Dapagliflozin protects Doxorubicin induced cardiotoxicity in patients with diabetes via suppressing ER stress

Abstract

Abstract Objectives Cancer patients with diabetes have an increasing risk of Doxorubicin (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 is to investigate the potentials of dapagliflozin in preventing Dox induced cardiotoxicity. Methods Using National Health Insurance Database, the incidence of heart failure of breast cancer patients with or without diabetes was investigated. Also, streptozotocin (STZ) induced diabetic rats were pretreated with oral dapagliflozin (10 mg/kg/day) for 6 weeks and received Dox (5 mg/kg/week) for 4 weeks via intraperitoneally injection. Sequential echocardiography was applied to assess the cardiac function. For in vitro analysis, H9C2 cardiomyocytes, cultured in high glucose (30 mM), were treated with dapagliflozin at 10 mM and subsequently exposed to Dox at 1 mM. The apoptosis and endoplasmic reticulum (ER) stress related protein expression were measured by immunohistochemistry and western blotting. Results Among the studied patients, those with diabetes have a higher risk of heart failure while patients prescribed with dapagliflozin lowered the risks. Correspondingly, dapagliflozin treatment effectively inhibited Dox-induced apoptosis and reactive oxygen species accumulation in cardiomyocytes. Also, the reduction of cardiac fibrosis as well as apoptosis in rats treated with dapagliflozin resulted in significantly improved cardiac function. Dapagliflozin also decreased the cardiac expression of Bax, cleaved caspase 3 and increased Bcl-2. Mechanistically, we showed that dapagliflozin significantly reduced ER stress-associated proteins including GRP78, PERK, eIF 2a, 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 in preventing cardiotoxicity in diabetic cancer patients receiving Dox treatment. Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): Chi-Mei Medical Center, Tainan, Taiwan