5‐Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes

Abstract

Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5‐fluorouracil (5‐FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5‐FU resistance. Some are disease‐specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5‐FU. In this review, we construct a global outline of different mechanisms from disruption of 5‐FU‐metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial‐mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.

Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy

“…Although the antimetabolite 5-fluorouracil (5-FU) has been the only drug available to successfully improve 12-month survival in CRC patients, clinical resistance is continuing to be a challenge to date [ 60 ]. The combination strategy has become especially important in CRC due to frequent resistance to 5-FU and different anti-cancer drugs that are administered at or close to the maximally tolerated dose [ 61 , 62 ]. Studies showed a synergistic cytotoxic effect of ATRA when combined with 5-FU in CRC and other cancer types [ 63 , 64 ].…”

The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer

“…Lastly, based on the drugs being administered, chemoresistance in CRC can also arise due to drug metabolism and specific targets/enzymes [12,13,17]. These two modes of resistance tend to be specific to the drug being administered, since different chemotherapeutics are targeted or metabolised by different targets/enzymes.…”

“…Most of these chemotherapeutic drugs function by interfering with the synthesis of RNA and DNA [11]. The antimetabolite pyrimidine analogue 5-FU [12] does so by incorporating itself into the DNA or RNA and by inhibiting the thymidylate synthases (TYMS) enzyme responsible for synthesising deoxythymidine monophosphate (dTMP) [13]. The platinum drugs, OXA and cisplatin interfere with the synthesis of DNA by acting as intercalating agents, forming intrastrand adducts between two purine residues (two guanine residues or between an adenine and guanine residue) [14,15].…”

Molecular Delivery of Cytotoxic Agents via Integrin Activation

“…It is a fluorinated pyrimidine antimetabolite, which irreversibly inhibits the enzyme thymidylate synthase and prevents cell proliferation by reducing the thymidine formation required for DNA synthesis [ 54 ]. It is widely used to treat breast, colorectal, and gastric cancers, but it showed several serious side effects such as toxic cardiac reaction, myelosuppression, mucositis, nausea, emesis, and development of resistance [ 55 , 56 ].…”