Abstract 263: Effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on hepatoma cell lines and liver tumorigenesis

Abstract

Obesity, diabetes mellitus, and their related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Anti-diabetic agents sodium glucose cotransporter (SGLT)-2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of the SGLT2 inhibitor tofogliflozin on the development of NAFLD-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The direct effects of tofogliflozin on human hepatoma cell lines were also evaluated. Male db/db mice were administered diethylnitrosamine-containing water for two weeks and were then treated with tofogliflozin throughout the experiment. Tofogliflozin was kindly provided by Kowa Co., Ltd. and the chemical structure will be disclosed at the time of presentation at the meeting. In mice treated with tofogliflozin, the development of hepatic pre-neoplastic lesions, foci of cellular alterations, was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the NAFLD activity score (NAS), in comparison to those in the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of SGLT2 protein-expressing hepatoma cells was not inhibited and the insulin signaling in those cells was not altered by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and NAFLD-related liver carcinogenesis by attenuating chronic inflammation and steatosis in the liver, while the agent had no significant direct effect on the proliferation of hepatoma cells. Therefore, SGLT2 inhibitors may have a chemopreventive effect on obesity-related HCC. Citation Format: Yohei Shirakami, Koki Obara, Masaya Kubota, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima. Effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on hepatoma cell lines and liver tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 263.