Abstract 2235: Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on liver tumorigenesis in obese and diabetic mice

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.2235-2235
• Main Authors: Shirakami, Yohei, Obara, Koki, Ohnishi, Masaya, Ideta, Takayasu, Sakai, Hiroyasu, Tanaka, Takuji, Shimizu, Masahito, Seishima, Mitsuru
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-2235

Obesity, diabetes mellitus, and their related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Sodium glucose cotransporter (SGLT)-2 inhibitors, recently approved anti-diabetic agents, 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 HCC cell proliferation were also evaluated. Male db/db mice were administered diethylnitrosamine-containing water for two weeks and were 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 was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the NAFLD activity score, 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 HCC cells was not inhibited 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 HCC cells. Therefore, SGLT2 inhibitors may have a chemopreventive effect on obesity-related HCC. Citation Format: Yohei Shirakami, Koki Obara, Masaya Ohnishi, Takayasu Ideta, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima. Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on liver tumorigenesis in obese and diabetic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2235. doi:10.1158/1538-7445.AM2017-2235