; Dai, C.; Yu, X.; Yin, X.B.; Zhou, F. Long noncoding RNA LEF1-AS1 acts as a microRNA-10a-5p regulator to enhance MSI1 expression and promote chemoresistance in hepatocellular carcinoma cells through activating AKT signaling pathway. J. Cell. Biochem. 2021, 122, 86–99. [Google Scholar] [CrossRef]
  223. Zhang, C.; Lin, T.; Nie, G.; Hu, R.; Pi, S.; Wei, Z.; Wang, C.; Xing, C.; Hu, G. Cadmium and molybdenum co-induce pyroptosis via ROS/PTEN/PI3K/AKT axis in duck renal tubular epithelial cells. Environ. Pollut. 2021, 272, 116403. [Google Scholar] [CrossRef] [PubMed]
  224. Wang, L.; Wang, L.; Shi, X.; Xu, S. Chlorpyrifos induces the apoptosis and necroptosis of L8824 cells through the ROS/PTEN/PI3K/AKT axis. J. Hazard. Mater. 2020, 398, 122905. [Google Scholar] [CrossRef] [PubMed]
  225. Zhang, C.; He, L.J.; Zhu, Y.B.; Fan, Q.Z.; Miao, D.D.; Zhang, S.P.; Zhao, W.Y.; Liu, X.P. Piperlongumine Inhibits Akt Phosphorylation to Reverse Resistance to Cisplatin in Human Non-Small Cell Lung Cancer Cells via ROS Regulation. Front. Pharmacol. 2019, 10, 1178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  226. Zhang, Y.; Zheng, S.; Zheng, J.S.; Wong, K.H.; Huang, Z.; Ngai, S.M.; Zheng, W.; Wong, Y.S.; Chen, T. Synergistic induction of apoptosis by methylseleninic acid and cisplatin, the role of ROS-ERK/AKT-p53 pathway. Mol. Pharm. 2014, 11, 1282–1293. [Google Scholar] [CrossRef]
  227. He, G.; He, G.; Zhou, R.; Pi, Z.; Zhu, T.; Jiang, L.; Xie, Y. Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo. Biochem. Biophys. Res. Commun. 2016, 469, 1075–1082. [Google Scholar] [CrossRef] [PubMed]
  228. Petroni, G.; Bagni, G.; Iorio, J.; Duranti, C.; Lottini, T.; Stefanini, M.; Kragol, G.; Becchetti, A.; Arcangeli, A. Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K. Cell Death Dis. 2020, 11, 161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  229. Zhou, B.; Xia, M.; Wang, B.; Thapa, N.; Gan, L.; Sun, C.; Guo, E.; Huang, J.; Lu, Y.; Cai, H. Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo. J. Ovarian Res. 2019, 12, 107. [Google Scholar] [CrossRef]
  230. Davra, V.; Kumar, S.; Geng, K.; Calianese, D.; Mehta, D.; Gadiyar, V.; Kasikara, C.; Lahey, K.C.; Chang, Y.J.; Wichroski, M.; et al. Axl and Mertk receptors cooperate to promote breast cancer progression by combined oncogenic signaling and evasion of host anti-tumor immunity. Cancer Res. 2020. [Google Scholar] [CrossRef]
  231. Lotsberg, M.L.; Wnuk-Lipinska, K.; Terry, S.; Tan, T.Z.; Lu, N.; Trachsel-Moncho, L.; Røsland, G.V.; Siraji, M.I.; Hellesøy, M.; Rayford, A.; et al. AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells. J. Thorac. Oncol. 2020, 15, 973–999. [Google Scholar] [CrossRef] [Green Version]
  232. Tian, M.; Chen, X.S.; Li, L.Y.; Wu, H.Z.; Zeng, D.; Wang, X.L.; Zhang, Y.; Xiao, S.S.; Cheng, Y. Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis. Acta Pharmacol. Sin. 2020. [Google Scholar] [CrossRef]
  233. Oien, D.B.; Garay, T.; Eckstein, S.; Chien, J. Cisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy. Front. Pharmacol. 2017, 8, 970. [Google Scholar] [CrossRef] [Green Version]
  234. Piotrowska, A.; Wierzbicka, J.; Rybarczyk, A.; Tuckey, R.C.; Slominski, A.T.; Żmijewski, M.A. Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line. Int. J. Oncol. 2019, 54, 1481–1495. [Google Scholar] [CrossRef] [Green Version]
  235. Xue, D.; Pan, S.T.; Zhou, X.; Ye, F.; Zhou, Q.; Shi, F.; He, F.; Yu, H.; Qiu, J. Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma. Oxid. Med. Cell Longev. 2020, 2020, 5649174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  236. Xie, C.; Zhang, L.Z.; Chen, Z.L.; Zhong, W.J.; Fang, J.H.; Zhu, Y.; Xiao, M.H.; Guo, Z.W.; Zhao, N.; He, X.; et al. A hMTR4-PDIA3P1-miR-125/124-TRAF6 Regulatory Axis and Its Function in NF kappa B Signaling and Chemoresistance. Hepatology 2020, 71, 1660–1677. [Google Scholar] [CrossRef] [PubMed]
  237. Zhong, Y.Y.; Chen, H.P.; Tan, B.Z.; Yu, H.H.; Huang, X.S. Triptolide avoids cisplatin resistance and induces apoptosis via the reactive oxygen species/nuclear factor-κB pathway in SKOV3(PT) platinum-resistant human ovarian cancer cells. Oncol. Lett 2013, 6, 1084–1092. [Google Scholar] [CrossRef]
  238. Oka, N.; Komuro, A.; Amano, H.; Dash, S.; Honda, M.; Ota, K.; Nishimura, S.; Ueda, T.; Akagi, M.; Okada, H. Ascorbate sensitizes human osteosarcoma cells to the cytostatic effects of cisplatin. Pharm. Res. Perspect. 2020, 8, e00632. [Google Scholar] [CrossRef] [PubMed]
  239. Roh, J.L.; Park, J.Y.; Kim, E.H.; Jang, H.J.; Kwon, M. Activation of mitochondrial oxidation by PDK2 inhibition reverses cisplatin resistance in head and neck cancer. Cancer Lett. 2016, 371, 20–29. [Google Scholar] [CrossRef]
  240. Petruzzella, E.; Sirota, R.; Solazzo, I.; Gandin, V.; Gibson, D. Triple action Pt(iv) derivatives of cisplatin: A new class of potent anticancer agents that overcome resistance. Chem. Sci. 2018, 9, 4299–4307. [Google Scholar] [CrossRef] [Green Version]
  241. Huang, Z.; Yang, G.; Shen, T.; Wang, X.; Li, H.; Ren, D. Dehydrobruceine B enhances the cisplatin-induced cytotoxicity through regulation of the mitochondrial apoptotic pathway in lung cancer A549 cells. Biomed. Pharm. 2017, 89, 623–631. [Google Scholar] [CrossRef]
  242. Lee, M.R.; Lin, C.; Lu, C.C.; Kuo, S.C.; Tsao, J.W.; Juan, Y.N.; Chiu, H.Y.; Lee, F.Y.; Yang, J.S.; Tsai, F.J. YC-1 induces G(0)/G(1) phase arrest and mitochondria-dependent apoptosis in cisplatin-resistant human oral cancer CAR cells. Biomedicine 2017, 7, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  243. Altaf, M.; Monim-Ul-Mehboob, M.; Kawde, A.N.; Corona, G.; Larcher, R.; Ogasawara, M.; Casagrande, N.; Celegato, M.; Borghese, C.; Siddik, Z.H.; et al. New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status. Oncotarget 2017, 8, 490–505. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  244. Wangpaichitr, M.; Wu, C.; You, M.; Maher, J.C.; Dinh, V.; Feun, L.G.; Savaraj, N. N’,N’-Dimethyl-N’,N’-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS). Cancers 2009, 1, 23–38. [Google Scholar] [CrossRef] [PubMed]
  245. Zeng, L.; Chen, Y.; Liu, J.; Huang, H.; Guan, R.; Ji, L.; Chao, H. Ruthenium(II) Complexes with 2-Phenylimidazo[4,5-f][1,10]phenanthroline Derivatives that Strongly Combat Cisplatin-Resistant Tumor Cells. Sci. Rep. 2016, 6, 19449. [Google Scholar] [CrossRef]
  246. Chen, L.; Liu, L.; Li, Y.; Gao, J. Melatonin increases human cervical cancer HeLa cells apoptosis induced by cisplatin via inhibition of JNK/Parkin/mitophagy axis. Vitr. Cell. Dev. Biol. Anim. 2018, 54, 1–10. [Google Scholar] [CrossRef]
  247. Shaaban, S.; Shabana, S.M.; Al-Faiyz, Y.S.; Manolikakes, G.; El-Senduny, F.F. Enhancing the chemosensitivity of HepG2 cells towards cisplatin by organoselenium pseudopeptides. Bioorganic Chem. 2021, 109, 104713. [Google Scholar] [CrossRef]
  248. Xiao, Y.; Deng, T.; Wang, D. Davanone terpenoid inhibits cisplatin-resistant acute myeloid leukemia cancer cell growth by inducing caspase-dependent apoptosis, loss of mitochondrial membrane potential, inhibition of cell migration and invasion and targeting PI3K/AKT/MAPK signalling pathway. J. Buon 2020, 25, 1607–1613. [Google Scholar]
  249. Hassanvand, F.; Mohammadi, T.; Ayoubzadeh, N.; Tavakoli, A.; Hassanzadeh, N.; Sanikhani, N.S.; Azimi, A.I.; Mirzaei, H.R.; Khodamoradi, M.; Goudarzi, K.A.; et al. Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells. J. Cancer Res. 2020, 16, 1412–1418. [Google Scholar] [CrossRef]
  250. Hu, X.; Wang, J.; Chai, J.; Yu, X.; Zhang, Y.; Feng, Y.; Qin, J.; Yu, H. Chaetomugilin J Enhances Apoptosis in Human Ovarian Cancer A2780 Cells Induced by Cisplatin Through Inhibiting Pink1/Parkin Mediated Mitophagy. OncoTargets Ther. 2020, 13, 9967–9976. [Google Scholar] [CrossRef]
  251. Pattarawat, P.; Hong, T.; Wallace, S.; Hu, Y.; Donnell, R.; Wang, T.H.; Tsai, C.L.; Wang, J.; Wang, H.R. Compensatory combination of romidepsin with gemcitabine and cisplatin to effectively and safely control urothelial carcinoma. Br. J. Cancer 2020, 123, 226–239. [Google Scholar] [CrossRef]
  252. Chen, F.; Qin, X.; Xu, G.; Gou, S.; Jin, X. Reversal of cisplatin resistance in human gastric cancer cells by a wogonin-conjugated Pt(IV) prodrug via attenuating Casein Kinase 2-mediated Nuclear Factor-κB pathways. Biochem. Pharm. 2017, 135, 50–68. [Google Scholar] [CrossRef]
  253. Lin, Y.H.; Chen, B.Y.; Lai, W.T.; Wu, S.F.; Guh, J.H.; Cheng, A.L.; Hsu, L.C. The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells. Naunyn Schmiedebergs Arch. Pharm. 2015, 388, 19–31. [Google Scholar] [CrossRef]
  254. Chan, D.W.; Yung, M.M.; Chan, Y.S.; Xuan, Y.; Yang, H.; Xu, D.; Zhan, J.B.; Chan, K.K.; Ng, T.B.; Ngan, H.Y. MAP30 protein from Momordica charantia is therapeutic and has synergic activity with cisplatin against ovarian cancer in vivo by altering metabolism and inducing ferroptosis. Pharm. Res. 2020, 161, 105157. [Google Scholar] [CrossRef] [PubMed]
  255. Yang, Z.; Guo, F.; Albers, A.E.; Sehouli, J.; Kaufmann, A.M. Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed. Pharm. 2019, 113, 108727. [Google Scholar] [CrossRef]
  256. Pluchino, L.A.; Choudhary, S.; Wang, H.C. Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of clonogenic resistance in breast cancer cells by combined cisplatin and FK228. Cancer Lett. 2016, 381, 124–132. [Google Scholar] [CrossRef] [PubMed]
  257. Huang, X.; Wang, M.; Wang, C.; Hu, W.; You, Q.; Yang, Y.; Yu, C.; Liao, Z.; Gou, S.; Wang, H. Dual-targeting antitumor conjugates derived from platinum(IV) prodrugs and microtubule inhibitor CA-4 significantly exhibited potent ability to overcome cisplatin resistance. Bioorg. Chem. 2019, 92, 103236. [Google Scholar] [CrossRef]
  258. Mai, L.; Luo, M.; Wu, J.J.; Yang, J.H.; Hong, L.Y. The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells. Neoplasma 2019, 66, 776–784. [Google Scholar] [CrossRef]
  259. Almotairy, A.R.Z.; Montagner, D.; Morrison, L.; Devereux, M.; Howe, O.; Erxleben, A. Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells. J. Inorg. Biochem. 2020, 210, 111125. [Google Scholar] [CrossRef]
  260. Xu, Y.; Gao, W.; Zhang, Y.; Wu, S.; Liu, Y.; Deng, X.; Xie, L.; Yang, J.; Yu, H.; Su, J.; et al. ABT737 reverses cisplatin resistance by targeting glucose metabolism of human ovarian cancer cells. Int. J. Oncol. 2018, 53, 1055–1068. [Google Scholar] [CrossRef] [Green Version]
  261. Yang, Y.I.; Ahn, J.H.; Choi, Y.S.; Choi, J.H. Brown algae phlorotannins enhance the tumoricidal effect of cisplatin and ameliorate cisplatin nephrotoxicity. Gynecol. Oncol. 2015, 136, 355–364. [Google Scholar] [CrossRef]
  262. Ayyagari, V.N.; Hsieh, T.J.; Diaz-Sylvester, P.L.; Brard, L. Evaluation of the cytotoxicity of the Bithionol—Cisplatin combination in a panel of human ovarian cancer cell lines. BMC Cancer 2017, 17, 49. [Google Scholar] [CrossRef] [Green Version]
  263. Ma, J.; Yang, J.; Wang, C.; Zhang, N.; Dong, Y.; Wang, C.; Wang, Y.; Lin, X. Emodin augments cisplatin cytotoxicity in platinum-resistant ovarian cancer cells via ROS-dependent MRP1 downregulation. Biomed. Res. Int. 2014, 2014, 107671. [Google Scholar] [CrossRef]
  264. Zhang, P.; Zhao, S.; Lu, X.; Shi, Z.; Liu, H.; Zhu, B. Metformin enhances the sensitivity of colorectal cancer cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway. Gene 2020, 745, 144623. [Google Scholar] [CrossRef]
  265. Lee, Y.; Kim, Y.J.; Choi, Y.J.; Lee, J.W.; Lee, S.; Chung, H.W. Enhancement of cisplatin cytotoxicity by benzyl isothiocyanate in HL-60 cells. Food Chem. Toxicol. 2012, 50, 2397–2406. [Google Scholar] [CrossRef]
  266. Qu, X.; Sheng, J.; Shen, L.; Su, J.; Xu, Y.; Xie, Q.; Wu, Y.; Zhang, X.; Sun, L. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS. PLoS ONE 2017, 12, e0173712. [Google Scholar] [CrossRef]
  267. Hsin, I.L.; Wang, S.C.; Li, J.R.; Ciou, T.C.; Wu, C.H.; Wu, H.M.; Ko, J.L. Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death via autophagy for resensitizing cisplatin-resistant urothelial cancer cells. Phytomedicine 2016, 23, 1566–1573. [Google Scholar] [CrossRef]
  268. Nur, G.; Nazıroğlu, M.; Deveci, H.A. Synergic prooxidant, apoptotic and TRPV1 channel activator effects of alpha-lipoic acid and cisplatin in MCF-7 breast cancer cells. J. Recept Signal. Transduct Res. 2017, 37, 569–577. [Google Scholar] [CrossRef]
  269. Sivalingam, K.S.; Paramasivan, P.; Weng, C.F.; Viswanadha, V.P. Neferine Potentiates the Antitumor Effect of Cisplatin in Human Lung Adenocarcinoma Cells Via a Mitochondria-Mediated Apoptosis Pathway. J. Cell. Biochem. 2017, 118, 2865–2876. [Google Scholar] [CrossRef] [PubMed]
  270. Zhu, Z. Miltirone-induced apoptosis in cisplatin-resistant lung cancer cells through upregulation of p53 signaling pathways. Oncol. Lett. 2018, 15, 8841–8846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  271. Yu, N.; Xiong, Y.; Wang, C. Bu-Zhong-Yi-Qi Decoction, the Water Extract of Chinese Traditional Herbal Medicine, Enhances Cisplatin Cytotoxicity in A549/DDP Cells through Induction of Apoptosis and Autophagy. Biomed. Res. Int. 2017, 2017, 3692797. [Google Scholar] [CrossRef] [PubMed]
  272. Liu, X.; Wang, W.; Yin, Y.; Li, M.; Li, H.; Xiang, H.; Xu, A.; Mei, X.; Hong, B.; Lin, W. A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer. Investig. New Drugs 2019, 37, 1166–1176. [Google Scholar] [CrossRef] [PubMed]
  273. Wang, R.; Ma, L.; Weng, D.; Yao, J.; Liu, X.; Jin, F. Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway. Oncol. Rep. 2016, 35, 3075–3083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  274. Chen, T.J.; Zhou, Y.F.; Ning, J.J.; Yang, T.; Ren, H.; Li, Y.; Zhang, S.; Chen, M.W. NBM-T-BMX-OS01, an Osthole Derivative, Sensitizes Human Lung Cancer A549 Cells to Cisplatin through AMPK-Dependent Inhibition of ERK and Akt Pathway. Cell Physiol. Biochem. 2015, 36, 893–906. [Google Scholar] [CrossRef]
  275. Lou, J.S.; Yan, L.; Bi, C.W.; Chan, G.K.; Wu, Q.Y.; Liu, Y.L.; Huang, Y.; Yao, P.; Du, C.Y.; Dong, T.T.; et al. Yu Ping Feng San reverses cisplatin-induced multi-drug resistance in lung cancer cells via regulating drug transporters and p62/TRAF6 signalling. Sci. Rep. 2016, 6, 31926. [Google Scholar] [CrossRef]
  276. Park, B.H.; Lim, J.E.; Jeon, H.G.; Seo, S.I.; Lee, H.M.; Choi, H.Y.; Jeon, S.S.; Jeong, B.C. Curcumin potentiates antitumor activity of cisplatin in bladder cancer cell lines via ROS-mediated activation of ERK1/2. Oncotarget 2016, 7, 63870–63886. [Google Scholar] [CrossRef]
  277. Liao, X.Z.; Tao, L.T.; Liu, J.H.; Gu, Y.Y.; Xie, J.; Chen, Y.; Lin, M.G.; Liu, T.L.; Wang, D.M.; Guo, H.Y.; et al. Matrine combined with cisplatin synergistically inhibited urothelial bladder cancer cells via down-regulating VEGF/PI3K/Akt signaling pathway. Cancer Cell Int. 2017, 17, 124. [Google Scholar] [CrossRef]
  278. Gan, D.; He, W.; Yin, H.; Gou, X. β-elemene enhances cisplatin-induced apoptosis in bladder cancer cells through the ROS-AMPK signaling pathway. Oncol. Lett. 2020, 19, 291–300. [Google Scholar] [CrossRef]
  279. Kakar, S.S.; Jala, V.R.; Fong, M.Y. Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem. Biophys. Res. Commun. 2012, 423, 819–825. [Google Scholar] [CrossRef] [Green Version]
  280. El-Senduny, F.F.; Badria, F.A.; El-Waseef, A.M.; Chauhan, S.C.; Halaweish, F. Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B. Tumour Biol. 2016, 37, 685–698. [Google Scholar] [CrossRef]
  281. Gökçe Kütük, S.; Gökçe, G.; Kütük, M.; Gürses Cila, H.E.; Nazıroğlu, M. Curcumin enhances cisplatin-induced human laryngeal squamous cancer cell death through activation of TRPM2 channel and mitochondrial oxidative stress. Sci. Rep. 2019, 9, 17784. [Google Scholar] [CrossRef] [PubMed]
  282. Tayeh, Z.; Ofir, R. Asteriscus graveolens Extract in Combination with Cisplatin/Etoposide/Doxorubicin Suppresses Lymphoma Cell Growth through Induction of Caspase-3 Dependent Apoptosis. Int. J. Mol. Sci. 2018, 19, 2219. [Google Scholar] [CrossRef] [Green Version]
  283. Liu, Y.S.; Li, H.S.; Qi, D.F.; Zhang, J.; Jiang, X.C.; Shi, K.; Zhang, X.J.; Zhang, X.H. Zinc protoporphyrin IX enhances chemotherapeutic response of hepatoma cells to cisplatin. World J. Gastroenterol. 2014, 20, 8572–8582. [Google Scholar] [CrossRef]
  284. Tan, J.; Song, M.; Zhou, M.; Hu, Y. Antibiotic tigecycline enhances cisplatin activity against human hepatocellular carcinoma through inducing mitochondrial dysfunction and oxidative damage. Biochem. Biophys. Res. Commun. 2017, 483, 17–23. [Google Scholar] [CrossRef]
  285. Deng, H.; Ma, J.; Liu, Y.; He, P.; Dong, W. Combining α-Hederin with cisplatin increases the apoptosis of gastric cancer in vivo and in vitro via mitochondrial related apoptosis pathway. Biomed. Pharm. 2019, 120, 109477. [Google Scholar] [CrossRef]
  286. Liu, Y.; Lei, H.; Ma, J.; Deng, H.; He, P.; Dong, W. α-Hederin Increases The Apoptosis Of Cisplatin-Resistant Gastric Cancer Cells By Activating Mitochondrial Pathway In Vivo And Vitro. OncoTargets Ther. 2019, 12, 8737–8750. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  287. Shin, J.I.; Jeon, Y.J.; Lee, S.; Lee, Y.G.; Kim, J.B.; Lee, K. G-Protein-Coupled Receptor 120 Mediates DHA-Induced Apoptosis by Regulating IP3R, ROS and, ER Stress Levels in Cisplatin-Resistant Cancer Cells. Mol. Cells 2019, 42, 252–261. [Google Scholar] [CrossRef]
  288. Liu, Y.; Qin, L.; Bi, T.; Dai, W.; Liu, W.; Gao, Q.; Shen, G. Oxymatrine Synergistically Potentiates the Antitumor Effects of Cisplatin in Human Gastric Cancer Cells. J. Cancer 2018, 9, 4527–4535. [Google Scholar] [CrossRef]
  289. Lee, Y.J.; Lee, G.J.; Yi, S.S.; Heo, S.H.; Park, C.R.; Nam, H.S.; Cho, M.K.; Lee, S.H. Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells. Food Chem. Toxicol. 2016, 97, 96–107. [Google Scholar] [CrossRef]
  290. Hammouda, M.B.; Riahi-Chebbi, I.; Souid, S.; Othman, H.; Aloui, Z.; Srairi-Abid, N.; Karoui, H.; Gasmi, A.; Magnenat, E.M.; Wells, T.N.C.; et al. Macrovipecetin, a C-type lectin from Macrovipera lebetina venom, inhibits proliferation migration and invasion of SK-MEL-28 human melanoma cells and enhances their sensitivity to cisplatin. Biochim. Biophys. Acta Gen. Subj. 2018, 1862, 600–614. [Google Scholar] [CrossRef]
  291. Allegra, M.; D’Anneo, A.; Frazzitta, A.; Restivo, I.; Livrea, M.A.; Attanzio, A.; Tesoriere, L. The Phytochemical Indicaxanthin Synergistically Enhances Cisplatin-Induced Apoptosis in HeLa Cells via Oxidative Stress-Dependent p53/p21(waf1) Axis. Biomolecules 2020, 10, 994. [Google Scholar] [CrossRef]
  292. Kim, E.H.; Baek, S.; Shin, D.; Lee, J.; Roh, J.L. Hederagenin Induces Apoptosis in Cisplatin-Resistant Head and Neck Cancer Cells by Inhibiting the Nrf2-ARE Antioxidant Pathway. Oxid. Med. Cell Longev. 2017, 2017, 5498908. [Google Scholar] [CrossRef]
  293. Ye, S.F.; Yang, Y.; Wu, L.; Ma, W.W.; Zeng, H.H. Ethaselen: A novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis. J. Zhejiang Univ. Sci. B 2017, 18, 373–382. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  294. Su, S.; Dou, H.; Wang, Z.; Zhang, Q. Bufalin inhibits ovarian carcinoma via targeting mTOR/HIF-α pathway. Basic Clin. Pharm. Toxicol. 2021, 128, 224–233. [Google Scholar] [CrossRef] [PubMed]
  295. Liu, Y.; Wang, X.; Li, W.; Xu, Y.; Zhuo, Y.; Li, M.; He, Y.; Wang, X.; Guo, Q.; Zhao, L.; et al. Oroxylin A reverses hypoxia-induced cisplatin resistance through inhibiting HIF-1α mediated XPC transcription. Oncogene 2020, 39, 6893–6905. [Google Scholar] [CrossRef]
  296. Zhu, J.; Li, B.; Xu, M.; Liu, R.; Xia, T.; Zhang, Z.; Xu, Y.; Liu, S. Graphene Oxide Promotes Cancer Metastasis through Associating with Plasma Membrane To Promote TGF-β Signaling-Dependent Epithelial-Mesenchymal Transition. ACS Nano 2020, 14, 818–827. [Google Scholar] [CrossRef] [PubMed]
  297. Song, Y.; Zou, X.; Zhang, D.; Liu, S.; Duan, Z.; Liu, L. Self-enforcing HMGB1/NF-κB/HIF-1α Feedback Loop Promotes Cisplatin Resistance in Hepatocellular Carcinoma Cells. J. Cancer 2020, 11, 3893–3902. [Google Scholar] [CrossRef]
  298. Bejjanki, N.K.; Xu, H.; Xie, M. GSH triggered intracellular aggregated-cisplatin-loaded iron oxide nanoparticles for overcoming cisplatin resistance in nasopharyngeal carcinoma. J. Biomater. Appl. 2021, 885328220982151. [Google Scholar] [CrossRef]
  299. Yu, M.; Ozaki, T.; Sun, D.; Xing, H.; Wei, B.; An, J.; Yang, J.; Gao, Y.; Liu, S.; Kong, C.; et al. HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4. J. Exp. Clin. Cancer Res. 2020, 39, 108. [Google Scholar] [CrossRef]
  300. Zhang, Q.; Zhang, H.; Ning, T.; Liu, D.; Deng, T.; Liu, R.; Bai, M.; Zhu, K.; Li, J.; Fan, Q.; et al. Exosome-Delivered c-Met siRNA Could Reverse Chemoresistance to Cisplatin in Gastric Cancer. Int. J. Nanomed. 2020, 15, 2323–2335. [Google Scholar] [CrossRef] [Green Version]
  301. Wu, B.; Yuan, Y.; Han, X.; Wang, Q.; Shang, H.; Liang, X.; Jing, H.; Cheng, W. Structure of LINC00511-siRNA-conjugated nanobubbles and improvement of cisplatin sensitivity on triple negative breast cancer. FASEB J. 2020, 34, 9713–9726. [Google Scholar] [CrossRef] [PubMed]
  302. Gu, J.; Li, Y.; Zeng, J.; Wang, B.; Ji, K.; Tang, Y.; Sun, Q. Knockdown of HIF-1α by siRNA-expressing plasmid delivered by attenuated Salmonella enhances the antitumor effects of cisplatin on prostate cancer. Sci. Rep. 2017, 7, 7546. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  303. Lou, J.S.; Zhao, L.P.; Huang, Z.H.; Chen, X.Y.; Xu, J.T.; Tai, W.C.; Tsim, K.W.K.; Chen, Y.T.; Xie, T. Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine 2021, 80, 153370. [Google Scholar] [CrossRef] [PubMed]
  304. Kim, H.R.; Kim, S.; Kim, E.J.; Park, J.H.; Yang, S.H.; Jeong, E.T.; Park, C.; Youn, M.J.; So, H.S.; Park, R. Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin. Lung Cancer 2008, 60, 47–56. [Google Scholar] [CrossRef] [PubMed]
  305. Delfi, M.; Sartorius, R.; Ashrafizadeh, M.; Sharifi, E.; Zhang, Y.; De Berardinis, P.; Zarrabi, A.; Varma, R.S.; Tay, F.R.; Smith, B.R.; et al. Self-assembled peptide and protein nanostructures for anti-cancer therapy: Targeted delivery, stimuli-responsive devices and immunotherapy. Nano Today 2021, 38, 101119. [Google Scholar] [CrossRef]
  306. Ashrafizadeh, M.; Delfi, M.; Hashemi, F.; Zabolian, A.; Saleki, H.; Bagherian, M.; Azami, N.; Farahani, M.V.; Sharifzadeh, S.O.; Hamzehlou, S.; et al. Biomedical application of chitosan-based nanoscale delivery systems: Potential usefulness in siRNA delivery for cancer therapy. Carbohydr. Polym. 2021, 260, 117809. [Google Scholar] [CrossRef]
  307. Xue, X.; Hall, M.D.; Zhang, Q.; Wang, P.C.; Gottesman, M.M.; Liang, X.-J. Nanoscale drug delivery platforms overcome platinum-based resistance in cancer cells due to abnormal membrane protein trafficking. ACS Nano 2013, 7, 10452–10464. [Google Scholar] [CrossRef] [Green Version]
  308. Bidram, E.; Esmaeili, Y.; Ranji-Burachaloo, H.; Al-Zaubai, N.; Zarrabi, A.; Stewart, A.; Dunstan, D.E. A concise review on cancer treatment methods and delivery systems. J. Drug Deliv. Sci. Technol. 2019, 54, 101350. [Google Scholar] [CrossRef]
  309. Huang, X.; Chen, J.; Wu, W.; Yang, W.; Zhong, B.; Qing, X.; Shao, Z. Delivery of MutT homolog 1 inhibitor by functionalized graphene oxide nanoparticles for enhanced chemo-photodynamic therapy triggers cell death in osteosarcoma. Acta Biomater. 2020, 109, 229–243. [Google Scholar] [CrossRef]
  310. Lima-Sousa, R.; de Melo-Diogo, D.; Alves, C.G.; Cabral, C.S.D.; Miguel, S.P.; Mendonça, A.G.; Correia, I.J. Injectable in situ forming thermo-responsive graphene based hydrogels for cancer chemo-photothermal therapy and NIR light-enhanced antibacterial applications. Mater. Sci. Eng. C Mater. Biol. Appl. 2020, 117, 111294. [Google Scholar] [CrossRef]
  311. Zhang, W.; Shen, J.; Su, H.; Mu, G.; Sun, J.H.; Tan, C.P.; Liang, X.J.; Ji, L.N.; Mao, Z.W. Co-Delivery of Cisplatin Prodrug and Chlorin e6 by Mesoporous Silica Nanoparticles for Chemo-Photodynamic Combination Therapy to Combat Drug Resistance. ACS Appl. Mater. Interfaces 2016, 8, 13332–13340. [Google Scholar] [CrossRef]
  312. Qian, G.; Wang, L.; Zheng, X.; Yu, T. Deactivation of cisplatin-resistant human lung/ovary cancer cells with pyropheophorbide-α methyl ester-photodynamic therapy. Cancer Biol. 2017, 18, 984–989. [Google Scholar] [CrossRef]
  313. Franskevych, D.; Prylutska, S.; Grynyuk, I.; Pasichnyk, G.; Drobot, L.; Matyshevska, O.; Ritter, U. Mode of photoexcited C(60) fullerene involvement in potentiating cisplatin toxicity against drug-resistant L1210 cells. Bioimpacts 2019, 9, 211–217. [Google Scholar] [CrossRef] [Green Version]
  314. Guo, L.; Cui, J.; Wang, H.; Medina, R.; Zhang, S.; Zhang, X.; Zhuang, Z.; Lin, Y. Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways. Mol. Oncolytics 2021, 20, 119–131. [Google Scholar] [CrossRef] [PubMed]
  315. Yang, T.; Yu, S.; Liu, L.; Sun, Y.; Lan, Y.; Ma, X.; Zhu, R.; Li, L.; Hou, Y.; Liu, Y. Dual polymeric prodrug co-assembled nanoparticles with precise ratiometric co-delivery of cisplatin and metformin for lung cancer chemoimmunotherapy. Biomater. Sci. 2020, 8, 5698–5714. [Google Scholar] [CrossRef]
  316. Saber, M.M.; Al-Mahallawi, A.M.; Nassar, N.N.; Stork, B.; Shouman, S.A. Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes. BMC Cancer 2018, 18, 822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  317. Pourbagher-Shahri, A.M.; Farkhondeh, T.; Ashrafizadeh, M.; Talebi, M.; Samargahndian, S. Curcumin and cardiovascular diseases: Focus on cellular targets and cascades. Biomed. Pharmacother. 2021, 136, 111214. [Google Scholar] [CrossRef]
  318. Pricci, M.; Girardi, B.; Giorgio, F.; Losurdo, G.; Ierardi, E.; Di Leo, A. Curcumin and colorectal cancer: From basic to clinical evidences. Int. J. Mol. Sci. 2020, 21, 2364. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  319. Farkhondeh, T.; Ashrafizadeh, M.; Azimi-Nezhad, M.; Samini, F.; Aschenr, M.; Samarghandian, S. Curcumin Efficacy in a Serum/glucose Deprivation-induced Neuronal PC12 Injury Model. Curr. Mol. Pharmacol. 2021. [Google Scholar] [CrossRef]
  320. Moballegh Nasery, M.; Abadi, B.; Poormoghadam, D.; Zarrabi, A.; Keyhanvar, P.; Khanbabaei, H.; Ashrafizadeh, M.; Mohammadinejad, R.; Tavakol, S.; Sethi, G. Curcumin Delivery Mediated by Bio-Based Nanoparticles: A Review. Molecules 2020, 25, 689. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  321. Tewari, D.; Nabavi, S.F.; Nabavi, S.M.; Sureda, A.; Farooqi, A.A.; Atanasov, A.G.; Vacca, R.A.; Sethi, G.; Bishayee, A. Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention. Pharm. Res. 2018, 128, 366–375. [Google Scholar] [CrossRef]
  322. Hong, Y.; Che, S.; Hui, B.; Wang, X.; Zhang, X.; Ma, H. Combination Therapy of Lung Cancer Using Layer-by-Layer Cisplatin Prodrug and Curcumin Co-Encapsulated Nanomedicine. Drug Des. Dev. 2020, 14, 2263–2274. [Google Scholar] [CrossRef]
  323. Abdul Satar, N.; Ismail, M.N.; Yahaya, B.H. Synergistic Roles of Curcumin in Sensitising the Cisplatin Effect on a Cancer Stem Cell-Like Population Derived from Non-Small Cell Lung Cancer Cell Lines. Molecules 2021, 26, 1056. [Google Scholar] [CrossRef] [PubMed]
  324. Cheng, Y.; Zhao, P.; Wu, S.; Yang, T.; Chen, Y.; Zhang, X.; He, C.; Zheng, C.; Li, K.; Ma, X.; et al. Cisplatin and curcumin co-loaded nano-liposomes for the treatment of hepatocellular carcinoma. Int. J. Pharm. 2018, 545, 261–273. [Google Scholar] [CrossRef]
  325. Chang, P.Y.; Peng, S.F.; Lee, C.Y.; Lu, C.C.; Tsai, S.C.; Shieh, T.M.; Wu, T.S.; Tu, M.G.; Chen, M.Y.; Yang, J.S. Curcumin-loaded nanoparticles induce apoptotic cell death through regulation of the function of MDR1 and reactive oxygen species in cisplatin-resistant CAR human oral cancer cells. Int. J. Oncol. 2013, 43, 1141–1150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  326. Sun, M.; He, L.; Fan, Z.; Tang, R.; Du, J. Effective treatment of drug-resistant lung cancer via a nanogel capable of reactivating cisplatin and enhancing early apoptosis. Biomaterials 2020, 257, 120252. [Google Scholar] [CrossRef]
  327. Raviadaran, R.; Ng, M.H.; Chandran, D.; Ooi, K.K.; Manickam, S. Stable W/O/W multiple nanoemulsion encapsulating natural tocotrienols and caffeic acid with cisplatin synergistically treated cancer cell lines (A549 and HEP G2) and reduced toxicity on normal cell line (HEK 293). Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 121, 111808. [Google Scholar] [CrossRef]
  328. Badea, M.A.; Prodana, M.; Dinischiotu, A.; Crihana, C.; Ionita, D.; Balas, M. Cisplatin Loaded Multiwalled Carbon Nanotubes Induce Resistance in Triple Negative Breast Cancer Cells. Pharmaceutics 2018, 10, 228. [Google Scholar] [CrossRef] [Green Version]
  329. Li, F.; Li, T.; Cao, W.; Wang, L.; Xu, H. Near-infrared light stimuli-responsive synergistic therapy nanoplatforms based on the coordination of tellurium-containing block polymer and cisplatin for cancer treatment. Biomaterials 2017, 133, 208–218. [Google Scholar] [CrossRef] [Green Version]
  330. Wang, X.; Gong, Q.; Song, C.; Fang, J.; Yang, Y.; Liang, X.; Huang, X.; Liu, J. Berberine-photodynamic therapy sensitizes melanoma cells to cisplatin-induced apoptosis through ROS-mediated P38 MAPK pathways. Toxicol. Appl. Pharm. 2021, 115484. [Google Scholar] [CrossRef]
  331. Xiang, J.; Li, Y.; Zhang, Y.; Wang, G.; Xu, H.; Zhou, Z.; Tang, J.; Shen, Y. Polyphenol-cisplatin complexation forming core-shell nanoparticles with improved tumor accumulation and dual-responsive drug release for enhanced cancer chemotherapy. J. Control. Release 2021, 330, 992–1003. [Google Scholar] [CrossRef]
  332. Shi, D.; Zhang, Y.; Tian, Y. SLAMF1 Promotes Methotrexate Resistance via Activating Autophagy in Choriocarcinoma Cells. Cancer Manag. Res. 2020, 12, 13427–13436. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Molecular pathways regulating ROS generation and their role in CP sensitivity. The interesting point is the overgeneration and inhibition of ROS levels in CP sensitivity. ROS can affect migration and proliferation of cancer cells in CP sensitivity. MiRNAs can also function as upstream mediators of ROS in CP sensitivity.
Figure 1. Molecular pathways regulating ROS generation and their role in CP sensitivity. The interesting point is the overgeneration and inhibition of ROS levels in CP sensitivity. ROS can affect migration and proliferation of cancer cells in CP sensitivity. MiRNAs can also function as upstream mediators of ROS in CP sensitivity.
Molecules 26 02382 g001
Figure 2. Molecular pathways regulating ROS in CP resistance. Mainly, ROS inhibition results in CP resistance, and upstream mediators including Nox2, GPX2, and SIRT1 can reduce ROS levels in mediating CP resistance. Furthermore, hypoxia affects ROS levels and mitochondrial function in CP resistance.
Figure 2. Molecular pathways regulating ROS in CP resistance. Mainly, ROS inhibition results in CP resistance, and upstream mediators including Nox2, GPX2, and SIRT1 can reduce ROS levels in mediating CP resistance. Furthermore, hypoxia affects ROS levels and mitochondrial function in CP resistance.
Molecules 26 02382 g002
Figure 3. Anti-tumor compounds targeting ROS and mediating CP sensitivity. Most of them are phytochemical and mainly enhance ROS levels in apoptosis induction and promoting potential of CP in cancer suppression.
Figure 3. Anti-tumor compounds targeting ROS and mediating CP sensitivity. Most of them are phytochemical and mainly enhance ROS levels in apoptosis induction and promoting potential of CP in cancer suppression.
Molecules 26 02382 g003
Figure 4. Nanoscale delivery systems in ROS regulating and CP sensitivity. Nanoparticles enhance penetration of CP through cell membrane and via increasing intracellular accumulation, promote its potential in ROS overgeneration and cancer cell death. Anti-tumor compounds such as curcumin and matrine can be co-delivered by CP in effective cancer suppression. Furthermore, phototherapy mediated by nanoparticles enhances CP sensitivity of cancer cells.
Figure 4. Nanoscale delivery systems in ROS regulating and CP sensitivity. Nanoparticles enhance penetration of CP through cell membrane and via increasing intracellular accumulation, promote its potential in ROS overgeneration and cancer cell death. Anti-tumor compounds such as curcumin and matrine can be co-delivered by CP in effective cancer suppression. Furthermore, phototherapy mediated by nanoparticles enhances CP sensitivity of cancer cells.
Molecules 26 02382 g004
Table 1. Enhanced CP sensitivity of cancer cells via ROS regulation.
Table 1. Enhanced CP sensitivity of cancer cells via ROS regulation.
Cancer TypeIn vitro/In vivoCell line/Animal ModelSignaling NetworkRemarksRefs
Osteosarcoma In vitro MG63/DDP and Saos-2/DDP cells STAT3/Nrf2/GPX4 High expression of STAT3, Nrf2 and GPX4 in CP resistant-cancer cells
STAT3 inhibition promotes CP sensitivity
Agonist of ferroptosis enhances CP sensitivity
ROS overgeneration partially is involved in triggering CP sensitivity
[108]
Sarcoma In vitro MG-63 cells Id3/ROS Enhancing Id3 expression increases CP sensitivity of cancer cells by apoptosis induction via ROS overgeneration [109]
Human maxillary cancer In vitro IMC-3CR cells SESN1/ROS Reducing apoptosis induction
Enhancing viability and survival of cancer cells
SENS1 decreases ROS levels
[110]
Tongue squamous cell carcinoma In vitro CAL27 cells - ROS overgeneration enhances anti-tumor activity of CP
Simultaneous induction of apoptosis and autophagy
[111]
Ovarian cancer In vitro OVCAR-3 cells - Higher levels of mitochondrial ROS in CP sensitive-cancer cells compared to CP resistant-cancer cells
Boosting CP-mediated apoptosis via enhancing ROS levels
[112]
Non-small cell lung cancer In vitro A549 cells MiRNA-140/SIRT1/ROS/JNK MiRNA-140 functions as a tumor-suppressing factor
SIRT1 down-regulation
Activating ROS/JNK axis
Increasing CP sensitivity
[113]
Breast cancer In vitro MCF-7 cells ACO2/ROS ACO2 promotes ROS accumulation in cancer cells
Subsequent stabilization and stimulation of p53 in nucleus and mitochondria
Apoptosis induction
[114]
Colorectal cancer In vitro HT29 and SW480 cells MiRNA-519d/TRIM32 Down-regulating TRIM32 by miRNA-519d
Promoting CP sensitivity via ROS generation, and mediating mitochondrial pathway of apoptosis
[94]
Colon cancer In vitro HCT-15 cells - Reduced levels of ROS
Down-regulation of KLF4
CP resistance
[86]
Hepatocellular carcinoma In vitro HepG2 and Huh7 cells MiRNA-124/SIRT1/ROS/JNK SIRT1 inhibition
Triggering JNK phosphorylation via ROS overgeneration
Mediating CP sensitivity
[91]
Table 2. Experiments related to CP resistance and role of ROS generation.
Table 2. Experiments related to CP resistance and role of ROS generation.
Cancer TypeIn Vitro/In VivoCell Line/Animal ModelSignaling NetworkRemarksRefs
Urothelial carcinomaIn vitro T24 and UMUC3 cells MUC1-C/xCT/GSHReducing ROS levels
MUC1 enhances expression level of xCT to promote GSH level
Inducing CP resistance
[179]
Squamous cell carcinomaIn vitroEC109 cellsMUTYH/ROSDown-regulation of MUTYH occurs in CP resistant cancer cells
MUTYH down-regulation is associated with decreased levels of ROS
[180]
Oral squamous cell carcinomaIn vitroTca8113 cellsSIRT1/ROSReducing ROS accumulation in cancer cells
Inducing CP resistance
[181]
Bladder cancerIn vitroHT1376 cellsAKR1C2/ROSReducing AKR1C2 expression promotes CP sensitivity of cancer cells, determining oncogene role of this factor
AKR1C2 diminishes ROS levels in mediating CP resistance
[182]
Bladder urothelial carcinoma In vitro NTUB1 cells CEBPD/ROS Upregulation of CEBPD in Cp resistant-cancer cells
Decreasing ROS levels
Apoptosis inhibition
[183]
OsteosarcomaIn vitro MG63, U2OS and 143B cells TERT/ROSTelomerase diminishes ROS levels in cells
Reducing apoptosis
Improving mitochondrial function
Inducing CP resistance
[184]
OsteosarcomaIn vitro U2OS, SAOS2, MG-63 and HOS cells APE1/ROSOverexpression of APE1 is observed in CP resistant-osteosarcoma cells
APE1 upregulation diminishes apoptosis and DNA damage
Preventing ROS generation by APE1 upon exposure to CP
[185]
Different cancersIn vitro 293T, Caov-3, BG-1, and KB-3-1 cells IP4/NOX4/ROSInhibition of NOX4 by IP4
Reducing ROS levels
Triggering CP resistance
[186]
Different cancersIn vitro H1299 and P31 cells SIRT3/ROS
HIF-1α/ROS
Increased levels of ROS in CP resistant-cancer cells, showing oncogene role of ROS
Simultaneous upregulation of HIF-1α with ROS overgeneration
SIRT3 down-regulation with simultaneous ROS overgeneration
[187]
Ovarian cancerIn vitroSKOV3 cellsP62/Keap1/Nrf2/AREUpregulation of p62 in CP resistant-ovarian cancer cells
Induction of Nrf2/ARE axis via Keap1 down-regulation
Reducing ROS levels
Preventing apoptosis
[176]
Ovarian cancer In vitro SKOV3 and A2780 cells RIP1/ROS Acting as a tumor-promoting factor via reducing ROS accumulation
Enhancing ROS accumulation promotes apoptosis and necroptosis in cancer cells
[188]
Human mesothelioma In vitro ZL55 cells ROS/PKC-α/EGFR/ERK1/2 CP induces ROS overgeneration that in turn, stimulates PKC-α
Activation of EGFR and subsequent phosphorylation of ERK1/2 are responsible for reduced CP cytotoxicity against cancer cells
[189]
Non-small cell lung cancer In vitro H460 cells ROS/CAV1 ROS overgeneration upon sub-toxic exposure to CP results in CAV1 upregulation and anoikis resistance, reducing efficacy of chemotherapy [190]
Glioma In vitro U251 cells ROS/Akt/mTOR Inducing Akt/mTOR signaling via ROS overgeneration
Promoting autophagy
Triggering CP resistance
Reducing ROS levels inhibit Akt signaling, showing role of ROS in CP resistance
[191]
Gastric cancer In vitro SNU-16 cells - Enhancing ROS levels
Inducing Akt signaling
Providing CP resistance
Upregulating p53 expression suppresses CP resistance of cancer cells
[192]
Table 3. Anti-tumor compounds applied in regulating ROS levels and enhancing CP sensitivity.
Table 3. Anti-tumor compounds applied in regulating ROS levels and enhancing CP sensitivity.
Anti-Tumor CompoundCancer TypeIn Vitro/In VivoCell Line/Animal ModelStudy DesignSignaling NetworkRemarksRefs
DisulfiramBreast cancerIn vitroMCF-7, SKB-R3, and MDA-MB-435S cells1 µM
24 h
-Enhancing ROS levels
Potentiating cytotoxicity of CP against breast cancer cells
[255]
FK228Breast cancerIn vitroMCF10A cells0–1 nMERK/NOX/ROSStimulating ERK/NOX axis via affecting Ras signaling
Increasing intracellular accumulation of ROS in cells
Mediating cell death and apoptosis
Enhancing CP sensitivity of cancer cells
[256]
CA-4 (microtubule inhibitor)Lung cancerIn vitroA549 cells0.21 µM-Enhancing ROS generation
Subsequent loss in mitochondrial membrane potential
Activating apoptosis through inducing caspase cascade
Enhancing CP sensitivity
[257]
LW6 (HIF-1α inhibitor)Non-small cell lung cancerIn vitroA549 cells0–96 h-Suppressing hypoxia-mediated resistance to CP chemotherapy
Increasing ROS levels
Decreasing MRP1 and MDR1 levels
Triggering CP sensitivity
[258]
4-phenylbutyrateOvarian cancerIn vitro A2780 cells0–50 µM-Increasing ROS generation
Inhibiting activity of histone deacetylase
Inducing apoptosis and DNA damage
[259]
ABT737Ovarian cancerIn vitroSKOV3 cells0–40 µM-Down-regulating Bcl-2 expression
Impairing glucose metabolism
Potentiating anti-tumor activity of CP
[260]
Brown algae phlorotanninsOvarian cancerIn vitro
In vivo
A2780 and SKOV3 cells
Mouse model
75 and 150 mg/kgROS/Akt/NF-κBIncreasing ROS levels and subsequent inhibition of Akt/NF-κB axis
Inducing cell death and tumor growth inhibition in vitro and in vivo
[261]
BithionolOvarian cancerIn vitroA2780 /A2780-CDDP and IGROV-1/, IGROV-1CDDP cells12.5 µM-Triggering ROS-mediated apoptosis
Down-regulation of XIAP, Bcl-2 and Bcl-Xl as pro-survival factors
Upregulating PARP, and caspase-3/7 as pro-apoptotic factors
Triggering cell cycle arrest via p21 and p27 upregulation
[262]
EmodinOvarian cancerIn vitroCOC1 cell line12.5, 25 and 50 µMROS/MRP1Down-regulating MRP1 expression via ROS overgeneration
Promoting CP sensitivity
[263]
MetforminColorectal cancerIn vitroSW480 and SW620 cells0–20 mMROS/PI3K/AktInducing ROS overgeneration
Subsequent inhibition of PI3K/Akt signaling
Increasing CP sensitivity
[264]
Benzyl IsothiocyanateLeukemiaIn vitroHL-60 cells0–5 µM-Reducing GSH levels
Inducing ROS overgeneration
Promoting cell death
Providing CP sensitivity
Triggering ERK signaling pathway
[265]
ChloroquineCholangiocarcinomaIn vitroQBC939 cells50 µM-Reducing G6PDH activity
Promoting ROS accumulation
Autophagy inhibition
Sensitizing to cell death and enhancing CP sensitivity
[266]
ChloroquineUrothelial cancerIn vitroNTUB1 and N/P (cisplatin-resistant sub-line) urothelial cancer cells10 µMROS/LC-3IIEnhancing ROS generation
ROS scavenger reduces LC-3II accumulation, showing role of ROS in upregulating LC-3II levels
Inducing cell death independent of caspase and based on autophagy
Increasing CP sensitivity
[267]
Table 4. Plant derived-natural compounds regulating ROS levels in CP chemotherapy.
Table 4. Plant derived-natural compounds regulating ROS levels in CP chemotherapy.
Anti-Tumor CompoundCancer TypeIn Vitro/In VivoCell Line/Animal ModelStudy DesignSignaling NetworkRemarksRefs
Alpha-lipoic acidBreast cancerIn vitroMCF-7 cells0.05 mMTRPV1/ROSInducing TRPV1 and subsequent increase in ROS levels
Decreasing viability and proliferation of cancer cells
Enhancing CP sensitivity
[268]
NeferineLung cancerIn vitroA549 cells10 µM-Enhancing ROS levels
Inducing mitochondrial dysfunction
Apoptosis induction
[269]
MiltironeLung cancerIn vitroA549 cells0–40 µM-Reducing ROS levels to promote p53 expression, demonstrating oncogene role of ROS[270]
Bu-Zhong-Yi-Qi DecoctionLung cancerIn vitroA549 cells0–5000 µg/mlROS/Apoptosis
ROS/Autophagy
Enhancing ROS generation and inducing cell death, both autophagy and apoptosis
ROS scavenger reduces cell death, showing role of ROS in CP-mediated cell death in cancer cells
[271]
AuranofinLung cancerIn vitro
In vivo
H69 and H196 cells
Xenografts
500 and 1000 nM
10 mg/kg
-Inducing ROS overgeneration
Triggering mitochondrial dysfunction
Enhancing DNA damage
Suppressing tumor growth in vivo
Increasing CP sensitivity
[272]
Gallic AcidSmall cell lung cancerIn vitroH446 cell line3 µg/mL
24 h
-Suppressing cancer growth
Apoptosis induction
Enhancing ROS levels
[273]
Osthole derivativeLung cancerIn vitroA549 cells0–10 µM-Triggering oxidative stress via ROS overgeneration
Enhancing CP sensitivity
[274]
Yu Ping Feng SanLung cancerIn vitro
In vivo
A549 cells
Tumor-bearing mice
0–20 µM
4 g/kg
-Decreasing tumor volume
Reducing cancer cell viability
Increasing ROS levels
Promoting CP sensitivity
[275]
CurcuminBladder cancerIn vitro253J-Bv cells10 µMROS/ERK1/2Enhancing ROS levels to induce ERK1/2
Apoptosis induction
Providing CP sensitivity
[276]
MatrineUrothelial bladder cancerIn vitroEJ, T24, BIU, 5637 cells1–16 mM-Increasing ROS generation and sensitizing cancer cells to apoptosis
Promoting CP sensitivity
[277]
β-elemeneBladder cancerIn vitroT24 and 5637 cells0–75 µg/mlROS/AMPKPreventing cancer cell proliferation
Triggering cell cycle arrest (G0/G1 phase)
Increasing intracellular accumulation of ROS
Stimulating AMPK signaling
Apoptosis induction
[278]
Osthole derivativeLung cancerIn vitroA549 cells0–10 µM-Triggering oxidative stress via ROS overgeneration
Enhancing CP sensitivity
[274]
Yu Ping Feng SanLung cancerIn vitro
In vivo
A549 cells
Tumor-bearing mice
0–20 µM
4 g/kg
-Decreasing tumor volume
Reducing cancer cell viability
Increasing ROS levels
Promoting CP sensitivity
[275]
CurcuminBladder cancerIn vitro253J-Bv cells10 µMROS/ERK1/2Enhancing ROS levels to induce ERK1/2
Apoptosis induction
Providing CP sensitivity
[276]
MatrineUrothelial bladder cancerIn vitroEJ, T24, BIU, 5637 cells1–16 mM-Increasing ROS generation and sensitizing cancer cells to apoptosis
Promoting CP sensitivity
[277]
β-elemeneBladder cancerIn vitroT24 and 5637 cells0–75 µg/mLROS/AMPKPreventing cancer cell proliferation
Triggering cell cycle arrest (G0/G1 phase)
Increasing intracellular accumulation of ROS
Stimulating AMPK signaling
Apoptosis induction
[278]
Withaferin AOvarian cancerIn vitroA2780 and A2780/CP70 cells0–7 µM-Inducing DNA damage through promoting ROS levels and sensitizing cancer cells to CP chemotherapy[279]
Cucurbitacin BOvarian cancerIn vitroA2780 cells0–8 µM-Significant decrease in viability and proliferation of cancer cells
Increasing their sensitivity to CP
Promoting ROS production
[280]
CurcuminLaryngeal squamous cell cancerIn vitroHep2 cells1 µM-CP administration enhances ROS levels to induce apoptosis in cancer cells
Combination chemotherapy with curcumin increases TRPM2 level to potentiate cytotoxicity against cancer cells and enhance efficacy of CP in increasing ROS levels
[281]
Asteriscus graveolensLymphomaIn vitroBS-24-1 cells0–8 µg/ml-Enhancing ROS levels
Sensitizing cancer cells to CP-mediated apoptosis
[282]
Zinc protoporphyrin IXLiver cancerIn vitroHepG2 cells10 µmol/LHO-1/ROSDown-regulating HO-1 expression
Increasing ROS levels
Activating caspase-3
Sensitizing to CP-mediated cell death
[283]
TigecyclinHepatocellular carcinomaIn vitroHepG2 and HuH6 cells1, 5 and 10 µM-Inducing oxidative stress through ROS overgeneration
Decreasing mitochondrial respiration
Increasing CP sensitivity
[284]
α-HederinGastric cancerIn vitro
In vivo
SGC-7901, HGC-27, and MGC-803 cells
Xenograft mouse model
4 mg/kg-Enhancing tumor growth inhibition capacity of CP in vivo
Promoting expression level of apoptosis proteins
Increasing ROS levels
[285]
α-HederinGastric cancerIn vitro
In vivo
HGC27 cells
Nude mice
0-25 µM
2, 4 and 6 mg/kg
-Apoptosis stimulation
Triggering GSH depletion
Increasing intracellular accumulation of ROS
[286]
Docosahexaenoic acidGastric cancerIn vitroSNU-601 cells and SNU-601/cis2 cells0-200 µMGPR120GPR120 mediates capacity of DHA in increasing ROS levels and inducing apoptosis in cancer cells[287]
OxymatrineGastric cancerIn vitroBGC-823 and SGC7901 cells1 mg/mLAkt/ERKInducing apoptosis in cancer cells in a ROS-dependent manner
Suppressing Akt/ERK axis
Upregulating p21 and p27 levels
[288]
ResveratrolMesothelioma cellsIn vitroMSTO-211H and H-2452 cells30 µM-Increasing ROS generation
Triggering loss of mitochondrial membrane potential
Enhancing Bax/Bcl-2 ratio
Apoptosis induction
Providing CP sensitivity
[289]
MacrovipecetinMelanomaIn vitroSK-MEL-28 cells0–1 µM-Impairing cancer proliferation
Decreasing ROS levels, showing tumor-promoting role of ROS
Promoting CP sensitivity
[290]
IndicaxanthinCervical cancerIn vitroHeLa cells60 µMROS/p53Enhancing ROS levels
Activating p53 and p21
Apoptosis induction
[291]
HederageninHead and neck cancerIn vitro
In vivo
AMC-HN2–10, SNU-1041, SNU-1066, and SNU-1076 cells50 and 100 µM
100 and 200 mg/kg
Nrf2/AREInhibiting Nrf2/ARE axis
Enhancing p53 expression
Subsequent increase in ROS levels
Increasing GSH depletion
Inducing cell death
[292]
EthaselenLeukemiaIn vitroK562 cells1.5 µmol/LTrxR/ROSIncreasing ROS generation via TrxR inhibition
Bax upregulation and Bcl-2 down-regulation
Cytochrome C release
Apoptosis induction
NF-κB down-regulation
[293]
AscorbateOsteosarcomaIn vitroU2OS and 143B cells0–100 µM-Increasing ROS levels to impair glycolysis and mitochondrial function in cancer cells
Reducing cell sphere formation capacity
Increasing CP sensitivity
[238]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Mirzaei, S.; Hushmandi, K.; Zabolian, A.; Saleki, H.; Torabi, S.M.R.; Ranjbar, A.; SeyedSaleh, S.; Sharifzadeh, S.O.; Khan, H.; Ashrafizadeh, M.; et al. Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies. Molecules 2021, 26, 2382. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26082382

AMA Style

Mirzaei S, Hushmandi K, Zabolian A, Saleki H, Torabi SMR, Ranjbar A, SeyedSaleh S, Sharifzadeh SO, Khan H, Ashrafizadeh M, et al. Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies. Molecules. 2021; 26(8):2382. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26082382

Chicago/Turabian Style

Mirzaei, Sepideh, Kiavash Hushmandi, Amirhossein Zabolian, Hossein Saleki, Seyed Mohammad Reza Torabi, Adnan Ranjbar, SeyedHesam SeyedSaleh, Seyed Omid Sharifzadeh, Haroon Khan, Milad Ashrafizadeh, and et al. 2021. "Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies" Molecules 26, no. 8: 2382. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26082382

Article Metrics

Back to TopTop