Mechanisms of Drug Resistance in Colon Cancer and Its Therapeutic Strategies

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2016 Aug 30

PMID 27570424

Citations 163

Authors

Tao Hu

Zhen Li

Chun-Ying Gao

Chi Hin Cho

Affiliations

Soon will be listed here.

Abstract

Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.

Citing Articles

KLF6-mediated recruitment of the p300 complex enhances H3K23su and cooperatively upregulates SEMA3C with FOSL2 to drive 5-FU resistance in colon cancer cells.

Zhang B, Qi T, Lin J, Zhai S, Wang X, Zhou L Exp Mol Med. 2025; .

PMID: 40082673 DOI: 10.1038/s12276-025-01424-1.

Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer.

Haynes J, Manogaran P Int J Mol Sci. 2025; 26(5).

PMID: 40076613 PMC: 11901061. DOI: 10.3390/ijms26051988.

Inhibiting HSP90 changes the expression pattern of PINK1 and BNIP3 and induces oxidative stress in colon cancer cells.

Abu-El-Rub E, Alzubi A, Almahasneh F, Khaswaneh R, Almazari R, Kasasbeh A Mol Biol Rep. 2025; 52(1):212.

PMID: 39921807 PMC: 11807072. DOI: 10.1007/s11033-025-10303-x.

Bufalin targets the SRC-3/c-Myc pathway in chemoresistant cells to regulate metastasis induced by chemoresistance in colorectal cancer.

Chen J, Wu C, Yu K, Liu J, Yang J, Li W J Cancer Res Clin Oncol. 2025; 151(2):71.

PMID: 39921753 PMC: 11807082. DOI: 10.1007/s00432-025-06124-x.

The prognostic importance of the negative regulators of ferroptosis, GPX4 and HSPB1, in patients with colorectal cancer.

Shimura T, Yin C, Ma R, Zhang A, Nagai Y, Shiratori A Oncol Lett. 2025; 29(3):144.

PMID: 39850719 PMC: 11755263. DOI: 10.3892/ol.2025.14890.

References

Slot A, Molinski S, Cole S . Mammalian multidrug-resistance proteins (MRPs). Essays Biochem. 2011; 50(1):179-207. DOI: 10.1042/bse0500179. View

Cunningham D, Atkin W, Lenz H, Lynch H, Minsky B, Nordlinger B . Colorectal cancer. Lancet. 2010; 375(9719):1030-47. DOI: 10.1016/S0140-6736(10)60353-4. View

Szakacs G, Paterson J, Ludwig J, Booth-Genthe C, Gottesman M . Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006; 5(3):219-34. DOI: 10.1038/nrd1984. View

Ding Z, Yang L, Xie X, Xie F, Pan F, Li J . Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. J Cancer Res Clin Oncol. 2010; 136(11):1697-707. PMC: 2944968. DOI: 10.1007/s00432-010-0828-5. View

Greenblatt M, BENNETT W, Hollstein M, Harris C . Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994; 54(18):4855-78. View

Martinet W, De Meyer G . Autophagy in atherosclerosis: a cell survival and death phenomenon with therapeutic potential. Circ Res. 2009; 104(3):304-17. DOI: 10.1161/CIRCRESAHA.108.188318. View

van Zanden J, de Mul A, Wortelboer H, Usta M, van Bladeren P, Rietjens I . Reversal of in vitro cellular MRP1 and MRP2 mediated vincristine resistance by the flavonoid myricetin. Biochem Pharmacol. 2005; 69(11):1657-65. DOI: 10.1016/j.bcp.2005.03.001. View

Shukla S, Zaher H, Hartz A, Bauer B, Ware J, Ambudkar S . Curcumin inhibits the activity of ABCG2/BCRP1, a multidrug resistance-linked ABC drug transporter in mice. Pharm Res. 2008; 26(2):480-7. PMC: 2662629. DOI: 10.1007/s11095-008-9735-8. View

Lewis A, Forrester L, Hayes J, Wareing C, Carmichael J, Harris A . Glutathione S-transferase isoenzymes in human tumours and tumour derived cell lines. Br J Cancer. 1989; 60(3):327-31. PMC: 2247197. DOI: 10.1038/bjc.1989.280. View

10.

Giacomini K, Huang S, Tweedie D, Benet L, Brouwer K, Chu X . Membrane transporters in drug development. Nat Rev Drug Discov. 2010; 9(3):215-36. PMC: 3326076. DOI: 10.1038/nrd3028. View

11.

Jung K, Choi B, Kwak M . The c-MET/PI3K signaling is associated with cancer resistance to doxorubicin and photodynamic therapy by elevating BCRP/ABCG2 expression. Mol Pharmacol. 2014; 87(3):465-76. DOI: 10.1124/mol.114.096065. View

12.

Lo Nigro C, Ricci V, Vivenza D, Monteverde M, Strola G, Lucio F . Evaluation of antibody-dependent cell-mediated cytotoxicity activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients. World J Gastrointest Oncol. 2016; 8(2):222-30. PMC: 4753173. DOI: 10.4251/wjgo.v8.i2.222. View

13.

Besbes S, Pocard M, Mirshahi M, Billard C . The first MCL-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia. Crit Rev Oncol Hematol. 2016; 100:32-6. DOI: 10.1016/j.critrevonc.2016.02.003. View

14.

Ke E, Wu Y . Afatinib in the first-line treatment of epidermal-growth-factor-receptor mutation-positive non-small cell lung cancer: a review of the clinical evidence. Ther Adv Respir Dis. 2016; 10(3):256-64. PMC: 5933608. DOI: 10.1177/1753465816634545. View

15.

Fichtner I, Slisow W, Gill J, Becker M, Elbe B, Hillebrand T . Anticancer drug response and expression of molecular markers in early-passage xenotransplanted colon carcinomas. Eur J Cancer. 2004; 40(2):298-307. DOI: 10.1016/j.ejca.2003.10.011. View

16.

Kanzawa T, Germano I, Komata T, Ito H, Kondo Y, Kondo S . Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 2004; 11(4):448-57. DOI: 10.1038/sj.cdd.4401359. View

17.

Choudhuri S, Klaassen C . Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol. 2006; 25(4):231-59. DOI: 10.1080/10915810600746023. View

18.

Chapman R, Whetton A, Dive C . The suppression of drug-induced apoptosis by activation of v-ABL protein tyrosine kinase. Cancer Res. 1994; 54(19):5131-7. View

19.

Reed J . Dysregulation of apoptosis in cancer. J Clin Oncol. 1999; 17(9):2941-53. DOI: 10.1200/JCO.1999.17.9.2941. View

20.

Mizushima N . Autophagy: process and function. Genes Dev. 2007; 21(22):2861-73. DOI: 10.1101/gad.1599207. View