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: Antonio González-Sarrías, Joao Tomé-Carneiro, Andrea Bellesia, Francisco A Tomás-Barberán, Juan Carlos Espín
• Journal: Food & function (Food Funct) Vol. 6 Issue 5 Pg. 1460-9 (May 2015) ISSN: 2042-650X [Electronic] England
• PMID: 25857357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Coumarins
• Cyclin A
• Cyclin B1
• 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
• Ellagic Acid
• Fluorouracil

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bacteria (metabolism)
• Caco-2 Cells
• Cell Cycle (drug effects)
• Colonic Neoplasms (drug therapy, genetics, metabolism, microbiology)
• Coumarins (metabolism)
• Cyclin A (genetics, metabolism)
• Cyclin B1 (genetics, metabolism)
• Ellagic Acid (metabolism)
• Fluorouracil (pharmacology)
• Gastrointestinal Microbiome
• HT29 Cells
• Humans