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.

Health benefits of walnut polyphenols: An exploration beyond their lipid profile

“…In addition to the anti-proliferative effects of walnut bioactive compounds, its main metabolite, urolithin A has been shown to potentiate the effects of 5-Fluorouracil (5-FU, drug of first choice in colorectal cancer therapy) on colon cancer cells. This would suggest the need for lower 5-FU doses to achieve therapeutic effects, which could in turn reduce possible adverse effects of treatment and may indicate a role of ellagitannins as chemotherapy adjuvants (González-Sarrías et al, 2015). Although, further studies are needed to confirm these findings in humans and explore underlying mechanisms in more detail, the previously mentioned studies highlight several targets modulated by EA and its metabolites in colon cancer.…”

5-Fluorouracil derivatives: a patent review (2012 – 2014)

“…Moreover, a recent study has evaluated the ability of urolithin A (Uro-A), the main metabolite produced by the human gut microbiota from the dietary polyphenol ellagic acid, to sensitize colon cancer cells to 5-FU and 5-FdUrd. Results indicate that Uro-A potentiates the effects of antitumor drugs and suggest its role as a chemotherapeutic adjuvant since lower doses of 5-FU are needed to achieve similar effects [88].…”

Study protocol on the role of intestinal microbiota in colorectal cancer treatment: a pathway to personalized medicine 2.0

“…TAS-102 consists of cytotoxin trifluridine and thymidine phosphorylase inhibitor (TPI) tipiracil. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine, which inhibits tumor cell growth [10]. …”

“…Only 10–15% of the advanced CRC patients actually respond positively to the administration of 5-FU alone. Furthermore, patients treated with the fluoropyrimidine capecitabine frequently experience chemotoxicity with grades 3–4 chemotoxicity diarrhea of 5%, 2% nausea or vomiting, 4% mucositis, 3% anemia, and 1% hand-foot syndrome [9, 10]. Response to a systemic therapy also depends on patient’s dihydropyrimidine deficiency (DPD) status [11].…”