urolithin-d and Colonic-Neoplasms

Urolithins, gut microbiota metabolites derived from ellagic acid and ellagitannins, reach micromolar concentrations in the colon lumen where can have anti-inflammatory and anticancer effects. The antiproliferative activity of urolithins (Uro-A, Uro-B, Uro-C and Uro-D) and their most relevant in vivo glucuronides were evaluated in three human colon cancer cell lines (Caco-2, SW480 and HT-29).. Cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and Trypan blue exclusion assays. Cell cycle was evaluated by flow cytometry and urolithins metabolism by HPLC–MS/MS.. Urolithins inhibited cell proliferation and cell cycle progression in a time- and dose-dependent manner and arrested the cells at S and G2/M phases, depending on the urolithin. Uro-A exerted the highest antiproliferative activity, followed by Uro-C, Uro-D and Uro-B. Unlike Caco-2 and SW480 cells, HT-29 cells partially overcame the effects after 48 h, which was related to the complete glucuronidation of urolithins. Uro-A or Uro-B glucuronides did not affect cell cycle and showed lower antiproliferative activity than their aglycone counterparts. Uro-A or Uro-B plus inhibitors of drug efflux ABC transporters partially prevented the glucuronidation of urolithins in HT-29 cells which became more sensitive.. Uro-A, Uro-B, Uro-C and Uro-D exerted different antiproliferative effects depending on the colon cancer cell line. We also report here, for the first time, the role of ABC transporters and Phase-II metabolism in HT-29 cells as a mechanism of cancer resistance against urolithins due to their conversion to glucuronide conjugates that exerted lower antiproliferative activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibiotics, Antineoplastic; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colon; Colonic Neoplasms; Coumarins; Drug Resistance, Neoplasm; G2 Phase; Glucuronides; Humans; Hydrolyzable Tannins; Intestinal Mucosa; Kinetics; Membrane Transport Modulators; Metabolic Detoxication, Phase II; S Phase