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Special Issue "New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2019).

Special Issue Editors

Prof. Dr. Chiara Riganti
E-Mail Website
Guest Editor
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Interests: multidrug resistance; immune-resistance; immune-evasion; cancer metabolism
Special Issues and Collections in MDPI journals
Dr. Marialessandra Contino
E-Mail
Guest Editor
Department of Pharmacy, University of Bari, Bari, Italy
Interests: pharmacological and medicinal chemist strategies to reverse multidrug resistance (ABC-transporters related); collateral sensitivity; cannabinoid receptors in cancer
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Up to 70% of solid and hematological tumors are chemoresistant at diagnosis, and/or become resistant during chemotherapy, enveloping a multiple cross-resistance towards drugs unrelated to structure and activity, termed “multidrug resistance” (MDR). In addition to being resistant to chemotherapy, MDR cells are often simultaneously resistant to multiple stresses, such as radiotherapy, hypoxia, and nutrient shortages. Of note, MDR cells are also less recognized by the immune system, because they produce immune-suppressive metabolites and poorly raise an anti-tumor adaptive response by the host immune system in response to chemotherapy or radiotherapy. The reasons of this chemo-immune-resistance rely on the superior ability of MDR cells to adapt to stressing conditions. Metabolic rewiring and epigenetic events, such as the expression of specific miRNAs or ncRNAs, play a key role in such adaptation.

This Special Issue of IJMS will focus on the latest studies dissecting the molecular linkages between chemoresistance and immune-resistance, and on new possible chemo-immune-sensitizer approaches, including radio-chemotherapy or radio-immune-chemo-therapy combinations, metabolic modifiers, and epigenetic modulators.

Dr. Chiara Riganti
Dr. Marialessandra Contino
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multidrug resistance (MDR)
  • stress adaptation
  • immune-resistance
  • immune-evasion
  • cancer cell metabolism
  • cancer epigenetics
  • miRNA
  • non coding RNA
  • radio-chemotherapy
  • radio-immune-chemo-therapy
  • epigenetic modulators

Published Papers (13 papers)

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Editorial

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Editorial
New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer
Int. J. Mol. Sci. 2019, 20(19), 4783; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194783 - 26 Sep 2019
Cited by 7 | Viewed by 862
Abstract
MultiDrug resistance (MDR) is a complex phenomenon responsible for multiple cross-resistance towards structurally unrelated drugs and it characterizes almost 70% of solid and haematological tumours at the diagnosis [...] Full article

Research

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Article
Pyruvate Treatment Restores the Effectiveness of Chemotherapeutic Agents in Human Colon Adenocarcinoma and Pleural Mesothelioma Cells
Int. J. Mol. Sci. 2018, 19(11), 3550; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113550 - 10 Nov 2018
Cited by 5 | Viewed by 1338
Abstract
Emerging evidence supports the idea that a dysfunction in cell metabolism could sustain a resistant phenotype in cancer cells. As the success of chemotherapeutic agents is often questioned by the occurrence of multidrug resistance (MDR), a multiple cross-resistance towards different anti-cancer drugs represent [...] Read more.
Emerging evidence supports the idea that a dysfunction in cell metabolism could sustain a resistant phenotype in cancer cells. As the success of chemotherapeutic agents is often questioned by the occurrence of multidrug resistance (MDR), a multiple cross-resistance towards different anti-cancer drugs represent a major obstacle to cancer treatment. The present study has clarified the involvement of the carbon metabolites in a more aggressive tumor colon adenocarcinoma phenotype and in a chemoresistant mesothelioma, and the role of pyruvate treatment in the reversion of the potentially related resistance. For the first time, we have shown that human colon adenocarcinoma cells (HT29) and its chemoresistant counterpart (HT29-dx) displayed different carbon metabolism: HT29-dx cells had a higher glucose consumption compared to HT29 cells, whereas human malignant mesothelioma (HMM) cells showed a lower glucose consumption compared to HT29 cells, accompanied by a lower pyruvate production and, consequently, a higher production of lactate. When treated with pyruvate, both HT29-dx and HMM cells exhibited a re-established accumulation of doxorubicin and a lower survival ability, a decreased activity of multidrug resistance protein 1 (MRP1) and a restored mitochondrial respiratory chain function, improving the effectiveness of the chemotherapeutic agents in these resistant cancer cells. Full article
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Article
The Novel Autophagy Inhibitor Alpha-Hederin Promoted Paclitaxel Cytotoxicity by Increasing Reactive Oxygen Species Accumulation in Non-Small Cell Lung Cancer Cells
Int. J. Mol. Sci. 2018, 19(10), 3221; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103221 - 18 Oct 2018
Cited by 19 | Viewed by 1850
Abstract
Chemoresistance is a major limiting factor that impairs the outcome of non-small cell lung cancer (NSCLC) chemotherapy. Paclitaxel (Tax) induces protective autophagy in NSCLC cells, leading to the development of drug resistance. We recently identified a new autophagy inhibitor (alpha-hederin) and hypothesized that [...] Read more.
Chemoresistance is a major limiting factor that impairs the outcome of non-small cell lung cancer (NSCLC) chemotherapy. Paclitaxel (Tax) induces protective autophagy in NSCLC cells, leading to the development of drug resistance. We recently identified a new autophagy inhibitor (alpha-hederin) and hypothesized that it may promote the killing effect of Tax on NSCLC cells. We found that alpha-hederin (α-Hed) could block late autophagic flux in NSCLC cells by altering lysosomal pH and inhibiting lysosomal cathepsin D maturation. Combination treatment of α-Hed and Tax synergistically reduced NSCLC cell proliferation and increased NSCLC cell apoptosis compared with treatment with α-Hed or Tax alone. Furthermore, α-Hed plus Tax enhanced the accumulation of intracellular reactive oxygen species (ROS) in NSCLC cells, while the ROS inhibitor N-acetylcysteine reversed the inhibitory effect of the combination treatment. Our findings suggest that α-Hed can increase the killing effect of Tax on NSCLC cells by promoting ROS accumulation, and that combining α-Hed with classical Tax represents a novel strategy for treating NSCLC. Full article
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Article
FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells
Int. J. Mol. Sci. 2018, 19(9), 2697; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092697 - 11 Sep 2018
Cited by 5 | Viewed by 1487
Abstract
Poor response to current treatments for glioblastoma has been attributed to the presence of glioblastoma stem-like cells (GSCs). GSCs are able to expel antitumor drugs to the extracellular medium using the multidrug resistance-associated protein 1 (MRP1) transporter. Tacrolimus (FK506) has been identified as [...] Read more.
Poor response to current treatments for glioblastoma has been attributed to the presence of glioblastoma stem-like cells (GSCs). GSCs are able to expel antitumor drugs to the extracellular medium using the multidrug resistance-associated protein 1 (MRP1) transporter. Tacrolimus (FK506) has been identified as an MRP1 regulator in differentiated glioblastoma (GBM) cells (non-GSCs); however, the effect of FK506 on GSCs is currently unknown. The objective of the following research is to evaluate the effect of FK506 on the MRP1-related chemo-resistant phenotype of GSCs. For this, U87MG and C6 glioma cell lines were used to generate non-GSCs and GSCs. mRNA and MRP1-positive cells were evaluated by RT-qPCR and flow cytometry, respectively. A Carboxyfluorescein Diacetate (CFDA)-retention assay was performed to evaluate the MRP1 activity. Apoptosis and MTT assays were employed to evaluate the cytotoxic effects of FK506 plus Vincristine (MRP1 substrate). GSC-derived subcutaneous tumors were generated to evaluate the in vivo effect of FK506/Vincristine treatment. No differences in transcript levels and positive cells for MRP1 were observed in FK506-treated cells. Lesser cell viability, increased apoptosis, and CFDA-retention in the FK506/Vincristine-treated cells were observed. In vivo, the FK506/Vincristine treatment decreased the tumor size as well as ki67, Glial Fibrillary Acidic Protein (GFAP), and nestin expression. We conclude that FK506 confers a chemo-sensitive phenotype to MRP1-drug substrate in GSCs. Full article
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Article
Differential Expression and Pathway Analysis in Drug-Resistant Triple-Negative Breast Cancer Cell Lines Using RNASeq Analysis
Int. J. Mol. Sci. 2018, 19(6), 1810; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061810 - 19 Jun 2018
Cited by 13 | Viewed by 3851
Abstract
Triple-negative breast cancer (TNBC) is among the most notorious types of breast cancer, the treatment of which does not give consistent results due to the absence of the three receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 [...] Read more.
Triple-negative breast cancer (TNBC) is among the most notorious types of breast cancer, the treatment of which does not give consistent results due to the absence of the three receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as well as high amount of molecular variability. Drug resistance also contributes to treatment unresponsiveness. We studied differentially expressed genes, their biological roles, as well as pathways from RNA-Seq datasets of two different TNBC drug-resistant cell lines of Basal B subtype SUM159 and MDA-MB-231 treated with drugs JQ1 and Dexamethasone, respectively, to elucidate the mechanism of drug resistance. RNA sequencing(RNA-Seq) data analysis was done using edgeR which is an efficient program for determining the most significant Differentially Expressed Genes (DEGs), Gene Ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. iPathway analysis was further used to obtain validated results using analysis that takes into consideration type, function, and interactions of genes in the pathway. The significant similarities and differences throw light into the molecular heterogeneity of TNBC, giving clues into the aspects that can be focused to overcome drug resistance. From this study, cytokine-cytokine receptor interaction pathway appeared to be a key factor in TNBC drug resistance. Full article
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Review

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Review
Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?
Int. J. Mol. Sci. 2019, 20(7), 1776; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20071776 - 10 Apr 2019
Cited by 13 | Viewed by 1585
Abstract
Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the [...] Read more.
Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-κB signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies. Full article
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Review
Targeting Cancer Stem Cells to Overcome Chemoresistance
Int. J. Mol. Sci. 2018, 19(12), 4036; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19124036 - 13 Dec 2018
Cited by 41 | Viewed by 2723
Abstract
Cancers are heterogeneous at the cell level, and the mechanisms leading to cancer heterogeneity could be clonal evolution or cancer stem cells. Cancer stem cells are resistant to most anti-cancer treatments and could be preferential targets to reverse this resistance, either targeting stemness [...] Read more.
Cancers are heterogeneous at the cell level, and the mechanisms leading to cancer heterogeneity could be clonal evolution or cancer stem cells. Cancer stem cells are resistant to most anti-cancer treatments and could be preferential targets to reverse this resistance, either targeting stemness pathways or cancer stem cell surface markers. Gold nanoparticles have emerged as innovative tools, particularly for photo-thermal therapy since they can be excited by laser to induce hyperthermia. Gold nanoparticles can be functionalized with antibodies to specifically target cancer stem cells. Preclinical studies using photo-thermal therapy have demonstrated the feasibility of targeting chemo-resistant cancer cells to reverse clinical chemoresistance. Here, we review the data linking cancer stem cells and chemoresistance and discuss the way to target them to reverse resistance. We particularly focus on the use of functionalized gold nanoparticles in the treatment of chemo-resistant metastatic cancers. Full article
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Review
Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy
Int. J. Mol. Sci. 2018, 19(12), 3950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123950 - 08 Dec 2018
Cited by 36 | Viewed by 2293
Abstract
Abstract: According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. The identification of novel targets for cancer treatment is an area of intense work that has led Bcl-2 over-expression to be proposed as one of the [...] Read more.
Abstract: According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. The identification of novel targets for cancer treatment is an area of intense work that has led Bcl-2 over-expression to be proposed as one of the hallmarks of cancer and Bcl-2 inhibition as a promising strategy for cancer treatment. In this review, we describe the different pathways related to programmed cell death, the role of Bcl-2 family members in apoptosis resistance to anti-cancer treatments, and the potential utility of Bcl-2 inhibitors to overcome resistance to chemo- and immunotherapy. Full article
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Review
Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma
Int. J. Mol. Sci. 2018, 19(12), 3798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123798 - 29 Nov 2018
Cited by 11 | Viewed by 1751
Abstract
Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and [...] Read more.
Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality. Full article
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Review
Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors
Int. J. Mol. Sci. 2018, 19(12), 3785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123785 - 28 Nov 2018
Cited by 31 | Viewed by 1698
Abstract
Multifunctional enzymes glutathione transferases (GSTs) are involved in the development of chemoresistance, thus representing a promising target for a novel approach in cancer treatment. This superfamily of polymorphic enzymes exhibits extraordinary substrate promiscuity responsible for detoxification of numerous conventional chemotherapeutics, at the same [...] Read more.
Multifunctional enzymes glutathione transferases (GSTs) are involved in the development of chemoresistance, thus representing a promising target for a novel approach in cancer treatment. This superfamily of polymorphic enzymes exhibits extraordinary substrate promiscuity responsible for detoxification of numerous conventional chemotherapeutics, at the same time regulating signaling pathways involved in cell proliferation and apoptosis. In addition to upregulated GST expression, different cancer cell types have a unique GST signature, enabling targeted selectivity for isoenzyme specific inhibitors and pro-drugs. As a result of extensive research, certain GST inhibitors are already tested in clinical trials. Catalytic properties of GST isoenzymes are also exploited in bio-activation of specific pro-drugs, enabling their targeted accumulation in cancer cells with upregulated expression of the appropriate GST isoenzyme. Moreover, the latest approach to increase specificity in treatment of solid tumors is development of GST pro-drugs that are derivatives of conventional anti-cancer drugs. A future perspective is based on the design of new drugs, which would selectively target GST overexpressing cancers more prone to developing chemoresistance, while decreasing side effects in off-target cells. Full article
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Review
From Friend to Enemy: Dissecting the Functional Alteration of Immunoregulatory Components during Pancreatic Tumorigenesis
Int. J. Mol. Sci. 2018, 19(11), 3584; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113584 - 13 Nov 2018
Cited by 6 | Viewed by 1342
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of approximately 8%. More than 80% of patients are diagnosed at an unresectable stage due to metastases or local extension. Immune system reactivation in patients by immunotherapy may eliminate tumor [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of approximately 8%. More than 80% of patients are diagnosed at an unresectable stage due to metastases or local extension. Immune system reactivation in patients by immunotherapy may eliminate tumor cells and is a new strategy for cancer treatment. The anti-CTLA-4 antibody ipilimumab and anti-PD-1 antibodies pembrolizumab and nivolumab have been approved for cancer therapy in different countries. However, the results of immunotherapy on PDAC are unsatisfactory. The low response rate may be due to poor immunogenicity with low tumor mutational burden in pancreatic cancer cells and desmoplasia that prevents the accumulation of immune cells in tumors. The immunosuppressive tumor microenvironment in PDAC is important in tumor progression and treatment resistance. Switching from an immune tolerance to immune activation status is crucial to overcome the inability of self-defense in cancer. Therefore, thoroughly elucidation of the roles of various immune-related factors, tumor microenvironment, and tumor cells in the development of PDAC may provide appropriate direction to target inflammatory pathway activation as a new therapeutic strategy for preventing and treating this cancer. Full article
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Review
Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance
Int. J. Mol. Sci. 2018, 19(6), 1765; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061765 - 14 Jun 2018
Cited by 19 | Viewed by 1865
Abstract
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis (the median survival is 14 months), GBMs demonstrate a resounding resilience against all current treatment modalities. The absence of a major progress in the [...] Read more.
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis (the median survival is 14 months), GBMs demonstrate a resounding resilience against all current treatment modalities. The absence of a major progress in the treatment of GBM maybe a result of our poor understanding of both GBM tumor biology and the mechanisms underlying the acquirement of treatment resistance in recurrent GBMs. A comprehensive understanding of these markers is mandatory for the development of treatments against therapy-resistant GBMs. This review also provides an overview of a novel marker called acid ceramidase and its implication in the development of radioresistant GBMs. Multiple signaling pathways were found altered in radioresistant GBMs. Given these global alterations of multiple signaling pathways found in radioresistant GBMs, an effective treatment for radioresistant GBMs may require a cocktail containing multiple agents targeting multiple cancer-inducing pathways in order to have a chance to make a substantial impact on improving the overall GBM survival. Full article
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Review
Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells
Int. J. Mol. Sci. 2018, 19(6), 1690; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061690 - 06 Jun 2018
Cited by 40 | Viewed by 4058
Abstract
Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed [...] Read more.
Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment. Full article
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