title: The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells.
abstract: Chemotherapy increases the overall survival in colorectal cancer (CRC) patients. 5-Fluorouracil (5-FU) remains as a drug of first choice in CRC therapy over the last four decades. However, only 10-15% of patients with advanced CRC respond positively to 5-FU monotherapy. Therefore, new strategies to enhance the 5-FU effectiveness, overcome the tumor cell resistance and decrease the unspecific toxicity are critically needed. Urolithin A (Uro-A) is the main metabolite produced by the human gut microbiota from the dietary polyphenol ellagic acid. Uro-A targets the colonic mucosa of CRC patients, and preclinical studies have shown the anti-inflammatory and cancer chemopreventive activities of this metabolite. We evaluated here whether Uro-A, at concentrations achievable in the human colorectum, could sensitize colon cancer cells to 5-FU and 5'DFUR (a pro-drug intermediate of 5-FU). We found that both 5-FU and 5'DFUR arrested the cell cycle at the S phase by regulating cyclins A and B1 in the human colon cancer cells Caco-2, SW-480 and HT-29, and also triggered apoptosis through the activation of caspases 8 and 9. Co-treatments with Uro-A decreased IC50 values for both 5-FU and 5'DFUR and additionally arrested the cell cycle at the G2/M phase together with a slight increase in caspases 8 and 9 activation. Overall, we show that Uro-A potentiated the effects of both 5-FU and 5'DFUR on colon cancer cells. This suggests the need for lower 5-FU doses to achieve similar effects, which could reduce possible adverse effects. Further in vivo investigations are warranted to explore the possible role of Uro-A as a chemotherapy adjuvant.
authors: Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain. agsarrias@cebas.csic.es.
authors: Antonio
authors: A
authors: González-Sarrías
authors: Joao
authors: J
authors: Tomé-Carneiro
authors: Andrea
authors: A
authors: Bellesia
authors: Francisco A
authors: FA
authors: Tomás-Barberán
authors: Juan Carlos
authors: JC
authors: Espín
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001419:Bacteria / Q000378:metabolism*; D018938:Caco-2 Cells; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000382:microbiology*; D003374:Coumarins / Q000378:metabolism*; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D004610:Ellagic Acid / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D000069196:Gastrointestinal Microbiome; D019073:HT29 Cells; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D019925:Cyclin A; D056744:Cyclin B1; C026423:3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one; D004610:Ellagic Acid; D005472:Fluorouracil