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Resistance to Anticancer Agents: Recent Trends

Ahmed M. Kabel , Maaly A. Abd Elmaaboud
Journal of Cancer Research and Treatment. 2020, 8(2), 11-14. DOI: 10.12691/jcrt-8-2-1
Received April 24, 2020; Revised May 26, 2020; Accepted June 02, 2020

Abstract

Resistance to the anticancer agents is a complex process that mainly results from alteration in the targets of the chemotherapeutic agents. Mechanisms that underlie resistance to the anticancer agents include inactivation of the drug, inhibition of cellular apoptosis, changes in the metabolic pathways of the drug, increased expression of the efflux proteins and enhancement of DNA repair and gene amplification. Several strategies were developed to overcome this resistance. The use of the combination chemotherapy is the best option for drug resistant types of cancer. This review throws light on resistance of cancer cells to the chemotherapeutic agents in view of the recent trends.

1. Introduction

Cancer is a group of disorders characterized by loss of control on cell growth and differentiation 1. The anticancer drugs act by different mechanisms that regulate different phases of cell cycle leading to inhibition of growth of cancer cells. However, development of drug resistance by cancer cells is the main cause of failure of cancer therapy 2. Drug resistance is a phenomenon that occurs when a disease becomes tolerant to pharmaceutical treatments. Resistance to chemotherapeutic agents occurs when cancer cells develop molecular alterations that make them insensitive to a certain drug. In some instances, cancer cells may adapt to the drug while it is being administered, acquiring molecular changes that render them resistant to its effects 3.

There are many mechanisms that promote resistance of cancer cells to chemotherapy, including interference with drug penetration, activation of the efflux mechanisms, drug inactivation, mutations in the target proteins, decreased the affinity for the drug, development of alternative biochemical pathways, DNA damage repair, inhibition of cell death, and the epithelial-mesenchymal transition 2. The increased prevalence of multi-drug resistant cancers necessitates exploration of the possible mechanisms and searching for ways of overcoming of this resistance 4. The aim of this review is to throw light on resistance of cancer cells to the chemotherapeutic agents in view of the recent trends regarding its prevalence, etiology, mechanisms, diagnosis and possible lines of management.

2. Etiology of Resistance to the Anticancer Drugs

2.1. Decreased Absorption of the Drugs

Absorption of the anticancer drugs into cancer cells occurs either by passive transfer, facilitated diffusion or activate transport 2. The anticancer agents enter the cells along the concentration gradient by ABC transporter molecules. Cancer cells may decrease absorption of the anticancer drugs by reducing the tendency to binding of the drugs to these transporters, decreasing the numbers of the transporters or by mutation of the transporters themselves 5. For example, resistance of cancer cells to methotrexate may be mediated via mutation in the human folate carrier's gene in patients with acute lymphoblastic leukemia 6.

2.2. Increased Release of the Anticancer Drugs outside the Cells

ATP-binding cassette (ABC) transporters are ATP-dependent transporters that are involved in the transport of the nutrients and other molecules across the cell membrane 7. The ABC family has three members, including P-glycoprotein, multi-drug Resistance-associated Protein 1 and breast cancer resistance proteins. P-glycoprotein is a multidrug membrane transporter that normally can bind to a wide range of chemotherapeutic agents 8. When these agents bind to P-glycoprotein, ATP is hydrolyzed and the structure of P-glycoprotein is altered leading to extrusion of the drug to the extracellular space. This is the mechanism responsible for resistance of cancer cells to doxorubicin, taxanes and vinblastine 2.

2.3. Inactivation of the Anticancer Agents

Cancer cells may become resistant to the anticancer drugs by reducing the activity of these drugs 9. For example, cytarabine which is used for treatment of acute myeloid leukemia needs multiple phosphorylations to be converted to cytarabine triphosphate which has high toxicity to cancer cells. Mutations in the proteins and enzymes that are involved in these phosphorylation reactions decrease the activity of cytarabine in cancer treatment 10. Another example of inhibition of the activity of anti-cancer drugs is glutathione S-transferase enzyme which increases resistance of cancer cells to chemotherapy by detoxification of the anti-cancer agents 11. Increased expression of glutathione S-transferase in cancer cells reduces the cytotoxic effect of a wide range of the anticancer drugs and increases resistance of cancer cells to apoptosis 12.

2.4. Inhibition of Apoptosis

Apoptosis is an important cellular event that regulates cell death. Several proteins are involved in the intrinsic and extrinsic pathways of apoptosis including B-cell lymphoma 2 (BCL-2) family proteins, caspase-3, caspase-9 and Akt 13. It was observed that in multi-drug resistant cancers, there was increased expression of the antiapoptotic proteins such as BCL-2 and Akt and increased activity of the down-stream transcription modulators such as nuclear factor kappa B 14. Moreover, the cancer cells may decrease the expression of c-Jun N-terminal kinases (JNK) with subsequent inhibition of apoptosis, which is frequently encountered in resistance to cisplatin 15.

2.5. Alteration of Metabolism of the Anticancer Drugs

Enzymatic metabolism of the anticancer agents is responsible for determination of the effective drug concentration inside cancer cells 2. Cytochrome P450 enzyme system is one of the enzymes responsible for phase I metabolism of some anticancer drugs. Cases of breast cancer resistant to docetaxel may be associated with increased activity of cytochrome P450 leading to docetaxel inactivation 16. Also, resistance of cancer cells to alkylating agents may be attributed to increased activity of the enzymes responsible for phase II reactions leading to loss of the electrophilic toxicity of these agents 17.

2.6. Alteration of Drug Targets

Mutations or modifications of the expression levels of the molecular targets of the drug have a direct influence on its efficacy 2. For example, topoisomerase II, which is an enzyme that prevents DNA from super- or under-coiling, represents an important target for some anticancer agents 18. The anticancer drugs stabilize the interaction between DNA and topoisomerase II resulting in serious DNA damage, inhibition of DNA replication, and arrest of mitosis. Cancer cells may show resistance to these anticancer agents through mutations in the expression of topoisomerase II gene 19.

2.7. DNA Damage Repair

Most chemotherapeutic agents may directly or indirectly damage DNA resulting in death of cancer cells 20. However, some cancer cells may develop DNA damage response mechanisms rendering these cells resistant to chemotherapy 21. For example, resistance of cancer cells to platinum-containing cytotoxic drugs often develop due to activation of DNA repair mechanisms such as homologous recombination and nucleotide excision repair. Inhibition of these repair mechanisms by combination chemotherapy often sensitizes cancer cells to the cytotoxic effects of the chemotherapeutic agents 22.

2.8. Epithelial-mesenchymal Transition and Metastasis

Epithelial to mesenchymal transition (EMT) is a mechanism that facilitates spread of solid tumors and formation of distant metastasis. This process involves the occurrence of changes in the cancer epithelial cells and the stromal cells associated with angiogenesis 23. During EMT, cancer cells increase the expression of cell adhesion receptors that enhance cell motility and decrease cell-to-cell attachment. Also, there is increased expression of metalloproteases on the tumor surface which facilitate cell motility and promote metastasis 24. Resistance of cancer cells to chemotherapeutic agents may develop during the signaling processes of differentiation, which are essential for EMT 2. For example, cases with refractory colon cancer were associated with increased expression of transforming growth factor β (TGF-β) which is required for EMT rendering them resistant to chemotherapy 25.

2.9. Gene Amplification

Gene amplification means increase in the numbers of target genes in some cancer cells especially in cases of leukemia and lymphoma 26. For example, resistance to methotrexate in some types of leukemia is mediated via providing multiple copies of the dihydrofolate reductase gene which target the site of action of methotrexate. This confers massive resistance to methotrexate making it even entirely ineffective on cancer cells 27.

2.10. Epigenetic Alteration

Epigenetic alteration is a heritable change that does not affect the DNA sequence but results in a change in gene expression 28. The mechanisms of epigenetic alterations include DNA methylation and alteration of histones. These mechanisms lead to alteration of the structure and composition of chromatin which in turn will affect the gene expression 29. For example, DNA methylation decreases the expression of the tumor suppressor genes associated with increased expression of the oncogenes 30. Also, the epigenetic alteration may affect the DNA repair mechanisms which may antagonize the effects of a wide variety of the anticancer drugs on DNA 2. Demethylation of the promoter oncogenes and recovery of the mismatch repair mechanisms causes the cells of colorectal cancer to be sensitive to fluorouracil. Accordingly, the combination of epigenetic and conventional chemotherapeutic agents are effective in treatment of resistant malignancies 31.

3. The Effects of Resistance to the Anticancer Drugs

Resistance to anticancer drugs represents a major impediment in medical oncology. This resistance may appear prior to or as a result of cancer therapy 2. The most important complication of drug resistance is that development of resistance to one drug may lead to resistance to other drugs 32. For example, loss of a drug transporter may lead to resistance to other compounds that utilize it. Also, elevation of ABC transporters resulting from one drug may have a direct impact on the efficacy of many other compounds 33. An additional obstacle is that resistance of cancer cells to a certain chemotherapeutic agent may necessitate increase in the dose of this agent which may have serious adverse effects on the normal tissues and organs 2. Furthermore, the presence of similarities between drug-resistant and metastatic cancer cells in terms of resistance to apoptosis may increase the morbidity and mortality rates 34.

4. Diagnosis of Resistance to the Anticancer Drugs

Drug resistance represents a major problem that is responsible for failure of chemotherapy to cure the majority of cancer patients 4. About 50% of patients with cancer have resistance to chemotherapeutic agents even before starting drug therapy and about 50% of the remaining cases may develop resistance during the course of treatment 35. All efforts to overcome resistance to chemotherapy should focus on early diagnosis of this resistance to plan effective measures to overcome this resistance. There are numerous methods for diagnosis of anticancer drug resistance including cancer biomarker tests, fresh tumor cell culture assays, and positron emission tomography tests 36.

5. Management of Resistance to the Anticancer Drugs

The use of combination chemotherapy represents the most effective measure to overcome cancer drug resistance 37. The rationale for combination chemotherapy is to use drugs that act by different mechanisms, thereby reducing the possibility of development of resistant cancer cells 38. For some types of cancers, the best strategy of management is a combination of surgery, radiotherapy and chemotherapy. Radiation therapy or chemotherapy may be given before surgery to decrease the size of the tumor, thereby increasing the possibility of complete surgical removal. Radiation therapy and low-dose chemotherapy may be used after surgery to destroy any remaining cancer cells and reduce the possibility of recurrence 39. Combination chemotherapy may be a valuable option for patients with advanced carcinoma that are not fit for surgery or radiation therapy 40.

6. Conclusion

Cancer cells with a high proliferation rate are genetically unstable, making them potential candidates to develop resistance to anticancer agents. The cancer drug resistance is a complex phenomenon that involves a wide range of different pathophysiologic mechanisms. Therefore, the combination therapy is the best option for refractory types of cancer. Further research is vitally needed to discover promising strategies for amelioration of this serious medical problem.

Conflict of Interest

The authors had no conflict of interest to declare.

References

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In article      
 
[2]  Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull 2017; 7(3): 339-348.
In article      View Article  PubMed
 
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In article      View Article  PubMed
 
[4]  Assaraf YG, Brozovic A, Gonçalves AC, Jurkovicova D, Line A, Machuqueiro M, et al. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist Updat 2019; 46: 100645.
In article      View Article  PubMed
 
[5]  Alfarouk KO, Stock CM, Taylor S, et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int 2015; 15:71.
In article      View Article  PubMed
 
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In article      View Article  PubMed
 
[7]  Xiong J, Feng J, Yuan D, Zhou J, Miao W. Tracing the structural evolution of eukaryotic ATP binding cassette transporter superfamily. Sci Rep 2015; 5: 16724.
In article      View Article  PubMed
 
[8]  Kabel AM, Atef A, Estfanous RS. Ameliorative potential of sitagliptin and/or resveratrol on experimentally-induced clear cell renal cell carcinoma. Biomed Pharmacother 2018; 97: 667-674.
In article      View Article  PubMed
 
[9]  Senapati S, Mahanta AK, Kumar S, Maiti P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduct Target Ther 2018;3:7.
In article      View Article  PubMed
 
[10]  Levin M, Stark M, Berman B, Assaraf YG. Surmounting Cytarabine-resistance in acute myeloblastic leukemia cells and specimens with a synergistic combination of hydroxyurea and azidothymidine. Cell Death Dis 2019; 10(6): 390.
In article      View Article  PubMed
 
[11]  Dong SC, Sha HH, Xu XY, et al. Glutathione S-transferase π: a potential role in antitumor therapy. Drug Des Devel Ther 2018; 12: 3535-3547.
In article      View Article  PubMed
 
[12]  Pljesa-Ercegovac M, Savic-Radojevic A, Matic M, et al. Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors. Int J Mol Sci 2018; 19(12): 3785.
In article      View Article  PubMed
 
[13]  Rathore R, McCallum JE, Varghese E, Florea AM, Büsselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis 2017; 22(7): 898-919.
In article      View Article  PubMed
 
[14]  García-Aranda M, Pérez-Ruiz E, Redondo M. Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy. Int J Mol Sci 2018; 19(12): 3950.
In article      View Article  PubMed
 
[15]  Dou Y, Jiang X, Xie H, He J, Xiao S. The Jun N-terminal kinases signaling pathway plays a "seesaw" role in ovarian carcinoma: a molecular aspect. J Ovarian Res 2019; 12(1): 99.
In article      View Article  PubMed
 
[16]  van Eijk M, Boosman RJ, Schinkel AH, Huitema ADR, Beijnen JH. Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes. Cancer Chemother Pharmacol 2019; 84(3): 487-499.
In article      View Article  PubMed
 
[17]  Rahman M, Hasan MR. Cancer Metabolism and Drug Resistance. Metabolites 2015; 5(4): 571-600.
In article      View Article  PubMed
 
[18]  Delgado JL, Hsieh CM, Chan NL, Hiasa H. Topoisomerases as anticancer targets. Biochem J 2018; 475(2): 373-398.
In article      View Article  PubMed
 
[19]  Shagisultanova EI, Piao Z, Li HR, Malkhosyan SR. Topoisomerase II gene mutations in tumors and tumor cell lines with microsatellite instability. Cancer Lett 2004; 216(2): 221-226.
In article      View Article  PubMed
 
[20]  Davalli P, Marverti G, Lauriola A, D'Arca D. Targeting Oxidatively Induced DNA Damage Response in Cancer: Opportunities for Novel Cancer Therapies. Oxid Med Cell Longev 2018; 2018: 2389523.
In article      View Article  PubMed
 
[21]  Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med 2015; 66: 129-143.
In article      View Article  PubMed
 
[22]  Damia G, Broggini M. Platinum Resistance in Ovarian Cancer: Role of DNA Repair. Cancers (Basel) 2019; 11(1): 119.
In article      View Article  PubMed
 
[23]  Lambert AW, Pattabiraman DR, Weinberg RA. Emerging Biological Principles of Metastasis. Cell 2017; 168(4): 670-691.
In article      View Article  PubMed
 
[24]  Yuan S, Lin LS, Gan RH, et al. Elevated matrix metalloproteinase 7 expression promotes the proliferation, motility and metastasis of tongue squamous cell carcinoma. BMC Cancer 2020; 20(1): 33.
In article      View Article  PubMed
 
[25]  Itatani Y, Kawada K, Sakai Y. Transforming Growth Factor-β Signaling Pathway in Colorectal Cancer and Its Tumor Microenvironment. Int J Mol Sci 2019; 20(23): 5822.
In article      View Article  PubMed
 
[26]  Bagci O, Kurtgöz S. Amplification of Cellular Oncogenes in Solid Tumors. N Am J Med Sci 2015; 7(8): 341-346.
In article      View Article  PubMed
 
[27]  Göker E, Waltham M, Kheradpour A, Trippett T, Mazumdar M, Elisseyeff Y, et al. Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 1995; 86(2): 677-684.
In article      View Article  PubMed
 
[28]  Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation 2011; 123(19): 2145-2156.
In article      View Article  PubMed
 
[29]  Miller JL, Grant PA. The role of DNA methylation and histone modifications in transcriptional regulation in humans. Subcell Biochem 2013; 61: 289-317.
In article      View Article  PubMed
 
[30]  Llinàs-Arias P, Esteller M. Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: an update. Open Biol 2017; 7(9):170152.
In article      View Article  PubMed
 
[31]  Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel) 2014; 6(3): 1769-1792.
In article      View Article  PubMed
 
[32]  Casals E, Gusta MF, Cobaleda-Siles M, Garcia-Sanz A, Puntes VF. Cancer resistance to treatment and antiresistance tools offered by multimodal multifunctional nanoparticles. Cancer Nanotechnol 2017; 8(1): 7.
In article      View Article  PubMed
 
[33]  Tamaki A, Ierano C, Szakacs G, Robey RW, Bates SE. The controversial role of ABC transporters in clinical oncology. Essays Biochem 2011; 50(1): 209-232.
In article      View Article  PubMed
 
[34]  Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog 2013; 18(1-2): 43-73.
In article      View Article  PubMed
 
[35]  Volm M, Efferth T. Prediction of Cancer Drug Resistance and Implications for Personalized Medicine. Front Oncol 2015;5:282.
In article      View Article  PubMed
 
[36]  Lippert TH, Ruoff HJ, Volm M. Current status of methods to assess cancer drug resistance. Int J Med Sci 2011; 8(3): 245-253.
In article      View Article  PubMed
 
[37]  Elshimali YI, Wu Y, Khaddour H, et al. Optimization Of Cancer Treatment Through Overcoming Drug Resistance. J Cancer Res Oncobiol 2018; 1(2): 107.
In article      View Article  PubMed
 
[38]  Bayat Mokhtari R, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget 2017; 8(23): 38022-38043.
In article      View Article  PubMed
 
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Published with license by Science and Education Publishing, Copyright © 2020 Ahmed M. Kabel and Maaly A. Abd Elmaaboud

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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Ahmed M. Kabel, Maaly A. Abd Elmaaboud. Resistance to Anticancer Agents: Recent Trends. Journal of Cancer Research and Treatment. Vol. 8, No. 2, 2020, pp 11-14. http://pubs.sciepub.com/jcrt/8/2/1
MLA Style
Kabel, Ahmed M., and Maaly A. Abd Elmaaboud. "Resistance to Anticancer Agents: Recent Trends." Journal of Cancer Research and Treatment 8.2 (2020): 11-14.
APA Style
Kabel, A. M. , & Elmaaboud, M. A. A. (2020). Resistance to Anticancer Agents: Recent Trends. Journal of Cancer Research and Treatment, 8(2), 11-14.
Chicago Style
Kabel, Ahmed M., and Maaly A. Abd Elmaaboud. "Resistance to Anticancer Agents: Recent Trends." Journal of Cancer Research and Treatment 8, no. 2 (2020): 11-14.
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[1]  Kabel AM, Abd Elmaaboud MA. Cancer: Role of Nutrition, Pathogenesis, Diagnosis and Management. World Journal of Nutrition and Health. 2014; 2(4): 48-51.
In article      
 
[2]  Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull 2017; 7(3): 339-348.
In article      View Article  PubMed
 
[3]  Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: a current overview. Clin Exp Metastasis 2018; 35(4): 309-318.
In article      View Article  PubMed
 
[4]  Assaraf YG, Brozovic A, Gonçalves AC, Jurkovicova D, Line A, Machuqueiro M, et al. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist Updat 2019; 46: 100645.
In article      View Article  PubMed
 
[5]  Alfarouk KO, Stock CM, Taylor S, et al. Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp. Cancer Cell Int 2015; 15:71.
In article      View Article  PubMed
 
[6]  Wojtuszkiewicz A, Peters GJ, van Woerden NL, et al. Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia. J Hematol Oncol 2015; 8:61.
In article      View Article  PubMed
 
[7]  Xiong J, Feng J, Yuan D, Zhou J, Miao W. Tracing the structural evolution of eukaryotic ATP binding cassette transporter superfamily. Sci Rep 2015; 5: 16724.
In article      View Article  PubMed
 
[8]  Kabel AM, Atef A, Estfanous RS. Ameliorative potential of sitagliptin and/or resveratrol on experimentally-induced clear cell renal cell carcinoma. Biomed Pharmacother 2018; 97: 667-674.
In article      View Article  PubMed
 
[9]  Senapati S, Mahanta AK, Kumar S, Maiti P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduct Target Ther 2018;3:7.
In article      View Article  PubMed
 
[10]  Levin M, Stark M, Berman B, Assaraf YG. Surmounting Cytarabine-resistance in acute myeloblastic leukemia cells and specimens with a synergistic combination of hydroxyurea and azidothymidine. Cell Death Dis 2019; 10(6): 390.
In article      View Article  PubMed
 
[11]  Dong SC, Sha HH, Xu XY, et al. Glutathione S-transferase π: a potential role in antitumor therapy. Drug Des Devel Ther 2018; 12: 3535-3547.
In article      View Article  PubMed
 
[12]  Pljesa-Ercegovac M, Savic-Radojevic A, Matic M, et al. Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors. Int J Mol Sci 2018; 19(12): 3785.
In article      View Article  PubMed
 
[13]  Rathore R, McCallum JE, Varghese E, Florea AM, Büsselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis 2017; 22(7): 898-919.
In article      View Article  PubMed
 
[14]  García-Aranda M, Pérez-Ruiz E, Redondo M. Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy. Int J Mol Sci 2018; 19(12): 3950.
In article      View Article  PubMed
 
[15]  Dou Y, Jiang X, Xie H, He J, Xiao S. The Jun N-terminal kinases signaling pathway plays a "seesaw" role in ovarian carcinoma: a molecular aspect. J Ovarian Res 2019; 12(1): 99.
In article      View Article  PubMed
 
[16]  van Eijk M, Boosman RJ, Schinkel AH, Huitema ADR, Beijnen JH. Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes. Cancer Chemother Pharmacol 2019; 84(3): 487-499.
In article      View Article  PubMed
 
[17]  Rahman M, Hasan MR. Cancer Metabolism and Drug Resistance. Metabolites 2015; 5(4): 571-600.
In article      View Article  PubMed
 
[18]  Delgado JL, Hsieh CM, Chan NL, Hiasa H. Topoisomerases as anticancer targets. Biochem J 2018; 475(2): 373-398.
In article      View Article  PubMed
 
[19]  Shagisultanova EI, Piao Z, Li HR, Malkhosyan SR. Topoisomerase II gene mutations in tumors and tumor cell lines with microsatellite instability. Cancer Lett 2004; 216(2): 221-226.
In article      View Article  PubMed
 
[20]  Davalli P, Marverti G, Lauriola A, D'Arca D. Targeting Oxidatively Induced DNA Damage Response in Cancer: Opportunities for Novel Cancer Therapies. Oxid Med Cell Longev 2018; 2018: 2389523.
In article      View Article  PubMed
 
[21]  Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med 2015; 66: 129-143.
In article      View Article  PubMed
 
[22]  Damia G, Broggini M. Platinum Resistance in Ovarian Cancer: Role of DNA Repair. Cancers (Basel) 2019; 11(1): 119.
In article      View Article  PubMed
 
[23]  Lambert AW, Pattabiraman DR, Weinberg RA. Emerging Biological Principles of Metastasis. Cell 2017; 168(4): 670-691.
In article      View Article  PubMed
 
[24]  Yuan S, Lin LS, Gan RH, et al. Elevated matrix metalloproteinase 7 expression promotes the proliferation, motility and metastasis of tongue squamous cell carcinoma. BMC Cancer 2020; 20(1): 33.
In article      View Article  PubMed
 
[25]  Itatani Y, Kawada K, Sakai Y. Transforming Growth Factor-β Signaling Pathway in Colorectal Cancer and Its Tumor Microenvironment. Int J Mol Sci 2019; 20(23): 5822.
In article      View Article  PubMed
 
[26]  Bagci O, Kurtgöz S. Amplification of Cellular Oncogenes in Solid Tumors. N Am J Med Sci 2015; 7(8): 341-346.
In article      View Article  PubMed
 
[27]  Göker E, Waltham M, Kheradpour A, Trippett T, Mazumdar M, Elisseyeff Y, et al. Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 1995; 86(2): 677-684.
In article      View Article  PubMed
 
[28]  Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation 2011; 123(19): 2145-2156.
In article      View Article  PubMed
 
[29]  Miller JL, Grant PA. The role of DNA methylation and histone modifications in transcriptional regulation in humans. Subcell Biochem 2013; 61: 289-317.
In article      View Article  PubMed
 
[30]  Llinàs-Arias P, Esteller M. Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: an update. Open Biol 2017; 7(9):170152.
In article      View Article  PubMed
 
[31]  Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel) 2014; 6(3): 1769-1792.
In article      View Article  PubMed
 
[32]  Casals E, Gusta MF, Cobaleda-Siles M, Garcia-Sanz A, Puntes VF. Cancer resistance to treatment and antiresistance tools offered by multimodal multifunctional nanoparticles. Cancer Nanotechnol 2017; 8(1): 7.
In article      View Article  PubMed
 
[33]  Tamaki A, Ierano C, Szakacs G, Robey RW, Bates SE. The controversial role of ABC transporters in clinical oncology. Essays Biochem 2011; 50(1): 209-232.
In article      View Article  PubMed
 
[34]  Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog 2013; 18(1-2): 43-73.
In article      View Article  PubMed
 
[35]  Volm M, Efferth T. Prediction of Cancer Drug Resistance and Implications for Personalized Medicine. Front Oncol 2015;5:282.
In article      View Article  PubMed
 
[36]  Lippert TH, Ruoff HJ, Volm M. Current status of methods to assess cancer drug resistance. Int J Med Sci 2011; 8(3): 245-253.
In article      View Article  PubMed
 
[37]  Elshimali YI, Wu Y, Khaddour H, et al. Optimization Of Cancer Treatment Through Overcoming Drug Resistance. J Cancer Res Oncobiol 2018; 1(2): 107.
In article      View Article  PubMed
 
[38]  Bayat Mokhtari R, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget 2017; 8(23): 38022-38043.
In article      View Article  PubMed
 
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