Title : Inhibition of intestinal bacterial b-Glucuronidase by Silymarin to alleviate Irinotecan induced diarrhea and myelotoxicity and to improve anti cancer therapeutic efficacy
Abstract:
I rinotecan (CPT-11), a chemotherapeutic agent for colon cancer, commonly induces adverse effects, such as diarrhea and myelotoxicity. After the non-toxic metabolite (SN-38-glucuronide) of irinotecan was excreted to intestine, bacterial β-glucuronidase (βG) converts it into the toxic aglycone (SN-38), causing severe Intestinal damage. Here, we discovered that silymarin, an extract of the milk thistle (Silybum marianum), is species-specific inhibitor blocking bacterial βG for alleviating the adverse effects of irinotecan. Silymarin showed specific inhibitory activity against E. coli, but not human, βG (purified enzyme and living cells) in an in vitro colorimetric assay. After the mice were orally gavaged with silymarin for 4 days, the enzyme activity of intestinal bacterial βG was reduced in a dose-dependent manner revealed by the in vivo optical imaging of a fluorescent βG probe (FDGlcU). Mice administered with silymarin prior to irinotecan showed less severe irinotecan-induced diarrhea, weight loss, histological intestinal lesions, anemia and leukopenia. Moreover, the co-treatment of silymarin and irinotecan significantly inhibited the tumor growth of human colorectal adenocarcinoma in mice when compared to either agent alone. Our data showed that silymarin alleviated irinotecan-induced adverse effects and enhanced the anti-cancer efficacy, indicating a prophylactic potential of silymarin for irinotecan-treated cancer patients
