Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Abstract

5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

“…Apoptotic extracellular vesicles with FASL induces myeloma FAS-mediated apoptosis to suppress tumor growth in vivo [ 12 ]. Compelling and emerging experimental data indicates that the FAS acts as a tumor suppressor in human cancer and is essential for CTL effector function in the suppression of tumor development [ 7 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. In addition, the FAS-FASL pathway is essential for the cytotoxicity of CTLs, including CAR-T cells, in the elimination of tumors in both tumor antigen-specific and antigen-independent manners [ 11 , 14 ].…”

Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells

“…The 5-FU inhibits the DNA synthesis by reducing thymidylate synthase activity, while PTX inhibits depolymerization of tubulin and subsequent cell division ( 21 , 22 ). Dysregulation of various components in distinct pathways is the major common cause for drug resistance, including alterations in drug transport, EMT transition, miRNA dysregulations, cell cycle changes, autophagy regulation, DNA damage repair machinery, tumor microenvironment interactions, and stemness enhancement ( 23 ).…”

MALAT1-miRNAs network regulate thymidylate synthase and affect 5FU-based chemotherapy

“…1 ). Fol inic acid and 5 F U in combination with ox aliplatin or iri notecan are used as the chemotherapy regimens FOLFOX and FOLFIRI, respectively, in the postoperative treatment of stage II CRC with high risk of recurrence, stage III CRC and palliative chemotherapy of metastatic stage IV CRC (Azwar et al 2021 ; Iveson 2020 ; Taieb and Gallois 2020 ; Collienne and Arnold 2020 ; Dienstmann et al 2015 ; Labianca et al 2013 ; Stec et al 2011 ; Grávalos et al 2009 ; Van den Eynde and Hendlisz 2009 ). In turn, cap ecitabine ( Xel oda) is used in combination with oxaliplatin or irinotecan as regimens XELOX (or CAPOX) and XELIRI, respectively.…”

“…The main failure of the fluoropyrimidine-based cancer therapy is the acquisition of drug resistance, which is a multifactorial process (Azwar et al 2021 ). Among the mechanisms of resistance to 5FU, there may be changes in drug transport into and out of the cell, in particular overexpression of ATP-binding cassette transporters (Hu et al 2016 ), as well as altered drug metabolism, increased level of the molecular target for an active drug, loss of cell cycle checkpoint control, increasing the threshold of apoptosis induction, the process of epithelial-mesenchymal transition (EMT) (Sun et al 2019b ), reprogramming cancer cells into cancer stem-like cells (CSCs) (Shibata et al 2018 ), as well as abnormal levels of expression of non-coding RNAs (Wei et al 2019a ).…”