Cancer is a major cause of death in patients with diabetes. Incretin therapy has received much attention, because of its tissue protective effects beyond glycemic control. We have previously reported anti-prostate cancer effect of Ex-4 and metformin (Diabetes 2014, PLOS ONE 2015). In addition, we have recently reported that Ex-4 attenuates breast cancer growth (Endocrinology 2017). Then, we next examined the effect of combined treatment of Ex-4 with Metformin in breast cancer cells. In human breast cancer cell lines, MCF-7, MDA-MB-231 and KPL-1 cell, Ex-4 or metformin reduced cell number in a dose-dependent manner. Further, combined treatment of 0.1mM Metformin and 10nM Ex-4 additively attenuated the growth curve progression of breast cancer cells. In BrdU assay, Ex-4 or Metformin significantly decreased breast cancer cell proliferation, and further reduction of BrdU incorporation was observed by combined treatment of Ex-4 and Metformin, suggesting that Ex-4 and Metformin additively decreased DNA synthesis in breast cancer cells. Although apoptotic cells were not observed in Ex-4 treated breast cancer cells similar to our previous study, apoptotic cells were clearly detected in metformin treated breast cancer cells using TUNEL assay. These data suggest that Ex-4 and metformin attenuates breast cancer cell proliferation and metformin induces apoptosis in breast cancer cells. Combined treatment of Ex-4 and Metformin could be an optional therapy to inhibit breast cancer progression.
C. Iwaya: None. T. Nomiyama: Research Support; Self; MSD K.K., Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan. T. Kawanami: None. Y. Hamaguchi: None. T. Tanaka: None. T. Yanase: Research Support; Self; MSD K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan.