Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice

Abstract

Sodium glucose cotransporter 2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease. In this study, we investigated the effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on the development of non-alcoholic fatty liver disease-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb obese and diabetic mice. The direct effects of tofogliflozin on human liver cancer cell proliferation were also evaluated. Mice were administered diethylnitrosamine-containing water for 2 weeks and were treated with tofogliflozin throughout the experiment. In mice treated with tofogliflozin, the development of hepatic preneoplastic lesions was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the non-alcoholic fatty liver disease activity score, in comparison with 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 sodium glucose cotransporter 2 protein-expressing liver cancer cells was not inhibited by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and non-alcoholic fatty liver disease-related hepatocarcinogenesis by attenuating chronic inflammation and hepatic steatosis. Therefore, sodium glucose cotransporter 2 inhibitors may have a chemopreventive effect on obesity-related hepatocellular carcinoma.

Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake

“…However, Obara et al has demonstrated that liver cancer cell growth was not directly suppressed by tofogliflozin, other kind of SGLT2-I, in contradiction to our in vitro results. 16 Their report also showed that tofogliflozin treatment did not potently affect the proliferation of liver cancer cells even under hyperglycemic and insulin resistance-mimicking conditions. These findings are of interest; the effects on liver cancer cell proliferation differ according to the type of SGLT2-I.…”

“…Diabetes is widely recognized as one of the most crucial risk factors for HCC, and various reports have provided clinical evidence supporting the preventive effects of pharmacological T2DM regulation on hepatocarcinogenesis . In addition to metformin and DPP4‐Is, a recent animal study demonstrated that SGLT2‐I suppresses diethylnitrosamine‐induced hepatocarcinogenesis in diabetic mice . Therefore, SGLT2‐Is would be expected to exert additional effects on HCC in diabetic patients.…”

“…Furthermore, SGLT2‐Is may directly suppress pancreatic cancer growth, potentially by blocking glucose uptake . Recent animal study has also shown that SGLT2‐I, tofogliflozin, suppresses liver tumorigenesis via reduced glucose and free fatty acid in obese and diabetic mice . However, little has been reported on the direct antitumor effects of SGLT2‐I on HCCs with the linkage of cancer metabolic reprograming.…”

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors

“…Interestingly, tofogliflozin has demonstrated chemopreventive activity on diethylnitrosamine‐induced hepatocellular carcinoma related to obesity in rats whereas canagliflozin has shown to attenuate hepatocellular carcinoma development in a non‐alcoholic hepatic steatosis model in melanocortin 4 receptor‐deficient mice induced via western diet …”

“…It has been suggested that the favourable pharmacological actions of SGLT-2 inhibitors in the treatment of hepatic steatosis is not only as a result of its insulin-independent anti-hyperglycaemic effect and caloric loss subsequent to glycosuria, but also because of their capability in balancing adipose and non-adipose tissues as well as in regulating energy homeostasis 24 Interestingly, tofogliflozin has demonstrated chemopreventive activity on diethylnitrosamine-induced hepatocellular carcinoma related to obesity in rats whereas canagliflozin has shown to attenuate hepatocellular carcinoma development in a non-alcoholic hepatic steatosis model in melanocortin 4 receptor-deficient mice induced via western diet. 24,25 An open-label, non-randomized clinical study involving 79 patients concluded that luseogliflozin significantly ameliorated alanine transaminase, aspartate transaminase, as well as γ-glutamyl transpeptidase levels in patients suffering from hepatic impairment in conjunction with T2DM. These results indicate towards the potential application of luseogliflozin in the therapy of T2DM patients with liver injury.…”