Skip to main content

Advertisement

SpringerLink
Log in

Drug resistance in cancer: mechanisms and tackling strategies

  • Review
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Drug resistance developed towards conventional therapy is one of the important reasons for chemotherapy failure in cancer. The various underlying mechanism for drug resistance development in tumor includes tumor heterogeneity, some cellular levels changes, genetic factors, and others novel mechanisms which have been highlighted in the past few years. In the present scenario, researchers have to focus on these novel mechanisms and their tackling strategies. The small molecules, peptides, and nanotherapeutics have emerged to overcome the drug resistance in cancer. The drug delivery systems with targeting moiety enhance the site-specificity, receptor-mediated endocytosis, and increase the drug concentration inside the cells, thus minimizing drug resistance and improve their therapeutic efficacy. These therapeutic approaches work by modulating the different pathways responsible for drug resistance. This review focuses on the different mechanisms of drug resistance and the recent advancements in therapeutic approaches to improve the sensitivity and effectiveness of chemotherapeutics.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–26.

    Article  CAS  PubMed  Google Scholar 

  2. Haider T, Tiwari R, Vyas SP, Soni V. Molecular determinants as therapeutic targets in cancer chemotherapy: An update. Pharmacol Ther. 2019;200:85–109.

    Article  CAS  PubMed  Google Scholar 

  3. Boehm T, Folkman J, Browder T, O’reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature. 1997;390(6658):404.

    Article  CAS  PubMed  Google Scholar 

  4. Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med. 1999;5(6):662–8.

    Article  CAS  PubMed  Google Scholar 

  5. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, et al. Drug resistance in cancer: an overview. Cancers (Basel). 2014;6(3):1769–92.

    Article  CAS  Google Scholar 

  6. Xue X, Liang XJ. Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology. Chin J Cancer. 2012;31(2):100–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gottesman MM, Pastan IH. The role of multidrug resistance efflux pumps in cancer: revisiting a JNCI publication exploring expression of the MDR1 (P-glycoprotein) Gene. J Natl Cancer Inst. 2015;107(9):djv222.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Lahtz C, Pfeifer GP. Epigenetic changes of DNA repair genes in cancer. J Mol Cell Biol. 2011;3(1):51–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wilson TR, Johnston PG, Longley DB. Anti-apoptotic mechanisms of drug resistance in cancer. Curr Cancer Drug Targets. 2009;9(3):307–19.

    Article  CAS  PubMed  Google Scholar 

  10. Nurwidya F, Takahashi F, Murakami A, Takahashi K. Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer. Cancer Res Treat. 2012;44(3):151–6.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sun Y. Tumor microenvironment and cancer therapy resistance. Cancer Lett. 2016;380(1):205–15.

    Article  CAS  PubMed  Google Scholar 

  12. Wang Y, Cheetham AG, Angacian G, Su H, Xie L, Cui H. Peptide–drug conjugates as effective prodrug strategies for targeted delivery. Adv Drug Del Rev. 2017;110:112–26.

    Article  CAS  Google Scholar 

  13. Wang M, Thanou M. Targeting nanoparticles to cancer. Pharmacol Res. 2010;62(2):90–9.

    Article  CAS  PubMed  Google Scholar 

  14. Yang Y, Jiang C, Yang Y, Guo L, Huang J, Liu X, et al. Silencing of LncRNA-HOTAIR decreases drug resistance of Non-Small Cell Lung Cancer cells by inactivating autophagy via suppressing the phosphorylation of ULK1. Biochem Biophys Res Commun. 2018;497(4):1003–100.

    Article  CAS  PubMed  Google Scholar 

  15. Budden T, van der Westhuizen A, Bowden NA. Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma. BMC Cancer. 2018;18(1):100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Roskoski R Jr. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacol Res. 2017;120:116–32.

    Article  CAS  PubMed  Google Scholar 

  17. Reinmuth N, Fan F, Liu W, Parikh AA, Stoeltzing O, Jung YD, et al. Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. Lab Invest. 2002;82(10):1377–89.

    Article  CAS  PubMed  Google Scholar 

  18. Huijbers EJ, van Beijnum JR, Thijssen VL, Sabrkhany S, Nowak-Sliwinska P, Griffioen AW. Role of the tumor stroma in resistance to anti-angiogenic therapy. Drug Resist Updat. 2016;25:26–37.

    Article  PubMed  Google Scholar 

  19. Ma S, Pradeep S, Hu W, Zhang D, Coleman R, Sood A. The role of tumor microenvironment in resistance to anti-angiogenic therapy. F1000Res. 2018;7:326.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Morin PJ. Drug resistance and the microenvironment: nature and nurture. Drug Resist Updat. 2003;6(4):169–72.

    Article  CAS  PubMed  Google Scholar 

  21. Tanaka K, Miyata H, Sugimura K, Fukuda S, Kanemura T, Yamashita K, et al. miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts. Carcinogenesis. 2015;36(8):894–903.

    Article  CAS  PubMed  Google Scholar 

  22. Xie X, Hu Y, Xu L, Fu Y, Tu J, Zhao H, et al. The role of miR-125b-mitochondria-caspase-3 pathway in doxorubicin resistance and therapy in human breast cancer. Tumour Biol. 2015;36(9):7185–94.

    Article  CAS  PubMed  Google Scholar 

  23. Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25(4):234–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Raghunand N, Mahoney BP, Gillies RJ. Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol. 2003;66(7):1219–29.

    Article  CAS  PubMed  Google Scholar 

  25. Pan ST, Li ZL, He ZX, Qiu JX, Zhou SF. Molecular mechanisms for tumour resistance to chemotherapy. Clin Exp Pharmacol Physiol. 2016;43(8):723–37.

    Article  CAS  PubMed  Google Scholar 

  26. Sharma A, Arambula JF, Koo S, Kumar R, Singh H, Sessler JL, et al. Hypoxia-targeted drug delivery. Chem Soc Rev. 2019;48(3):771–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Avril T, Vauleon E, Chevet E. Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis. 2017;6(8):e373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gong T, Cui L, Wang H, Wang H, Han N. Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway. J Transl Med. 2018;16(1):164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm. 2011;8(6):2032–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gullotti E, Yeo Y. Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm. 2009;6(4):1041–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhao L, Liu W, Xiao J, Cao B. The role of exosomes and “exosomal shuttle microRNA” in tumorigenesis and drug resistance. Cancer Lett. 2015;356(2):339–46.

    Article  CAS  PubMed  Google Scholar 

  32. Shedden K, Xie XT, Chandaroy P, Chang YT, Rosania GR. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res. 2003;63(15):4331–7.

    CAS  PubMed  Google Scholar 

  33. Song Z, Lin Y, Xia Zhang CF, Lu Y, Gao Y, Dong C. Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects. Int J Nanomed. 2017;12:1941.

    Article  CAS  Google Scholar 

  34. Yamamoto S, Kato A, Sakurai Y, Hada T, Harashima H. Modality of tumor endothelial VEGFR2 silencing-mediated improvement in intratumoral distribution of lipid nanoparticles. J Control Rel. 2017;251:1–10.

    Article  CAS  Google Scholar 

  35. Mitamura T, Pradeep S, McGuire M, Wu SY, Ma S, Hatakeyama H, et al. Induction of anti-VEGF therapy resistance by upregulated expression of microseminoprotein (MSMP). Oncogene. 2018;37(6):722–31.

    Article  CAS  PubMed  Google Scholar 

  36. Smith BD, Kaufman MD, Leary CB, Turner BA, Wise SC, Ahn YM, et al. Altiratinib inhibits tumor growth, invasion, angiogenesis, and microenvironment-mediated drug resistance via balanced inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther. 2015;14(9):2023–34.

    Article  CAS  PubMed  Google Scholar 

  37. Avril S, Dincer Y, Malinowsky K, Wolff C, Gundisch S, Hapfelmeier A, et al. Increased PDGFR-beta and VEGFR-2 protein levels are associated with resistance to platinum-based chemotherapy and adverse outcome of ovarian cancer patients. Oncotarget. 2017;8(58):97851–61.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kim S-J, Uehara H, Yazici S, Busby JE, Nakamura T, He J, et al. Targeting platelet-derived growth factor receptor on endothelial cells of multidrug-resistant prostate cancer. J Natl Cancer Inst. 2006;98(11):783–93.

    Article  CAS  PubMed  Google Scholar 

  39. Min H-Y, Lee S-C, Woo JK, Jung HJ, Park KH, Jeong HM, et al. Essential role of DNA methyltransferase 1-mediated transcription of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors. Clin Cancer Res. 2017;23(5):1299–311.

    Article  CAS  PubMed  Google Scholar 

  40. Eichten A, Su J, Adler AP, Zhang L, Ioffe E, Parveen AA, et al. Resistance to anti-VEGF therapy mediated by autocrine IL6/STAT3 signaling and overcome by IL6 blockade. Cancer Res. 2016;76(8):2327–39.

    Article  CAS  PubMed  Google Scholar 

  41. Scherbakov AM, Borunov AM, Buravchenko GI, Andreeva OE, Kudryavtsev IA, Dezhenkova LG, et al. Novel quinoxaline-2-carbonitrile-1,4-dioxide derivatives suppress HIF1alpha activity and circumvent MDR in cancer cells. Cancer Invest. 2018;36(3):199–209.

    Article  PubMed  Google Scholar 

  42. Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15(2):81–94.

    Article  CAS  PubMed  Google Scholar 

  43. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17.

    CAS  PubMed  Google Scholar 

  44. Makohon-Moore AP, Zhang M, Reiter JG, Bozic I, Allen B, Kundu D, et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet. 2017;49(3):358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Negri T, Pavan GM, Virdis E, Greco A, Fermeglia M, Sandri M, et al. T670X KIT mutations in gastrointestinal stromal tumors: making sense of missense. J Natl Cancer Inst. 2009;101(3):194–204.

    Article  CAS  PubMed  Google Scholar 

  46. Kwak EL, Ahronian LG, Siravegna G, Mussolin B, Borger DR, Godfrey JT, et al. Molecular heterogeneity and receptor coamplification drive resistance to targeted therapy in MET-amplified esophagogastric cancer. Cancer Discov. 2015;5(12):1271–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao BX, Wang J, Song B, Wei H, Lv WP, Tian LM, et al. Establishment and biological characteristics of acquired gefitinib resistance in cell line NCI-H1975/gefinitib-resistant with epidermal growth factor receptor T790M mutation. Mol Med Rep. 2015;11(4):2767–74.

    Article  CAS  PubMed  Google Scholar 

  48. Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal. 2011;4(166):ra17-ra.

    Article  CAS  Google Scholar 

  49. Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J, Sakai W, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29(22):3008–155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kemper K, Krijgsman O, Cornelissen-Steijger P, Shahrabi A, Weeber F, Song JY, et al. Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts. EMBO Mol Med. 2015;7(9):1104–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Oshimori N, Oristian D, Fuchs E. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015;160(5):963–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pestova TV, Kolupaeva VG, Lomakin IB, Pilipenko EV, Shatsky IN, Agol VI, et al. Molecular mechanisms of translation initiation in eukaryotes. Proc Natl Acad Sci USA. 2001;98(13):7029–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I. Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015;14(4):261–78.

    Article  CAS  PubMed  Google Scholar 

  54. Chu J, y Cajal SR, Sonenberg N, Pelletier J. Eukaryotic initiation factor 4F—sidestepping resistance mechanisms arising from expression heterogeneity. Curr Opin Genet Dev. 2018;48:89–96.

    Article  CAS  PubMed  Google Scholar 

  55. Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle. 2007;6(19):2332–8.

    Article  CAS  PubMed  Google Scholar 

  56. Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, et al. Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int. 2018;2018:5416923.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Makena MR, Ranjan A, Thirumala V, Reddy AP. Cancer stem cells: road to therapeutic resistance and strategies to overcome resistance. Biochim Biophys Acta Mol Basis Dis. 2020;1866(4):165339.

    Article  CAS  PubMed  Google Scholar 

  58. Boshuizen J, Koopman LA, Krijgsman O, Shahrabi A, van den Heuvel EG, Ligtenberg MA, et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med. 2018;24(2):203–12.

    Article  CAS  PubMed  Google Scholar 

  59. Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov. 2016;6(2):147–53.

    Article  CAS  PubMed  Google Scholar 

  60. Somasundaram R, Zhang G, Fukunaga-Kalabis M, Perego M, Krepler C, Xu X, et al. Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat Commun. 2017;8(1):607.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Ahmed F, Haass NK. Microenvironment-driven dynamic heterogeneity and phenotypic plasticity as a mechanism of melanoma therapy resistance. Front Oncol. 2018;8:173.

  62. Iwasaki S, Floor SN, Ingolia NT. Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor. Nature. 2016;534(7608):558–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SM, Wendel HG, et al. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008;118(7):2651–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Muntimadugu E, Kumar R, Saladi S, Rafeeqi TA, Khan W. CD44 targeted chemotherapy for co-eradication of breast cancer stem cells and cancer cells using polymeric nanoparticles of salinomycin and paclitaxel. Colloids Surf B Biointerfaces. 2016;143:532–46.

    Article  CAS  PubMed  Google Scholar 

  65. Jin C, Yang Z, Yang J, Li H, He Y, An J, et al. Paclitaxel-loaded nanoparticles decorated with anti-CD133 antibody: a targeted therapy for liver cancer stem cells. J Nanopart Res. 2013;16(1):2157.

    Article  CAS  Google Scholar 

  66. Liu Q, Li RT, Qian HQ, Wei J, Xie L, Shen J, et al. Targeted delivery of miR-200c/DOC to inhibit cancer stem cells and cancer cells by the gelatinases-stimuli nanoparticles. Biomaterials. 2013;34(29):7191–203.

    Article  CAS  PubMed  Google Scholar 

  67. Meijer C, Mulder NH, Timmer-Bosscha H, Sluiter WJ, Meersma GJ, de Vries EG. Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds. Cancer Res. 1992;52(24):6885–9.

    CAS  PubMed  Google Scholar 

  68. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205(2):275–92.

    Article  CAS  PubMed  Google Scholar 

  69. Hughes LR, Stephens TC, Boyle FT, Jackman AL. Raltitrexed (Tomudex TM), a highly polyglutamatable antifolate thymidylate synthase inhibitor. In: Jackman AL, editor. Antifolate drugs in cancer therapy Cancer Drug Discovery and Development. Totowa: Humana Press; 1999. p. 147–165.

    Chapter  Google Scholar 

  70. Marin JJ, Al-Abdulla R, Lozano E, Briz O, Bujanda L, Banales JM, et al. Mechanisms of resistance to chemotherapy in gastric cancer. Anticancer Agents Med Chem. 2016;16(3):318–34.

    Article  CAS  PubMed  Google Scholar 

  71. Be H. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989;16(4):215–37.

    Article  Google Scholar 

  72. Zhao R, Babani S, Gao F, Liu L, Goldman ID. The mechanism of transport of the multitargeted antifolate (MTA) and its cross-resistance pattern in cells with markedly impaired transport of methotrexate. Clin Cancer Res. 2000;6(9):3687–95.

    CAS  PubMed  Google Scholar 

  73. Gagnon J-F, Bernard O, Villeneuve L, Têtu B, Guillemette C. Irinotecan inactivation is modulated by epigenetic silencing of UGT1A1 in colon cancer. Clin Cancer Res. 2006;12(6):1850–8.

    Article  CAS  PubMed  Google Scholar 

  74. Saatci O, Borgoni S, Akbulut O, Durmus S, Raza U, Eyupoglu E, et al. Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer. Oncogene. 2018;37(17):2251–69.

    Article  CAS  PubMed  Google Scholar 

  75. Du Z, Liu X, Chen T, Gao W, Wu Z, Hu Z, et al. Targeting a Sirt5-positive subpopulation overcomes multidrug resistance in wild-type kras colorectal carcinomas. Cell Rep. 2018;22(10):2677–89.

    Article  CAS  PubMed  Google Scholar 

  76. Schumacher D, Andrieux G, Boehnke K, Keil M, Silvestri A, Silvestrov M, et al. Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures. PLoS Genet. 2019;15(3):e1008076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Shee K, Yang W, Hinds JW, Hampsch RA, Varn FS, Traphagen NA, et al. Therapeutically targeting tumor microenvironment-mediated drug resistance in estrogen receptor-positive breast cancer. J Exp Med. 2018;215(3):895–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lippolis C, Refolo MG, D'Alessandro R, Carella N, Messa C, Cavallini A, et al. Resistance to multikinase inhibitor actions mediated by insulin like growth factor-1. J Exp Clin Cancer Res. 2015;34(1):90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Fox CA, Sapinoso LM, Zhang H, Zhang W, McLeod HL, Petroni GR, et al. Altered expression of TFF-1 and CES-2 in Barrett's Esophagus and associated adenocarcinomas. Neoplasia. 2005;7(4):407–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Boige V, Taïeb J, Hebbar M, Malka D, Debaere T, Hannoun L, et al. Irinotecan as first-line chemotherapy in patients with advanced hepatocellular carcinoma: a multicenter phase II study with dose adjustment according to baseline serum bilirubin level. Eur J Cancer. 2006;42(4):456–9.

    Article  CAS  PubMed  Google Scholar 

  81. Sampath D, Cortes J, Estrov Z, Du M, Shi Z, Andreeff M, et al. Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood. 2006;107(6):2517–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Shen D-w, Pastan I, Gottesman MM. Cross-resistance to methotrexate and metals in human cisplatin-resistant cell lines results from a pleiotropic defect in accumulation of these compounds associated with reduced plasma membrane binding proteins. Cancer Res. 1998;58(2):268–75.

    CAS  PubMed  Google Scholar 

  83. Peterson RH, Biedler JL. Plasma membrane proteins and glycoproteins from Chinese hamster cells sensitive and resistant to actinomycin D. J Supramol Struct. 1978;9(3):289–98.

    Article  CAS  PubMed  Google Scholar 

  84. Eichholtz-Wirth H, Hietel B. The relationship between cisplatin sensitivity and drug uptake into mammalian cells in vitro. Br J Cancer. 1986;54(2):239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kreitman RJ, Pastan I. Immunotoxins for targeted cancer therapy. Adv Drug Del Rev. 1998;31(1–2):53–88.

    Article  CAS  Google Scholar 

  86. Zhang XW, Bu P, Liu L, Zhang XZ, Li J. Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance. Biochem Biophys Res Commun. 2015;462(3):227–32.

    Article  CAS  PubMed  Google Scholar 

  87. Roundhill E, Fletcher J, Haber M, Norris M. Clinical relevance of multidrug-resistance-proteins (MRPs) for anticancer drug resistance and prognosis. In: Efferth T, editor. Resistance to targeted ABC transporters in cancer. Resistance to targeted anti-cancer therapeutics, vol. 4. Cham: Springer; 2015. p. 27–52.

    Chapter  Google Scholar 

  88. Singh SK, Lillard JW Jr, Singh R. Reversal of drug resistance by planetary ball milled (PBM) nanoparticle loaded with resveratrol and docetaxel in prostate cancer. Cancer Lett. 2018;427:49–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhang Y, Wang Q. Sunitinib reverse multidrug resistance in gastric cancer cells by modulating Stat3 and inhibiting P-gp function. Cell Biochem Biophys. 2013;67(2):575–81.

    Article  CAS  PubMed  Google Scholar 

  90. He L, Wang X, Liu K, Wu X, Yang X, Song G, et al. Integrative PDGF/PDGFR and focal adhesion pathways are downregulated in ERCC1-defective non-small cell lung cancer undergoing sodium glycididazole-sensitized cisplatin treatment. Gene. 2019;691:70–6.

    Article  CAS  PubMed  Google Scholar 

  91. Hahne JC, Valeri N. Non-coding RNAs and resistance to anticancer drugs in gastrointestinal tumours. Front Oncol. 2018;8:226.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol. 2008;26(25):4189–99.

    Article  CAS  PubMed  Google Scholar 

  93. Sun WL, Lan D, Gan TQ, Cai ZW. Autophagy facilitates multidrug resistance development through inhibition of apoptosis in breast cancer cells. Neoplasma. 2015;62(2):199–208.

    Article  CAS  PubMed  Google Scholar 

  94. Zhu W, Shan X, Wang T, Shu Y, Liu P. miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines. Int J Cancer. 2010;127(11):2520–9.

    Article  CAS  PubMed  Google Scholar 

  95. Luan M, Chang J, Pan W, Chen Y, Li N, Tang B. Simultaneous fluorescence visualization of epithelial–mesenchymal transition and apoptosis processes in tumor cells for evaluating the impact of epithelial–mesenchymal transition on drug efficacy. Anal Chem. 2018;90(18):10951–7.

    Article  CAS  PubMed  Google Scholar 

  96. Tyler A, Johansson A, Karlsson T, Gudey SK, Brannstrom T, Grankvist K, et al. Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells. Exp Cell Res. 2015;336(1):23–322.

    Article  CAS  PubMed  Google Scholar 

  97. Buckley D, Duke G, Heuer TS, O'Farrell M, Wagman AS, McCulloch W, et al. Fatty acid synthase—modern tumor cell biology insights into a classical oncology target. Pharmacol Ther. 2017;177:23–31.

    Article  CAS  PubMed  Google Scholar 

  98. Grunt TW. Interacting cancer machineries: cell signaling, lipid metabolism, and epigenetics. Trends Endocrinol Metab. 2018;29(2):86–988.

    Article  CAS  PubMed  Google Scholar 

  99. Shan L, Shan X, Zhang T, Zhai K, Gao G, Chen X, et al. Transferrin-conjugated paclitaxel prodrugs for targeted cancer therapy. RSC Adv. 2016;6(81):77987–98.

    Article  CAS  Google Scholar 

  100. Huang XC, Huang RZ, Gou SH, Wang ZM, Liao ZX, Wang HS. Platinum(IV) complexes conjugated with phenstatin analogue as inhibitors of microtubule polymerization and reverser of multidrug resistance. Bioorg Med Chem. 2017;25(17):4686–700.

    Article  CAS  PubMed  Google Scholar 

  101. Xu Z, Hu W, Wang Z, Gou S. Platinum (IV) prodrugs multiply targeting genomic DNA, histone deacetylases and PARP-1. Eur J Med Chem. 2017;141:211–20.

    Article  CAS  PubMed  Google Scholar 

  102. Huang P, Wang D, Su Y, Huang W, Zhou Y, Cui D, et al. Combination of small molecule prodrug and nanodrug delivery: amphiphilic drug–drug conjugate for cancer therapy. J Am Chem Soc. 2014;136(33):11748–56.

    Article  CAS  PubMed  Google Scholar 

  103. Zhao D, Zhang H, Tao W, Wei W, Sun J, He Z. A rapid albumin-binding 5-fluorouracil prodrug with a prolonged circulation time and enhanced antitumor activity. Biomater Sci. 2017;5(3):502–10.

    Article  CAS  PubMed  Google Scholar 

  104. Gao C, Tang F, Gong G, Zhang J, Hoi MP, Lee SM, et al. pH-responsive prodrug nanoparticles based on a sodium alginate derivative for selective co-release of doxorubicin and curcumin into tumor cells. Nanoscale. 2017;9(34):12533–42.

    Article  CAS  PubMed  Google Scholar 

  105. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53(1):615–27.

    Article  CAS  PubMed  Google Scholar 

  106. Marin JJ, Monte MJ, Blazquez AG, Macias RI, Serrano MA, Briz O. The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy. Acta Pharmacol Sin. 2014;35(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  107. Tiwari R, Jain P, Asati S, Haider T, Soni V, Pandey V. State-of-art based approaches for anticancer drug-targeting to nucleus. J Drug Deliv Sci Technol. 2018;48:383–92.

    Article  CAS  Google Scholar 

  108. Chauhan SS, Liang XJ, Su AW, Pai-Panandiker A, Shen DW, Hanover JA, et al. Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines. Br J Cancer. 2003;88(8):1327–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest. 2006;116(7):1955–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bar-Shavit R, Nag JK, Grisaru-Granovsky S, Uziely B. G-protein coupled receptor PAR(1) is overexpressed in glioma progenitor cells. Transl Cancer Res. 2016;5(6):S1185–S1188188.

    Article  Google Scholar 

  111. Kübler E, Albrecht H. Large set data mining reveals overexpressed GPCRs in prostate and breast cancer: potential for active targeting with engineered anti-cancer nanomedicines. Oncotarget. 2018;9(38):24882.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int. 2014;2014:852748.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Pandey V, Gajbhiye KR, Soni V. Lactoferrin-appended solid lipid nanoparticles of paclitaxel for effective management of bronchogenic carcinoma. Drug Deliv. 2015;22(2):199–205.

    Article  CAS  PubMed  Google Scholar 

  114. Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol. 2018;11(1):64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 2001;61(9):3550–5.

    CAS  PubMed  Google Scholar 

  116. Kapse-Mistry S, Govender T, Srivastava R, Yergeri M. Nanodrug delivery in reversing multidrug resistance in cancer cells. Front Pharmacol. 2014;5:159.

    PubMed  PubMed Central  Google Scholar 

  117. Lei M, Ma G, Sha S, Wang X, Feng H, Zhu Y, et al. Dual-functionalized liposome by co-delivery of paclitaxel with sorafenib for synergistic antitumor efficacy and reversion of multidrug resistance. Drug Deliv. 2019;26(1):262–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bansal D, Yadav K, Pandey V, Ganeshpurkar A, Agnihotri A, Dubey N. Lactobionic acid coupled liposomes: an innovative strategy for targeting hepatocellular carcinoma. Drug Deliv. 2016;23(1):140–6.

    Article  CAS  PubMed  Google Scholar 

  119. Hee Choi Y, Yu A-M. ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr Pharm Des. 2014;20(5):793–807.

    Article  CAS  Google Scholar 

  120. Binkhathlan Z, Lavasanifar A. P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives. Curr Cancer Drug Targ. 2013;13(3):326–46.

    Article  CAS  Google Scholar 

  121. Allen J, Brinkhuis R, Wijnholds J, Schinkel AH. The mouse Bcrpl/Mxr/Abcp gene: amplification and overexpression in cell lines selected fbr resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res. 1999;59:4237–41.

    CAS  PubMed  Google Scholar 

  122. Wang H, Gao Z, Liu X, Agarwal P, Zhao S, Conroy DW, et al. Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance. Nat Commun. 2018;9(1):562.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Orlando UD, Castillo AF, Medrano MAR, Solano AR, Maloberti PM, Podesta EJ. Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression. Biochem Pharmacol. 2019;159:52–63.

    Article  CAS  PubMed  Google Scholar 

  124. Zheng X, Andruska N, Lambrecht MJ, He S, Parissenti A, Hergenrother PJ, et al. Targeting multidrug-resistant ovarian cancer through estrogen receptor α dependent ATP depletion caused by hyperactivation of the unfolded protein response. Oncotarget. 2018;9(19):14741.

    Article  PubMed  Google Scholar 

  125. Capranico G, De Isabella P, Castelli C, Supino R, Parmiani G, Zunino F. P-glycoprotein gene amplification and expression in multidrug-resistant murine P388 and B16 cell lines. Br J Cancer. 1989;59(5):682–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zheng L-S, Wang F, Li Y-H, Zhang X, Chen L-M, Liang Y-J, et al. Vandetanib (Zactima, ZD6474) antagonizes ABCC1-and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS ONE. 2009;4(4):e5172.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Fung SW, Cheung PF-Y, Yip CW, Ng LW-C, Cheung TT, Chong CC-N, et al. The ATP-binding cassette transporter ABCF1 is a hepatic oncofetal protein that promotes chemo-resistance, EMT and cancer stemness in hepatocellular carcinoma. Cancer Lett. 2019;457:98–109.

  128. Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Targ Insights. 2013;7:27–34.

    Google Scholar 

  129. Li PY, Lai PS, Hung WC, Syu WJ. Poly(L-lactide)-vitamin E TPGS nanoparticles enhanced the cytotoxicity of doxorubicin in drug-resistant MCF-7 breast cancer cells. Biomacromol. 2010;11(10):2576–82.

    Article  CAS  Google Scholar 

  130. Dintaman JM, Silverman JA. Inhibition of P-glycoprotein by D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharm Res. 1999;16(10):1550–6.

    Article  CAS  PubMed  Google Scholar 

  131. Negi LM, Talegaonkar S, Jaggi M, Verma AK. Hyaluronated imatinib liposomes with hybrid approach to target CD44 and P-gp overexpressing MDR cancer: an in-vitro, in-vivo and mechanistic investigation. J Drug Target. 2019;27(2):183–92.

    Article  CAS  PubMed  Google Scholar 

  132. Hartz A, Schulz J, Sokola B, Bauer B. CSIG-32 DUAL PI3K/Akt inhibition to overcome the P-gp/BCRP drug efflux system for improved drug delivery in glioblastoma therapy. Neuro Oncol. 2018;20(suppl_6):vi50–vi51.

    Article  PubMed Central  Google Scholar 

  133. Zhang YK, Zhang XY, Zhang GN, Wang YJ, Xu H, Zhang D, et al. Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881. Biochem Pharmacol. 2017;132:29–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Durmus S, Xu N, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387. Pharmacol Res. 2013;76:9–16.

    Article  CAS  PubMed  Google Scholar 

  135. Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, et al. Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma. PLoS ONE. 2010;5(5):e10764.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Nourbakhsh M, Jaafari MR, Lage H, Abnous K, Mosaffa F, Badiee A, et al. Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer. Iran J Basic Med Sci. 2015;18(4):385–92.

    PubMed  PubMed Central  Google Scholar 

  137. Burg D, Wielinga P, Zelcer N, Saeki T, Mulder GJ, Borst P. Inhibition of the multidrug resistance protein 1 (MRP1) by peptidomimetic glutathione-conjugate analogs. Mol Pharmacol. 2002;62(5):1160–6.

    Article  CAS  PubMed  Google Scholar 

  138. Tong WY, Alnakhli M, Bhardwaj R, Apostolou S, Sinha S, Fraser C, et al. Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma. J Nanobiotechnol. 2018;16(1):38.

    Article  CAS  Google Scholar 

  139. Lo Y-L, Liu Y. Reversing multidrug resistance in Caco-2 by silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL using liposomal antisense oligonucleotides. PLoS ONE. 2014;9(3):e90180.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587–98.

    Article  CAS  PubMed  Google Scholar 

  141. Cummings M, Higginbottom K, McGurk CJ, Wong OG-W, Köberle B, Oliver RTD, et al. XPA versus ERCC1 as chemosensitising agents to cisplatin and mitomycin C in prostate cancer cells: role of ERCC1 in homologous recombination repair. Biochem Pharmacol. 2006;72(2):166–75.

    Article  CAS  PubMed  Google Scholar 

  142. Liu JL, Huang WS, Lee KC, Tung SY, Chen CN, Chang SF. Effect of 5-fluorouracil on excision repair cross-complementing 1 expression and consequent cytotoxicity regulation in human gastric cancer cells. J Cell Biochem. 2018;119(10):8472–80.

    Article  CAS  PubMed  Google Scholar 

  143. Tung SY, Lin CT, Chen CN, Huang WS. Effect of mitomycin C on X-ray repair cross complementing group 1 expression and consequent cytotoxicity regulation in human gastric cancer cells. J Cell Biochem. 2019;120(5):8333–422.

    Article  CAS  Google Scholar 

  144. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci USA. 2010;107(49):21098–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ma P, Xu T, Huang M, Shu Y. Increased expression of LncRNA PANDAR predicts a poor prognosis in gastric cancer. Biomed Pharmacother. 2016;78:172–6.

    Article  CAS  PubMed  Google Scholar 

  146. Wang X, Li M, Wang Z, Han S, Tang X, Ge Y, et al. Silencing of long noncoding RNA MALAT1 by miR-101 and miR-217 inhibits proliferation, migration, and invasion of esophageal squamous cell carcinoma cells. J Biol Chem. 2015;290(7):3925–35.

    Article  CAS  PubMed  Google Scholar 

  147. Glasspool RM, Teodoridis JM, Brown R. Epigenetics as a mechanism driving polygenic clinical drug resistance. Br J Cancer. 2006;94(8):1087–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gifford G, Paul J, Vasey PA, Kaye SB, Brown R. The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res. 2004;10(13):4420–6.

    Article  CAS  PubMed  Google Scholar 

  149. Si W, Shen J, Zheng H, Fan W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenet. 2019;11(1):25.

    Article  Google Scholar 

  150. Xiong T, Wei H, Chen X, Xiao H. PJ34, a poly(ADP-ribose) polymerase (PARP) inhibitor, reverses melphalan-resistance and inhibits repair of DNA double-strand breaks by targeting the FA/BRCA pathway in multidrug resistant multiple myeloma cell line RPMI8226/R. Int J Oncol. 2015;46(1):223–32.

    Article  CAS  PubMed  Google Scholar 

  151. Tian H, Gao Z, Li H, Zhang B, Wang G, Zhang Q, et al. DNA damage response—a double-edged sword in cancer prevention and cancer therapy. Cancer Lett. 2015;358(1):8–16.

    Article  CAS  PubMed  Google Scholar 

  152. Nam AR, Jin MH, Park JE, Bang JH, Oh DY, Bang YJ. Therapeutic targeting of the DNA damage response using an ATR inhibitor in biliary tract cancer. Cancer Res Treat. 2019;51(3):1167–79.

    Article  CAS  PubMed  Google Scholar 

  153. Chen P, Li J, Jiang HG, Lan T, Chen YC. Curcumin reverses cisplatin resistance in cisplatin-resistant lung caner cells by inhibiting FA/BRCA pathway. Tumour Biol. 2015;36(5):3591–9.

    Article  CAS  PubMed  Google Scholar 

  154. Song AL, Zhao L, Wang YW, He DQ, Li YM. Chemoresistance in gastric cancer is attributed to the overexpression of excision repair cross‐complementing 1 (ERCC1) caused by microRNA‐122 dysregulation. J Cell Comp Physiol. 2019;234(12):22485–92

  155. He L, Liu K, Wang X, Chen H, Zhou J, Wu X, et al. NDRG1 disruption alleviates cisplatin/sodium glycididazole-induced DNA damage response and apoptosis in ERCC1-defective lung cancer cells. Int J Biochem Cell Biol. 2018;100:54–60.

    Article  CAS  PubMed  Google Scholar 

  156. Ning J, Jiao Y, Xie X, Deng X, Zhang Y, Yang Y, et al. miR-138-5p modulates the expression of excision repair cross-complementing proteins ERCC1 and ERCC4, and regulates the sensitivity of gastric cancer cells to cisplatin. Oncol Rep. 2019;41(2):1131–9.

    CAS  PubMed  Google Scholar 

  157. Ju X, Yu H, Liang D, Jiang T, Liu Y, Chen L, et al. LDR reverses DDP resistance in ovarian cancer cells by affecting ERCC-1, Bcl-2, Survivin and Caspase-3 expressions. Biomed Pharmacother. 2018;102:549–54.

    Article  CAS  PubMed  Google Scholar 

  158. Liu Y, Yue C, Li J, Wu J, Wang S, Sun D, et al. Enhancement of cisplatin cytotoxicity by Retigeric acid B involves blocking DNA repair and activating DR5 in prostate cancer cells. Oncol Lett. 2018;15(3):2871–80.

    PubMed  Google Scholar 

  159. Teng X, Fan XF, Li Q, Liu S, Wu DY, Wang SY, et al. XPC inhibition rescues cisplatin resistance via the Akt/mTOR signaling pathway in A549/DDP lung adenocarcinoma cells. Oncol Rep. 2019;41(3):1875–82.

    CAS  PubMed  Google Scholar 

  160. Han Z, Shi L. Long non-coding RNA LUCAT1 modulates methotrexate resistance in osteosarcoma via miR-200c/ABCB1 axis. Biochem Biophys Res Commun. 2018;495(1):947–53.

    Article  CAS  PubMed  Google Scholar 

  161. Ge XS, Chen YB, Liao XY, Liu DQ, Li FF, Ruan HL, et al. Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer. Med Oncol. 2013;30(2):588.

    Article  PubMed  CAS  Google Scholar 

  162. Qiao L, Liu X, Tang Y, Zhao Z, Zhang J, Liu H. Knockdown of long non-coding RNA prostate cancer-associated ncRNA transcript 1 inhibits multidrug resistance and c-Myc-dependent aggressiveness in colorectal cancer Caco-2 and HT-29 cells. Mol Cell Biochem. 2018;441(1–2):99–108.

    Article  CAS  PubMed  Google Scholar 

  163. Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 2000;60(21):6039–44.

    CAS  PubMed  Google Scholar 

  164. Sabharwal A, Corrie PG, Midgley RS, Palmer C, Brady J, Mortimer P, et al. A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer. Cancer Chemother Pharmacol. 2010;66(5):829–35.

    Article  CAS  PubMed  Google Scholar 

  165. Li YJ, Lei YH, Yao N, Wang CR, Hu N, Ye WC, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer. 2017;36(1):52.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Huerta S, Heinzerling JH, Anguiano-Hernandez YM, Huerta-Yepez S, Lin J, Chen D, et al. Modification of gene products involved in resistance to apoptosis in metastatic colon cancer cells: roles of Fas, Apaf-1, NFkappaB, IAPs, Smac/DIABLO, and AIF. J Surg Res. 2007;142(1):184–94.

    Article  CAS  PubMed  Google Scholar 

  167. Xia L, Zhang D, Du R, Pan Y, Zhao L, Sun S, et al. miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 2008;123(2):372–9.

    Article  CAS  PubMed  Google Scholar 

  168. Teixeira C, Reed JC, Pratt MA. Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res. 1995;55(17):3902–7.

    CAS  PubMed  Google Scholar 

  169. Jeong SH, Lee HW, Han JH, Kang SY, Choi JH, Jung YM, et al. Low expression of Bax predicts poor prognosis in resected non-small cell lung cancer patients with non-squamous histology. Jpn J Clin Oncol. 2008;38(10):661–9.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655–7.

    Article  CAS  PubMed  Google Scholar 

  171. Skalniak L, Kocik J, Polak J, Skalniak A, Rak M, Wolnicka-Glubisz A, Holak TA. Prolonged idasanutlin (RG7388) treatment leads to the generation of p53-mutated cells. Cancers. 2018;10(11):396.

  172. Indran IR, Tufo G, Pervaiz S, Brenner C. Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta. 2011;1807(6):735–45.

    Article  CAS  PubMed  Google Scholar 

  173. Wu CE, Koay TS, Ho YH, Lovat P, Lunec J. TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response. Cancer Cell Int. 2019;19(1):53.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Park J, Kim C, Gupta S. Differential transcriptional regulation of silencer of death domains in cord blood and peripheral blood lymphocytes. Int J Mol Med. 2000;6(3):289–93.

    CAS  PubMed  Google Scholar 

  175. Greer YE, Gilbert SF, Gril B, Narwal R, Peacock Brooks DL, Tice DA, et al. MEDI3039, a novel highly potent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 2 agonist, causes regression of orthotopic tumors and inhibits outgrowth of metastatic triple-negative breast cancer. Breast Cancer Res. 2019;21(1):27.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Sun CY, Zhu Y, Li XF, Wang XQ, Tang LP, Su ZQ, et al. Scutellarin increases cisplatin-induced apoptosis and autophagy to overcome cisplatin resistance in non-small cell lung cancer via ERK/p53 and c-met/AKT signaling pathways. Front Pharmacol. 2018;9:92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu H-Y, Lin L-T, et al. Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol. 2015;35:S78–S103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. van Staalduinen J, Baker D, ten Dijke P, van Dam H. Epithelial–mesenchymal-transition-inducing transcription factors: new targets for tackling chemoresistance in cancer? Oncogene. 2018; 37(48):6195–211.

  179. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20(2):69–84.

    Article  CAS  PubMed  Google Scholar 

  180. Song KA, Niederst MJ, Lochmann TL, Hata AN, Kitai H, Ham J, et al. Epithelial-to-MESENCHYMAL TRANSITION ANTAGONIZES RESPONSE TO TARGETED THERAPIES IN LUNG CANCER BY SUPPRESSINg BIM. Clin Cancer Res. 2018;24(1):197–208.

    Article  CAS  PubMed  Google Scholar 

  181. Xu J, Zhao X, He D, Wang J, Li W, Liu Y, et al. Loss of EGFR confers acquired resistance to AZD9291 in an EGFR-mutant non-small cell lung cancer cell line with an epithelial-mesenchymal transition phenotype. J Cancer Res Clin Oncol. 2018;144(8):1413–22.

    Article  CAS  PubMed  Google Scholar 

  182. Yuan X, Wu H, Han N, Xu H, Chu Q, Yu S, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7(1):87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Wilson C, Nicholes K, Bustos D, Lin E, Song Q, Stephan JP, et al. Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition. Oncotarget. 2014;5(17):7328–41.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson E, Noël A, et al. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene. 2012;31(33):3741.

    Article  CAS  PubMed  Google Scholar 

  185. Davis FM, Stewart TA, Thompson EW, Monteith GR. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci. 2014;35(9):479–88.

    Article  CAS  PubMed  Google Scholar 

  186. Halder SK, Beauchamp RD, Datta PK. A specific inhibitor of TGF-β receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia. 2005;7(5):509–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Thaiparambil JT, Bender L, Ganesh T, Kline E, Patel P, Liu Y, et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int J Cancer. 2011;129(11):2744–55.

    Article  CAS  PubMed  Google Scholar 

  188. Guo Z, Li W, Yuan Y, Zheng K, Tang Y, Ma K, et al. Improvement of chemosensitivity and inhibition of migration via targeting tumor epithelial-to-mesenchymal transition cells by ADH-1-modified liposomes. Drug Deliv. 2018;25(1):112–21.

    Article  CAS  PubMed  Google Scholar 

  189. Hendrich A, Michalak K. Lipids as a target for drugs modulating multidrug resistance of cancer cells. Curr Drug Targets. 2003;4(1):23–30.

    Article  CAS  PubMed  Google Scholar 

  190. Merchant TE, Meneses P, Gierke LW, Den Otter W, Glonek T. 31 P Magnetic resonance phospholipid profiles of neoplastic human breast tissues. Br J Cancer. 1991;63(5):693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Merchant TE, de Graaf PW, Minsky BD, Obertop H, Glonek T. Esophageal cancer phospholipid characterization by 31P NMR. NMR Biomed. 1993;6(3):187–93.

    Article  CAS  PubMed  Google Scholar 

  192. Raghavan V, Vijayaraghavalu S, Peetla C, Yamada M, Morisada M, Labhasetwar V. Sustained epigenetic drug delivery depletes cholesterol–sphingomyelin rafts from resistant breast cancer cells, influencing biophysical characteristics of membrane lipids. Langmuir. 2015;31(42):11564–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Wegner MS, Gruber L, Mattjus P, Geisslinger G, Grosch S. The UDP-glucose ceramide glycosyltransferase (UGCG) and the link to multidrug resistance protein 1 (MDR1). BMC Cancer. 2018;18(1):153.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Jennemann R, Federico G, Mathow D, Rabionet M, Rampoldi F, Popovic ZV, et al. Inhibition of hepatocellular carcinoma growth by blockade of glycosphingolipid synthesis. Oncotarget. 2017;8(65):109201–166.

    Article  PubMed  PubMed Central  Google Scholar 

  195. Wegner MS, Schomel N, Gruber L, Ortel SB, Kjellberg MA, Mattjus P, et al. UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells. Cell Mol Life Sci. 2018;75(18):3393–410.

    Article  CAS  PubMed  Google Scholar 

  196. Liu Q, Luo Q, Halim A, Song G. Targeting lipid metabolism of cancer cells: a promising therapeutic strategy for cancer. Cancer Lett. 2017;401:39–45.

    Article  CAS  PubMed  Google Scholar 

  197. Veigel D, Wagner R, Stubiger G, Wuczkowski M, Filipits M, Horvat R, et al. Fatty acid synthase is a metabolic marker of cell proliferation rather than malignancy in ovarian cancer and its precursor cells. Int J Cancer. 2015;136(9):2078–90.

    Article  CAS  PubMed  Google Scholar 

  198. Li CF, Fang FM, Chen YY, Liu TT, Chan TC, Yu SC, et al. Overexpressed fatty acid synthase in gastrointestinal stromal tumors: targeting a progression-associated metabolic driver enhances the antitumor effect of imatinib. Clin Cancer Res. 2017;23(16):4908–18.

    Article  CAS  PubMed  Google Scholar 

  199. Chatterjee S, Alsaeedi N, Hou J, Bandaru VV, Wu L, Halushka MK, et al. Use of a glycolipid inhibitor to ameliorate renal cancer in a mouse model. PLoS ONE. 2013;8(5):e63726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Liu H, Wu X, Dong Z, Luo Z, Zhao Z, Xu Y, et al. Fatty acid synthase causes drug resistance by inhibiting TNF-alpha and ceramide production. J Lipid Res. 2013;54(3):776–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Wu S, Naar AM. SREBP1-dependent de novo fatty acid synthesis gene expression is elevated in malignant melanoma and represents a cellular survival trait. Sci Rep. 2019;9(1):10369.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Bobba RK, Arya M, Benakanakere I, Johnson T, Freter C. Lipid cell membrane composition: a novel therapeutic target in cancer. J Clin Oncol. 2014;32(15_suppl):7062.

    Article  Google Scholar 

  203. Vijayaraghavalu S, Peetla C, Lu S, Labhasetwar V. Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions. Mol Pharm. 2012;9(9):2730–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Zhang RX, Li LY, Li J, Xu Z, Abbasi AZ, Lin L, et al. Coordinating biointeraction and bioreaction of a nanocarrier material and an anticancer drug to overcome membrane rigidity and target mitochondria in multidrug-resistant cancer cells. Adv Func Mater. 2017;27(39):1700804.

    Article  CAS  Google Scholar 

  205. Hou TY, Davidson LA, Kim E, Fan YY, Fuentes NR, Triff K, et al. Nutrient-gene interaction in colon cancer, from the membrane to cellular physiology. Annu Rev Nutr. 2016;36:543–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Fuentes NR, Kim E, Fan YY, Chapkin RS. Omega-3 fatty acids, membrane remodeling and cancer prevention. Mol Aspects Med. 2018;64:79–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Poolsri WA, Phokrai P, Suwankulanan S, Phakdeeto N, Phunsomboon P, Pekthong D, et al. Combination of mitochondrial and plasma membrane citrate transporter inhibitors inhibits de novo lipogenesis pathway and triggers apoptosis in hepatocellular carcinoma cells. Biomed Res Int. 2018;2018:3683026.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Wu X, Qin L, Fako V, Zhang JT. Molecular mechanisms of fatty acid synthase (FASN)-mediated resistance to anti-cancer treatments. Adv Biol Regul. 2014;54:214–21.

    Article  CAS  PubMed  Google Scholar 

  209. Stepanova DS, Semenova G, Kuo YM, Andrews AJ, Ammoun S, Hanemann CO, et al. An essential role for the tumor-suppressor merlin in regulating fatty acid synthesis. Cancer Res. 2017;77(18):5026–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Brandi J, Dando I, Pozza ED, Biondani G, Jenkins R, Elliott V, et al. Proteomic analysis of pancreatic cancer stem cells: Functional role of fatty acid synthesis and mevalonate pathways. J Proteom. 2017;150:310–22.

    Article  CAS  Google Scholar 

  211. Chang L, Fang S, Chen Y, Yang Z, Yuan Y, Zhang J, et al. Inhibition of FASN suppresses the malignant biological behavior of non-small cell lung cancer cells via deregulating glucose metabolism and AKT/ERK pathway. Lipids Health Dis. 2019;18(1):118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The funding (Grant No. EMR/2017/001738) provided by Science & Engineering Research Board (SERB), Department of Science and Technology (DST), New Delhi, India, is gratefully acknowledged. Authors acknowledge to the Indian Council of Medical Research (ICMR), New Delhi for financial support as SRF funding (Grant number for Haider T. 45/7/2018-Nan/BMS and for Pandey V. 45/01/2018-NAN/BMS) for research work.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, 470003, Madhya Pradesh, India

    Tanweer Haider, Vikas Pandey, Nagma Banjare & Vandana Soni

  2. Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India

    Nagma Banjare & Prem N. Gupta

Authors
  1. Tanweer Haider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vikas Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nagma Banjare
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Prem N. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vandana Soni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Prem N. Gupta or Vandana Soni.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haider, T., Pandey, V., Banjare, N. et al. Drug resistance in cancer: mechanisms and tackling strategies. Pharmacol. Rep 72, 1125–1151 (2020). https://doi.org/10.1007/s43440-020-00138-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43440-020-00138-7

Keywords

Search

Navigation