Impact of dapagliflozin on apoptosis and effector cytotoxic cells using breast cancer cells in mice

Background: Dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor with anti-inflammatory, antioxidant, and apoptosis modulator activity. Our purpose of this study was to assess the immediate impact of dapagliflozin on cytotoxicity and apoptosis of Ehrlich Ascites Carcinoma (EAC) cell lines in vitro and investigate its effect with a standard or high insulin diet in solid EAC-bearing mice compared to cyclophosphamide (CTX) chemotherapy. Methods: EAC cell lines were seeded for in vitro cytotoxicity by MTT assay and apoptosis after treatment with serial concentrations of dapagliflozin (1, 4, 10, 25, 50, and 100 M) for 24 hours. After that, solid EAC-bearing mice were inoculated subcutaneously at tumor growth, Mice were divided and treated with dapagliflozin in the presence of a low or high insulin diet or with a combination of dapagliflozin and CTX. Results: In vitro results showed that dapagliflozin at 25 M had a cytotoxic effect on EAC cell viability at 13.8% compared to untreated cells at 100%. Dapagliflozin at (25, 50, and 100) M gradually increased late apoptotic cell percentage (21, 33, and 46% respectively). In vivo results showed that the administration of EAC-bearing mice with an average glucose diet in the presence of dapagliflozin increased the percentage of effector CD8 T cells population (CD8+ KLRG1+) to 13.6% compared to CTX, and control group 2.8%, 7.7% respectively. Conclusions: Dapagliflozin and cyclophosphamide can be used as a combination to increase antitumor activity and enhance immunologic and pathological outcomes.