Effect of dapagliflozin and/or L-arginine on solid tumor model in mice: The interaction between nitric oxide, transforming growth factor-beta 1, autophagy, and apoptosis

Abstract

Background: Nitric oxide was reported to play an essential role in various physiological and pathological processes in the body. Recent reports suggested that nitric oxide may affect the pathogenesis of cancer. Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor which is commonly used for type-2 diabetes mellitus management.

Purpose: The current work aimed to detect the potential impact of dapagliflozin and/or L-arginine on solid Ehrlich carcinoma (SEC) in mice.

Methods: Six equal groups of male BALB/c mice were divided as follows: Control; SEC; SEC + Dapagliflozin; SEC + L-arginine; SEC + carboxymethyl cellulose; and SEC + Dapagliflozin + L-arginine group. Tumor volume, survival rate, tissue total nitrate/nitrite, paraoxonase-1, interleukin 1 alpha (IL-1α), and transforming growth factor-beta 1 (TGF-β1) were determined. Also, caspase 3, beclin-1, and c-Jun NH2-terminal kinase (JNK) activities were estimated in the tumor tissues. Sections of the tumor tissues were examined by histopathology and immunohistochemistry.

Results: Dapagliflozin and/or L-arginine induced a significant increment of the survival rate, tissue total nitrate/nitrite, paraoxonase-1, caspase 3, beclin-1, and JNK activities, significant lowering of the tumor volume, tissue TGF-β1, and IL-1α expression alongside an improvement of the histopathologic findings, versus the SEC group. Notably, the combination of dapagliflozin/L-arginine exerted more pronounced effects versus each agent alone.

Conclusion: Dapagliflozin/L-arginine combination may confer a novel therapeutic line for cancer therapy.

Keywords: L-arginine; apoptosis; cancer; dapagliflozin; mice; nitric oxide.