Abstract
Among cancer-related deaths worldwide, colorectal cancer ranks second, accounting for 1.2% of deaths in those under 50 years and 0.6% of deaths in those between 50 and 54 years. The anticancer drug 5-fluorouracil is widely used to treat colorectal cancer. Due to a better understanding of the drug's mechanism of action, its anticancer activity has been increased through a variety of therapeutic alternatives. Clinical use of 5-FU has been severely restricted due to drug resistance. The chemoresistance mechanism of 5-FU is challenging to overcome because of the existence of several drug efflux transporters, DNA repair enzymes, signaling cascades, classical cellular processes, cancer stem cells, metastasis, and angiogenesis. Curcumin, a potent phytocompound derived from Curcuma longa, functions as a nuclear factor (NF)-κB inhibitor and sensitizer to numerous chemotherapeutic drugs. Piperine, an alkaloid found in Piper longum, inhibits cancer cell growth, causing cell cycle arrest and apoptosis. This review explores the mechanism of 5-FU-induced chemoresistance in colon cancer cells and the role of curcumin and piperine in enhancing the sensitivity of 5-FU-based chemotherapy.
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The authors would like to acknowledge SRM Institute of Science and Technology, Kattankulathur, Chengalpattu district, Tamil Nadu.
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Highlights
• 5-FU resistance occurs due to overexpression of the transporter protein and a change in its membrane dynamics due to ATP hydrolysis.
• 5-FU is effluxed from the cells due to overexpression of MRP5 (ABCC5) and MRP8 (ABCC11) transporters.
• Curcumin can reverse MDR by blocking NF-κB, upregulating cytochrome p450, and downregulating GST. It is a substrate of p-gp and has low bioavailability. Piperine can reverse MDR by competing with the ATP binding site, and it binds at NBD between the linker peptide and the consensus sequence of the Walker ATP loop.
• Piperine, when used as an adjuvant with curcumin, can increase its bioavailability by decreasing the rate of curcumin metabolic breakdown, increasing the residence time, changing the dynamics of membrane lipids, and altering the confirmation of enzymes in the intestine by blocking curcumin efflux through MDR transporters.
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Bhattacharjya, D., Sivalingam, N. Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03189-2
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DOI: https://doi.org/10.1007/s00210-024-03189-2