Abstract
Simple SummaryAcquired resistance to chemotherapy by cancer cells is the predominant factor in chemotherapy failure, which ultimately leads to disease progression and death. Recent studies have presented compelling evidence of the various mechanisms and pathways through which cancer cells have developed resistance to drugs. This review summarises the mechanisms pertaining to 5-FU resistance and discusses ongoing efforts to prevent chemotherapy resistance in cancer cells and to re-sensitise them to cancer drugs.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.
Highlights
Mechanisms of Action of 5-FluorouracilIt was initially discovered that uracil is metabolized more rapidly than any other pyrimidine nucleotides in pre-neoplastic and hepatoma rats when compared to healthy rats [12]
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
The mechanism as to how CXCL-13 participates in 5-FU resistance was not stated, it is highly plausible that resistance is achieved through piggybacking the same pathways responsible in promoting tumor growth, migration, and invasion in CXCR5-expressing colon cancer cells; through the activation of
Summary
It was initially discovered that uracil is metabolized more rapidly than any other pyrimidine nucleotides in pre-neoplastic and hepatoma rats when compared to healthy rats [12]. 3 of 38 FUTP or to REVIEW another phosphorylation process that converts it to either active metabolite into fluorodeoxyuridine diphosphate (FdUDP) by the enzyme ribonucleotide reductase fluorodeoxyuridine diphosphate (FdUDP). FdUDP is further phosphorylated to active misincorporated into the DNA tumor to cells alternatively cause DNA damage. Metabolite FdUTP and is misincorporated into theof of cells tumor to alternatively cause. Prodrug 5-FU conversion to FdUR is facilitated by the enzyme thymidine phosphorylase (TYMP). With 5,10-methylenetetrahydrofolate (CH2 THF) as a methyl donor to irreversibly inhibit methylenetetrahydrofolate (CH2THF) as a methyl donor to irreversibly inhibit the enzymatic activity the enzymatic activity of TYMS [18] This in turn prevents the conversion of substrate of TYMS [18].
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