Suppressive effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin on colorectal tumorigenesis in diabetic and obese mice

Sodium-glucose cotransporter 2 inhibitors were developed for the treatment of diabetes mellitus. Although recent studies have indicated that sodium-glucose cotransporter 2 inhibitors have suppressive effects on several types of cancer, their effects against colorectal cancer remain unknown. The purpose of the present study was to investigate the effects of tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, on the development of colorectal cancer in diabetic and obese mice. The direct effects of tofogliflozin on the proliferation of colorectal cancer cells were also evaluated. C57BL/KsJ-db/db mice were injected with azoxymethane to induce colorectal pre-malignancy and they received drinking water with or without tofogliflozin. At the end of the study, administration of tofogliflozin was revealed to significantly suppress the development of colorectal neoplastic lesions and beta-catenin accumulated crypts. In the tofogliflozin-treated mice, the levels of blood glucose and serum TNF-alpha, as well as mRNA expression of the pro-inflammatory markers in the white adipose tissue, were reduced. Furthermore, macrophage infiltrations in the white adipose tissues were also reduced significantly. The proliferation of the sodium-glucose cotransporter 2-expressing human colorectal cancer cells was not altered by tofogliflozin. These results indicated that tofogliflozin ameliorated chronic inflammation and hyperglycemic condition leading to prevention of colorectal tumorigenesis in a diabetes- and obesity-related colorectal cancer model.