Overcoming chemo/radio-resistance of rectal cancer using antidiabetic drug

Abstract

Colorectal cancer is often treated by a combination of chemotherapy and targeted biological agents. Metformin and phenformin, previously used in the treatment of diabetes, has been known to have anti-cancer activity in various cancer including breast, lung, and prostate cancer. However, its molecular mechanisms of treatment is still unclear.In this study, we identify that metformin and phenformin inhibit cell proliferation, clonogenic ability and dramatically induce apoptotic cell death in rectal cancer cells, which are resistant to 5-Fluorouracil (5-FU) and ionizing radiation (IR) than colon cancer cells such as HCT116 and LS513. Signal transducer and activator of transcription 3 (STAT3) and TGF-β/Smad signaling pathway are activated in rectal cancer cells. Inhibition of STAT3 by a inhibitor or small interfering RNA (siRNA) sensitizes rectal cancer to 5-FU and IR through the inhibition of expression of the anti-apoptotic proteins such as XAIP, survivin and cIAP1. Moreover, metformin and phenformin inhibits cell migration and invasion by suppression of TGFβRII-mediated snail and twist expression in rectal cancer cells. Therefore, metformin and phenformin provide a novel strategy for rectal cancer therapy via targeting STAT3 and TGFβ/Smad signaling. Collectively, we suggest that metformin and phenformin use for adjuvant therapy is effective on chemo/radio-resistant cancer.