Background: Recent increase in the relative proportion of cancer death in diabetic patients has become a major issue. A hypoglycemic agent, sodium-glucose cotransporter (SGLT) 2 inhibitor has attracted attention because of its potency in reducing cardiovascular risks. Several lines of evidence has emerged suggesting a potential anti-oncotic effect. Here we address potential effects of canagliflozin (Cana) on human colon cancer cell growth and underlying mechanisms and compared with empagliflozin (Empa).
Material and Methods: We examined the effects of Cana and Empa on 1) cell proliferation using colon cancer cell lines, SW480 and HCT116 by MTT assay, 2) DNA synthesis by flow cytometry-based analysis of bromodeoxyuridine (BrdU) uptake. We further examined 3) the expression of SGLT1 and 2 in these cells and 4) investigated molecules of signal transduction pathways with established roles in cancer cell growth such as AMPK, 4EBP1, mTOR by western blotting. Finally, we analyzed 5) time-dependent changes of metabolomic signatures after the treatment with Cana.
Results: While SGLT1 and 2 mRNA and protein expression was detected in both cell lines, Cana but not Empa significantly inhibited cell proliferation and in a dose-dependent manner. Cana suppressed BrdU positive cells and enhanced AMPK phosphorylation with a consequent suppression of 4EBP1 and mTOR activity. Metabolomic profiling revealed that, as a function of time, intermediate metabolites of glycolysis especially phosphoenolpyruvate was decreased with an acute rise in ADP and gradual decrease in ATP and GSSG.
Conclusion: We demonstrate that Cana deprives human colon cancer cells of energy and anti-oxidative capacity possibly through an inhibition of SGLT1-mediated glucose influx, and thereby activates AMPK and inhibits cancer cell growth. Our data herein suggest a potential beneficial effect of Cana in suppressing colon cancer progression especially in patients with diabetes.
T. Yagi: None. T. Tanaka: Research Support; Self; Japan Society for the Promotion of Science. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Taisho Toyama Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited. E. Kubota: None. H. Koyama: None. T. Guo: None. K. Ogawa: None. D. Aotani: None. H. Kataoka: None.