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14 pages, 2596 KiB

Open AccessArticle

Mebendazole Impedes the Proliferation and Migration of Pancreatic Cancer Cells through SK1 Inhibition Dependent Pathway

by Khem Raj Limbu, Rashmi Bhandari Chhetri, Yoon Sin Oh, Dong Jae Baek and Eun-Young Park

Molecules 2022, 27(23), 8127; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27238127 - 22 Nov 2022

Cited by 2 | Viewed by 2036

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates and requires the development of highly efficacious medications that can improve the efficiency of existing treatment methods. In particular, in PDAC, resistance to conventional chemotherapy reduces the effectiveness of anticancer drugs, decreasing [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates and requires the development of highly efficacious medications that can improve the efficiency of existing treatment methods. In particular, in PDAC, resistance to conventional chemotherapy reduces the effectiveness of anticancer drugs, decreasing the therapeutic efficiency. Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SK), plays a vital role in cancer growth, metastasis, chemotherapy, and drug resistance. Focusing on the structural characteristics of mebendazole (MBZ), we studied whether MBZ would affect metastasis, invasion, and drug resistance in cancer by lowering S1P production through inhibition of SK activity. MBZ selectively inhibited SK1 more than SK2 and regulated the levels of sphingolipids. MBZ inhibited the proliferation and migration of cancer cells in other PDAC cell lines. To determine whether the effect of MBZ on cancer cell growth and migration is S1P-mediated, S1P was treated, and the growth and migration of cancer cells were observed. It was found that MBZ inhibited S1P-induced cancer cell growth, and MBZ showed a growth inhibitory effect by regulating the JAK2/STAT3/Bcl-2 pathway. The phosphorylation of focal adhesion kinase (FAK), a transcription factor that regulates migration, was inhibited by MBZ, so it was found that the effect of MBZ regulates the migration of cancer cells through the S1P/FAK/vimentin pathway. In conclusion, our study suggests that the anthelmintic MBZ can be used as a potential therapeutic agent for treating PDAC and for structural synthesis studies of its analogs. Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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14 pages, 6462 KiB

Open AccessArticle

2,4-Dinitrophenol as an Uncoupler Augments the Anthracyclines Toxicity against Prostate Cancer Cells

by Grzegorz Adamczuk, Ewelina Humeniuk, Kamila Adamczuk, Aneta Grabarska and Jarosław Dudka

Molecules 2022, 27(21), 7227; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27217227 - 25 Oct 2022

Cited by 3 | Viewed by 1726

Abstract

One of the strategies for the treatment of advanced cancer diseases is targeting the energy metabolism of the cancer cells. The compound 2,4-DNP (2,4-dinitrophenol) disrupts the cell energy metabolism through the ability to decouple oxidative phosphorylation. The aim of the study was to [...] Read more.

One of the strategies for the treatment of advanced cancer diseases is targeting the energy metabolism of the cancer cells. The compound 2,4-DNP (2,4-dinitrophenol) disrupts the cell energy metabolism through the ability to decouple oxidative phosphorylation. The aim of the study was to determine the ability of 2,4-DNP to sensitize prostate cancer cells with different metabolic phenotypes to the action of known anthracyclines (doxorubicin and epirubicin). The synergistic effect of the anthracyclines and 2,4-DNP was determined using an MTT assay, apoptosis detection and a cell cycle analysis. The present of oxidative stress in cancer cells was assessed by CellROX, the level of cellular thiols and DNA oxidative damage. The study revealed that the incubation of LNCaP prostate cancer cells (oxidative phenotype) with epirubicin and doxorubicin simultaneously with 2,4-DNP showed the presence of a synergistic effect for both the cytostatics. Moreover, it contributes to the increased induction of oxidative stress, which results in a reduced level of cellular thiols and an increased number of AP sites in the DNA. The synergistic activity may consist of an inhibition of ATP synthesis and the simultaneous production of toxic amounts of ROS, destroying the mitochondria. Additionally, the sensitivity of the LNCaP cell line to the anthracyclines is relatively higher compared to the other two (PC-3, DU-145). Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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17 pages, 2107 KiB

Open AccessArticle

Antiproliferative Ruthenium Complexes Containing Curcuminoid Ligands Tested In Vitro on Human Ovarian Tumor Cell Line A2780, towards Their Capability to Modulate the NF-κBTranscription Factor, FGF-2 Growth Factor, and MMP-9 Pathway

by Janka Leskovská, Natalia Miklášová, Paul Milan Kubelac, Patriciu Achimaş-Cadariu, Jindra Valentová, Mário Markuliak and Eva Fischer-Fodor

Molecules 2022, 27(14), 4565; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27144565 - 18 Jul 2022

Cited by 3 | Viewed by 2144

Abstract

So far, the polyphenolic components of turmeric have shown a significant pharmacological preventative activity for a wide spectrum of diseases, including oncological disorders. This type of natural product could be of great interest for the inhibition of cancer cell proliferation, displaying less side [...] Read more.

So far, the polyphenolic components of turmeric have shown a significant pharmacological preventative activity for a wide spectrum of diseases, including oncological disorders. This type of natural product could be of great interest for the inhibition of cancer cell proliferation, displaying less side effects in comparison to classical chemotherapeutics. The poor bioavailability and quick metabolism of such natural compounds require new investigative methods to improve their stability in the organisms. A synthetic approach to increase the efficiency of curcuminoids is to coordinate them to metals through the beta-dicarbonyl moiety. We report the synthesis and the biological attempts on human ovarian carcinoma A2780 of ruthenium(II) complexes 1–4, containing curcuminoid ligands. The cytotoxicity of complexes 1–4 proves their antiproliferative capability, and a correlation between the IC₅₀ values and NF-κB transcription factor, FGF-2, and MMP-9 levels was figured out through the principal component analysis (PCA). Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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12 pages, 1475 KiB

Open AccessArticle

In Vivo Evaluation of (−)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site

by Leila Takahashi-Ruiz, Joseph D. Morris, Phillip Crews, Tyler A. Johnson and April L. Risinger

Molecules 2022, 27(13), 4244; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27134244 - 01 Jul 2022

Cited by 3 | Viewed by 2061

Abstract

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however [...] Read more.

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (−)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (−)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (−)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms. Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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16 pages, 3352 KiB

Open AccessArticle

5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT, and ERK Activity

by Wan-Chi Tsai, Wen-Hung Wang, Bo-Cian Huang, Chiung-Yao Huang and Jyh-Horng Sheu

Molecules 2021, 26(22), 6932; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26226932 - 17 Nov 2021

Cited by 7 | Viewed by 1665

Abstract

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been [...] Read more.

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been demonstrated to possess cytotoxic activity against cancer cells. However, the cytotoxicity against pancreatic cancer cells and the related mechanisms are unknown. The aim of this study was to evaluate the anti-pancreatic cancer potential of 5-epi-sinuleptolide and to elucidate the underlying mechanisms. The inhibitory effects of 5-epi-sinuleptolide treatment on the proliferation of pancreatic cancer cells were determined and the results showed that 5-epi-sinuleptolide treatment inhibited cell proliferation, induced apoptosis and G2/M cell cycle arrest, and suppressed the invasion of pancreatic cancer cells. The results of western blotting further revealed that 5-epi-sinuleptolide could inhibit JAK2/STAT3, AKT, and ERK phosphorylation, which may account for the diverse cytotoxic effects of 5-epi-sinuleptolide. Taken together, our present investigation unveils a new therapeutic and anti-metastatic potential of 5-epi-sinuleptolide for pancreatic cancer treatment. Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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Review

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31 pages, 14211 KiB

Open AccessReview

Bimetallic Nanomaterials: A Promising Nanoplatform for Multimodal Cancer Therapy

by Guiming Niu, Fucheng Gao, Yandong Wang, Jie Zhang, Li Zhao and Yanyan Jiang

Molecules 2022, 27(24), 8712; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27248712 - 09 Dec 2022

Cited by 3 | Viewed by 1692

Abstract

Bimetallic nanomaterials (BMNs) composed of two different metal elements have certain mixing patterns and geometric structures, and they often have superior properties than monometallic nanomaterials. Bimetallic-based nanomaterials have been widely investigated and extensively used in many biomedical fields especially cancer therapy because of [...] Read more.

Bimetallic nanomaterials (BMNs) composed of two different metal elements have certain mixing patterns and geometric structures, and they often have superior properties than monometallic nanomaterials. Bimetallic-based nanomaterials have been widely investigated and extensively used in many biomedical fields especially cancer therapy because of their unique morphology and structure, special physicochemical properties, excellent biocompatibility, and synergistic effect. However, most reviews focused on the application of BMNs in cancer diagnoses (sensing, and imaging) and rarely mentioned the application of the treatment of cancer. The purpose of this review is to provide a comprehensive perspective on the recent progress of BNMs as therapeutic agents. We first introduce and discuss the synthesis methods, intrinsic properties (size, morphology, and structure), and optical and catalytic properties relevant to cancer therapy. Then, we highlight the application of BMNs in cancer therapy (e.g., drug/gene delivery, radiotherapy, photothermal therapy, photodynamic therapy, enzyme-mediated tumor therapy, and multifunctional synergistic therapy). Finally, we put forward insights for the forthcoming in order to make more comprehensive use of BMNs and improve the medical system of cancer treatment. Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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19 pages, 1596 KiB

Open AccessReview

A Mini Review on Molecules Inducing Caspase-Independent Cell Death: A New Route to Cancer Therapy

by Kakali Bhadra

Molecules 2022, 27(19), 6401; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27196401 - 28 Sep 2022

Cited by 14 | Viewed by 3590

Abstract

Most anticancer treatments trigger tumor cell death through apoptosis, where initiation of proteolytic action of caspase protein is a basic need. But under certain circumstances, apoptosis is prevented by the apoptosis inhibitor proteins, survivin and Hsp70. Several drugs focusing on classical programmed death [...] Read more.

Most anticancer treatments trigger tumor cell death through apoptosis, where initiation of proteolytic action of caspase protein is a basic need. But under certain circumstances, apoptosis is prevented by the apoptosis inhibitor proteins, survivin and Hsp70. Several drugs focusing on classical programmed death of the cell have been reported to have low anti-tumorogenic potency due to mutations in proteins involved in the caspase-dependent programmed cell death with intrinsic and extrinsic pathways. This review concentrates on the role of anti-cancer drug molecules targeting alternative pathways of cancer cell death for treatment, by providing a molecular basis for the new strategies of novel anti-cancer treatment. Under these conditions, active agents targeting alternative cell death pathways can be considered as potent chemotherapeutic drugs. Many natural compounds and other small molecules, such as inorganic and synthetic compounds, including several repurposing drugs, are reported to cause caspase-independent cell death in the system. However, few molecules indicated both caspase-dependent as well caspase-free cell death in specific cancer lines. Cancer cells have alternative methods of caspase-independent programmed cell death which are equally promising for being targeted by small molecules. These small molecules may be useful leads for rational therapeutic drug design, and can be of potential interest for future cancer-preventive strategies. Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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34 pages, 10201 KiB

Open AccessReview

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer

by Muhammad Naeem, Muhammad Omer Iqbal, Humaira Khan, Muhammad Masood Ahmed, Muhammad Farooq, Muhammad Moeen Aadil, Mohamad Ikhwan Jamaludin, Abu Hazafa and Wan-Chi Tsai

Molecules 2022, 27(11), 3412; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27113412 - 25 May 2022

Cited by 9 | Viewed by 3654

Abstract

Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, [...] Read more.

Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current challenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their efficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations. Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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18 pages, 1465 KiB

Open AccessReview

The Regulation of Endoplasmic Reticulum Stress in Cancer: Special Focuses on Luteolin Patents

by Roohi Mohi-ud-din, Reyaz Hassan Mir, Taha Umair Wani, Khalaf F. Alsharif, Waqas Alam, Ashraf Albrakati, Luciano Saso and Haroon Khan

Molecules 2022, 27(8), 2471; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27082471 - 12 Apr 2022

Cited by 6 | Viewed by 2546

Abstract

Cancer is a major health problem across the globe, and is expeditiously growing at a faster rate worldwide. The endoplasmic reticulum (ER) is a membranous cell organelle having inextricable links in cellular homeostasis. Altering ER homeostasis initiates various signaling events known as the [...] Read more.

Cancer is a major health problem across the globe, and is expeditiously growing at a faster rate worldwide. The endoplasmic reticulum (ER) is a membranous cell organelle having inextricable links in cellular homeostasis. Altering ER homeostasis initiates various signaling events known as the unfolded protein response (UPR). The basic purpose of the UPR is to reinstate the homeostasis; however, a continuous UPR can stimulate pathways of cell death, such as apoptosis. As a result, there is great perturbation to target particular signaling pathways of ER stress. Flavonoids have gained significant interest as a potential anticancer agent because of their considerable role in causing cytotoxicity of the cancerous cells. Luteolin, a flavonoid isolated from natural products, is a promising phytochemical used in the treatment of cancer. The current study is designed to review the different endoplasmic reticulum stress pathways involved in the cancer, mechanistic insights of luteolin as an anticancer agent in modulating ER stress, and the available luteolin patent formulations were also highlighted. The patents were selected on the basis of pre-clinical and/or clinical trials, and established antitumor effects using patent databases of FPO IP and Espacenet. The patented formulation of luteolin studied so far has shown promising anticancer potential against different cancer cell lines. However, further research is still required to determine the molecular targets of such bioactive molecules so that they can be used as anticancer drugs. Full article

(This article belongs to the Special Issue Natural Compounds and Chemical Compounds in Cancer Treatment)

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