Dapagliflozin Protects Doxorubicin-induced Cardiotoxicity in Breast Cancer Patients With Diabetes via Suppressing ER Stress

Background: Cancer patients with diabetes have an increasing risk of Dox-induced cardiotoxicity. Despite previous studies reporting benefits of dapagliflozin on the cardiovascular system, it remains unknown whether dapagliflozin has a cardioprotective effect in cancer patients with diabetes receiving Dox therapy. The purpose of this study was to investigate the potential of dapagliflozin for preventing doxorubicin (Dox)-induced cardiotoxicity. Methods: : Using Taiwan National Health Insurance Database, the incidence of heart failure of cancer patients with or without diabetes was investigated. Streptozotocin (STZ)-induced diabetic rats were pretreated with oral dapagliflozin (10 mg/kg/day) for 6 weeks followed by Dox (5 mg/kg/week) for 4 weeks via intraperitoneal injection. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes cultured in high glucose (30 mM) were treated with dapagliflozin at 10 M and subsequently exposed to Dox at 1 M. Apoptosis and endoplasmic reticulum (ER) stress-related protein expression were measured by immunohistochemistry and Western blotting. Results: : Among the studied patients, those with diabetes had a higher risk of major adverse cardiovascular events including the development of heart failure. In diabetic rats, dapagliflozin reduced cardiac fibrosis and significantly improved cardiac function. Dapagliflozin effectively inhibited Dox-induced apoptosis and reactive oxygen species in cardiomyocytes under high glucose. Mechanistically, we showed that dapagliflozin decreased the cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2. Dapagliflozin also significantly reduced ER stress-associated proteins including GRP78, PERK, eIF-2, ATF-4, and CHOP. Conclusions: : Our study revealed for the first time that dapagliflozin mitigated Dox-induced cardiomyocyte apoptosis in diabetes via inhibiting ER stress. These results indicate that dapagliflozin could be useful for preventing cardiotoxicity in diabetic cancer patients receiving Dox treatment.