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Clinical Cancer Drugs

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ISSN (Print): 2212-697X
ISSN (Online): 2212-6988

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Review Article

Chemoresistance Mechanisms in Colon Cancer: Focus on Conventional Chemotherapy

Author(s): Klara Mladenić and Mirela Sedić*

Volume 8, Issue 2, 2021

Published on: 28 December, 2021

Article ID: e061221198577 Pages: 39

DOI: 10.2174/2212697X08666211206102503

Price: $65

Abstract

Background: Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops.

Methods: In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool.

Results: The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity), leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed, including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway.

Conclusion: This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for the development of chemoresistance and whose targeting might enable the design of novel combination strategies to overcome resistance to conventional treatment in CRC.

Keywords: Colon cancer, colorectal cancer, 5-fluorouracil, oxaliplatin, irinotecan, chemoresistance.

Graphical Abstract

[1]
American Cancer Society. Colorectal Cancer Facts & Figures 2017-2019. Atlanta: American Cancer Society 2017.
[2]
Cancer Council Australia Colorectal Cancer Guidelines Working Party. Clinical practice guidelines for the prevention, early detection and management of colorectal cancer. [Version URL: https://wiki.cancer.org.au/australiawiki/index.php?oldid=213460, cited 2020 Sep 28 Available from: https://wiki.cancer.org.au/australia/Guidelines:Colorectal_cancer
[3]
Xie Y-H, Chen Y-X, Fang J-Y. Comprehensive review of targeted therapy for colorectal cancer. Sig Transduct Target Ther 2020; 22(5): 22.
[http://dx.doi.org/10.1038/s41392-020-0116-z]
[4]
Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol 2016; 8(1): 57-84.
[http://dx.doi.org/10.1177/1758834015614530] [PMID: 26753006]
[5]
Chin C-H, Chen S-H, Wu H-H, Ho C-W, Ko M-T, Lin CY. cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 2014; 8(4): S11.
[http://dx.doi.org/10.1186/1752-0509-8-S4-S11] [PMID: 25521941]
[6]
Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3(5): 330-8.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[7]
Muhale FA, Wetmore BA, Thomas RS, McLeod HL. Systems pharmacology assessment of the 5-fluorouracil pathway. Pharmacogenomics 2011; 12(3): 341-50.
[http://dx.doi.org/10.2217/pgs.10.188] [PMID: 21449674]
[8]
He L, Zhu H, Zhou S, et al. Wnt pathway is involved in 5-FU drug resistance of colorectal cancer cells. Exp Mol Med 2018; 50(8): 1-12.
[http://dx.doi.org/10.1038/s12276-018-0128-8] [PMID: 30111797]
[9]
Xu X, Wang Y, Deng H, Liu C, Wu J, Lai M. HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway. Oncotarget 2018; 9(11): 9963-74.
[http://dx.doi.org/10.18632/oncotarget.24133] [PMID: 29515783]
[10]
Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29(34): 4741-51.
[http://dx.doi.org/10.1038/onc.2010.215] [PMID: 20531305]
[11]
Liu Z, Chen J, Yuan W, et al. Nuclear factor I/B promotes colorectal cancer cell proliferation, epithelial-mesenchymal transition and 5-fluorouracil resistance. Cancer Sci 2019; 110(1): 86-98.
[http://dx.doi.org/10.1111/cas.13833] [PMID: 30320939]
[12]
Kim A-Y, Kwak J-H, Je N-K, Lee YH, Jung Y-S. Epithelial-mesenchymal transition is associated with acquired resistance to 5-fluorocuracil in ht-29 colon cancer cells. Toxicol Res 2015; 31(2): 151-6.
[http://dx.doi.org/10.5487/TR.2015.31.2.151] [PMID: 26191381]
[13]
Shen W, Cui L, Chen W. DKK4 is important in Snail1-induced chemoresistance to fluorouracil in colorectal cancer. Transl Cancer Res 2017; 6(2): 304-11.
[http://dx.doi.org/10.21037/tcr.2017.03.18]
[14]
Sun L, Ke J, He Z, et al. HES1 promotes colorectal cancer cell resistance To 5-Fu by inducing Of EMT and ABC transporter proteins. J Cancer 2017; 8(14): 2802-8.
[http://dx.doi.org/10.7150/jca.19142] [PMID: 28928869]
[15]
Zhang B, Zhang B, Chen X, et al. Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway. Br J Cancer 2014; 110(4): 946-57.
[http://dx.doi.org/10.1038/bjc.2013.789] [PMID: 24384683]
[16]
Zhang G, Luo X, Zhang W, et al. CXCL-13 regulates resistance to 5-fluorouracil in colorectal cancer. Cancer Res Treat 2020; 52(2): 622-33.
[http://dx.doi.org/10.4143/crt.2019.593] [PMID: 32019285]
[17]
Liu C, Zhao Y, Wang J, et al. FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway. Cancer Lett 2020; 470: 29-42.
[http://dx.doi.org/10.1016/j.canlet.2019.11.042] [PMID: 31811910]
[18]
Xie T, Geng J, Wang Y, et al. FOXM1 evokes 5-fluorouracil resistance in colorectal cancer depending on ABCC10. Oncotarget 2017; 8(5): 8574-89.
[http://dx.doi.org/10.18632/oncotarget.14351] [PMID: 28051999]
[19]
Yao S, Fan LY-N, Lam EW-F. The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance. Semin Cancer Biol 2018; 50: 77-89.
[http://dx.doi.org/10.1016/j.semcancer.2017.11.018] [PMID: 29180117]
[20]
Körber MI, Staribacher A, Ratzenböck I, Steger G, Mader RM. NFκB-associated pathways in progression of chemoresistance to 5-fluorouracil in an in vitro model of colonic carcinoma. Anticancer Res 2016; 36(4): 1631-9.
[PMID: 27069140]
[21]
Sui X, Kong N, Wang X, et al. JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy. Sci Rep 2014; 4: 4694.
[http://dx.doi.org/10.1038/srep04694] [PMID: 24733045]
[22]
Rubio MF, Lira MC, Rosa FD, Sambresqui AD, Salazar Güemes MC, Costas MA. RAC3 influences the chemoresistance of colon cancer cells through autophagy and apoptosis inhibition. Cancer Cell Int 2017; 17: 111.
[http://dx.doi.org/10.1186/s12935-017-0483-x] [PMID: 29209153]
[23]
He J, Pei L, Jiang H, Yang W, Chen J, Liang H. Chemoresistance of colorectal cancer to 5-fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation. J Cancer 2017; 8(7): 1187-96.
[http://dx.doi.org/10.7150/jca.18171] [PMID: 28607593]
[24]
Sakai A, Otani M, Miyamoto A, Yoshida H, Furuya E, Tanigawa N. Identification of phosphorylated serine-15 and -82 residues of HSPB1 in 5-fluorouracil-resistant colorectal cancer cells by proteomics. J Proteomics 2012; 75(3): 806-18.
[http://dx.doi.org/10.1016/j.jprot.2011.09.023] [PMID: 21989268]
[25]
Tanaka S, Sakai A, Kimura K, et al. Proteomic analysis of the basic proteins in 5-fluorouracil resistance of human colon cancer cell line using the radical-free and highly reducing method of two-dimensional polyacrylamide gel electrophoresis. Int J Oncol 2008; 33(2): 361-70.
[PMID: 18636157]
[26]
Zhao Z, Zhang G, Li W. Elevated expression of ERCC6 confers resistance to 5-fluorouracil and is associated with poor patient survival in colorectal cancer. DNA Cell Biol 2017; 36(9): 781-6.
[http://dx.doi.org/10.1089/dna.2017.3768] [PMID: 28665687]
[27]
Yang A-D, Fan F, Camp ER, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res 2006; 12(14 Pt 1): 4147-53.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0038] [PMID: 16857785]
[28]
Mao L, Li Y, Zhao J, et al. Transforming growth factor-β1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition. Oncol Lett 2017; 14(1): 647-54.
[http://dx.doi.org/10.3892/ol.2017.6209] [PMID: 28693217]
[29]
Guo C, Ma J, Deng G, et al. ZEB1 promotes oxaliplatin resistance through the induction of epithelial - mesenchymal transition in colon cancer cells. J Cancer 2017; 8(17): 3555-66.
[http://dx.doi.org/10.7150/jca.20952] [PMID: 29151941]
[30]
Chen Y, Deng G, Fu Y, et al. FOXC2 promotes oxaliplatin resistance by inducing epithelial-mesenchymal transition via MAPK/ERK signaling in colorectal cancer. OncoTargets Ther 2020; 13: 1625-35.
[http://dx.doi.org/10.2147/OTT.S241367] [PMID: 32110058]
[31]
Zhang Y, Xu Z, Sun Y, Chi P, Lu X. Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell. OncoTargets Ther 2018; 11: 809-21.
[http://dx.doi.org/10.2147/OTT.S151867] [PMID: 29497313]
[32]
Suzuki S, Tanigawara Y. Forced expression of S100A10 reduces sensitivity to oxaliplatin in colorectal cancer cells. Proteome Sci 2014; 12: 26.
[http://dx.doi.org/10.1186/1477-5956-12-26] [PMID: 24851084]
[33]
Tong J, Shen Y, Chen X, et al. FKBP3 mediates oxaliplatin resistance in colorectal cancer cells by regulating HDAC2 expression. Oncol Rep 2019; 42(4): 1404-12.
[http://dx.doi.org/10.3892/or.2019.7259] [PMID: 31524278]
[34]
Yan D, Tu L, Yuan H, et al. WBSCR22 confers oxaliplatin resistance in human colorectal cancer. Sci Rep 2017; 7(1): 15443.
[http://dx.doi.org/10.1038/s41598-017-15749-z] [PMID: 29133897]
[35]
Wang X, Ghareeb WM, Zhang Y, et al. Hypermethylated and downregulated MEIS2 are involved in stemness properties and oxaliplatin-based chemotherapy resistance of colorectal cancer. J Cell Physiol 2019; 234(10): 18180-91.
[http://dx.doi.org/10.1002/jcp.28451] [PMID: 30859572]
[36]
Chen Z-H, Qi J-J, Wu Q-N, et al. Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer. J Exp Clin Cancer Res 2019; 38(1): 196.
[http://dx.doi.org/10.1186/s13046-019-1178-z] [PMID: 31088567]
[37]
Martinez-Balibrea E, Plasencia C, Ginés A, et al. A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines. Mol Cancer Ther 2009; 8(4): 771-8.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0882] [PMID: 19372549]
[38]
da Silva MR, Moreira GA, Gonçalves da Silva RA, et al. Splicing regulators and their roles in cancer biology and therapy. BioMed Res Int 2015; 2015(4): 150514.
[http://dx.doi.org/10.1155/2015/150514] [PMID: 26273588]
[39]
Samimi G, Katano K, Holzer AK, Safaei R, Howell SB. Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Mol Pharmacol 2004; 66(1): 25-32.
[http://dx.doi.org/10.1124/mol.66.1.25] [PMID: 15213293]
[40]
Fang Z, Gong C, Yu S, et al. NFYB-induced high expression of E2F1 contributes to oxaliplatin resistance in colorectal cancer via the enhancement of CHK1 signaling. Cancer Lett 2018; 415: 58-72.
[http://dx.doi.org/10.1016/j.canlet.2017.11.040] [PMID: 29203250]
[41]
Li J-M, Jiang G-M, Zhao L, et al. Dehydrogenase/reductase SDR family member 2 silencing sensitizes an oxaliplatin-resistant cell line to oxaliplatin by inhibiting excision repair cross-complementing group 1 protein expression. Oncol Rep 2019; 42(5): 1725-34.
[http://dx.doi.org/10.3892/or.2019.7291] [PMID: 31436301]
[42]
Baba H, Watanabe M, Okabe H, et al. Upregulation of ERCC1 and DPD expressions after oxaliplatin-based first-line chemotherapy for metastatic colorectal cancer. Br J Cancer 2012; 107(12): 1950-5.
[http://dx.doi.org/10.1038/bjc.2012.502] [PMID: 23169295]
[43]
Di Salvatore M, Orlandi A, Paolillo C, et al. ERCC1 biomarker in colorectal cancer: to induce or not to induce? this is the matter! Oncomedicine 2016; 1: 25-7.
[http://dx.doi.org/10.7150/oncm.16256]
[44]
Plasencia C, Martínez-Balibrea E, Martinez-Cardús A, Quinn DI, Abad A, Neamati N. Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells. Int J Oncol 2006; 29(1): 225-35.
[http://dx.doi.org/10.3892/ijo.29.1.225] [PMID: 16773204]
[45]
Myint K, Li Y, Paxton J, McKeage M. Multidrug resistance-associated protein 2 (mrp2) mediated transport of oxaliplatin-derived platinum in membrane vesicles. PLoS One 2015; 10(7): e0130727.
[http://dx.doi.org/10.1371/journal.pone.0130727] [PMID: 26131551]
[46]
Xu Y, Villalona-Calero MA. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol 2002; 13(12): 1841-51.
[http://dx.doi.org/10.1093/annonc/mdf337] [PMID: 12453851]
[47]
Fujiwara Y, Minami H. An overview of the recent progress in irinotecan pharmacogenetics. Pharmacogenomics 2010; 11(3): 391-406.
[http://dx.doi.org/10.2217/pgs.10.19] [PMID: 20235794]
[48]
Raynal C, Pascussi J-M, Leguelinel G, et al. Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. Mol Cancer 2010; 9: 46.
[http://dx.doi.org/10.1186/1476-4598-9-46] [PMID: 20196838]
[49]
Zhou Y, Bollu LR, Tozzi F, et al. ATP citrate lyase mediates resistance of colorectal cancer cells to SN38. Mol Cancer Ther 2013; 12(12): 2782-91.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0098] [PMID: 24132143]
[50]
Woo J-K, Kang J-H, Kim B, et al. Humanized anti-hepatocyte growth factor (HGF) antibody suppresses innate irinotecan (CPT-11) resistance induced by fibroblast-derived HGF. Oncotarget 2015; 6(27): 24047-60.
[http://dx.doi.org/10.18632/oncotarget.4369] [PMID: 26090722]
[51]
Murono K, Tsuno N-H, Kawai K, et al. SN-38 overcomes chemoresistance of colorectal cancer cells induced by hypoxia, through HIF1alpha. Anticancer Res 2012; 32(3): 865-72.
[PMID: 22399605]
[52]
Paillas S, Causse A, Marzi L, et al. MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy. Autophagy 2012; 8(7): 1098-112.
[http://dx.doi.org/10.4161/auto.20268] [PMID: 22647487]
[53]
Chen M-C, Lee N-H, Hsu H-H, et al. Inhibition of NF-κB and metastasis in irinotecan (CPT-11)-resistant LoVo colon cancer cells by thymoquinone via JNK and p38. Environ Toxicol 2017; 32(2): 669-78.
[http://dx.doi.org/10.1002/tox.22268] [PMID: 27060453]
[54]
Fenouille N, Grosso S, Yunchao S, et al. Calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance in colorectal cancer xenografts. J Pathol 2012; 227(1): 118-29.
[http://dx.doi.org/10.1002/path.3034] [PMID: 22069124]
[55]
Zheng H, Kang Y. Multilayer control of the EMT master regulators. Oncogene 2014; 33(14): 1755-63.
[http://dx.doi.org/10.1038/onc.2013.128] [PMID: 23604123]
[56]
Yang Y, Wang G, Zhu D, et al. Epithelial-mesenchymal transition and cancer stem cell-like phenotype induced by Twist1 contribute to acquired resistance to irinotecan in colon cancer. Int J Oncol 2017; 51(2): 515-24.
[http://dx.doi.org/10.3892/ijo.2017.4044] [PMID: 28627611]
[57]
Su P, Yang Y, Wang G, Chen X, Ju Y. Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells. Int J Oncol 2018; 53(3): 1343-53.
[http://dx.doi.org/10.3892/ijo.2018.4461] [PMID: 29956726]
[58]
Usui T, Sakurai M, Umata K, et al. Hedgehog signals mediate anti-cancer drug resistance in three-dimensional primary colorectal cancer organoid culture. Int J Mol Sci 2018; 19(4): 1098.
[http://dx.doi.org/10.3390/ijms19041098] [PMID: 29642386]
[59]
Izumi D, Ishimoto T, Miyake K, et al. Colorectal cancer stem cells acquire chemoresistance through the upregulation of F-Box/WD repeat-containing protein 7 and the consequent degradation of c-Myc. Stem Cells 2017; 35(9): 2027-36.
[http://dx.doi.org/10.1002/stem.2668] [PMID: 28699179]
[60]
Ruihua H, Mengyi Z, Chong Z, et al. RhoA regulates resistance to irinotecan by regulating membrane transporter and apoptosis signaling in colorectal cancer. Oncotarget 2016; 7(52): 87136-46.
[http://dx.doi.org/10.18632/oncotarget.13548] [PMID: 27888624]
[61]
Abdallah EA, Fanelli MF, Souza E Silva V, et al. MRP1 expression in CTCs confers resistance to irinotecan-based chemotherapy in metastatic colorectal cancer. Int J Cancer 2016; 139(4): 890-8.
[http://dx.doi.org/10.1002/ijc.30082] [PMID: 26950035]
[62]
Tuy H-D, Shiomi H, Mukaisho K-I, et al. ABCG2 expression in colorectal adenocarcinomas may predict resistance to irinotecan. Oncol Lett 2016; 12(4): 2752-60.
[http://dx.doi.org/10.3892/ol.2016.4937] [PMID: 27698852]
[63]
Flis S, Gnyszka A, Spławiński J. HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines. Biochem Biophys Res Commun 2009; 387(2): 336-41.
[http://dx.doi.org/10.1016/j.bbrc.2009.07.017] [PMID: 19596269]
[64]
Faria Andrade A, Moreaux J, Vié N, Del Rio M, Gongora C. PO-481 Alteration in epigenetic-related genes and histones modifications levels revealed as a potential resistance factor to oxaliplatin in colorectal cancer cells. ESMO Open 2018; 3(2): A210-1.
[http://dx.doi.org/10.1136/esmoopen-2018-EACR25.499]
[65]
Liu L, Yan X, Wu D, et al. High expression of Ras-related protein 1A promotes an aggressive phenotype in colorectal cancer via PTEN/FOXO3/CCND1 pathway. J Exp Clin Cancer Res 2018; 37(1): 178.
[http://dx.doi.org/10.1186/s13046-018-0827-y] [PMID: 30064475]
[66]
Zhang H-L, Wang P, Lu M-Z, Zhang S-D, Zheng L. c-Myc maintains the self-renewal and chemoresistance properties of colon cancer stem cells. Oncol Lett 2019; 17(5): 4487-93.
[http://dx.doi.org/10.3892/ol.2019.10081] [PMID: 30944638]
[67]
Vétillard A, Jonchère B, Moreau M, et al. Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis. Oncotarget 2015; 6(41): 43342-62.
[http://dx.doi.org/10.18632/oncotarget.6126] [PMID: 26485768]
[68]
Grbčić P, Sedić M. Sphingosine 1-phosphate signaling and metabolism in chemoprevention and chemoresistance in colon cancer. Molecules 2020; 25(10): 2436.
[http://dx.doi.org/10.3390/molecules25102436] [PMID: 32456134]

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