Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 901, Zhonghua Road, Yongkang District, Tainan, Taiwan R.O.C.
Division of Cardiology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan.
Arch Toxicol. 2021 Feb;95(2):659-671. doi: 10.1007/s00204-020-02951-8. Epub 2020 Nov 19.
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. We aimed to investigate the potential of dapagliflozin for preventing doxorubicin (Dox)-induced cardiotoxicity. 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 for 6 weeks followed by Dox for 4 weeks via intraperitoneal injection. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes cultured in high glucose were treated with dapagliflozin at 10 μM and subsequently exposed to Dox at 1 μM. Apoptosis and endoplasmic reticulum (ER) stress-related protein expression were measured. 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-2α, ATF-4, and CHOP. Our study revealed for the first time that dapagliflozin mitigated Dox-induced cardiomyocyte apoptosis in diabetes. These results indicate that dapagliflozin could be useful for preventing cardiotoxicity in diabetic cancer patients receiving Dox treatment.
患有糖尿病的癌症患者发生 dox 诱导性心脏毒性的风险增加。尽管先前的研究报告称达格列净对心血管系统有益，但尚不清楚达格列净是否对患有糖尿病的癌症患者具有心脏保护作用。我们旨在研究达格列净预防多柔比星（Dox）诱导的心脏毒性的潜力。我们使用台湾全民健康保险数据库调查了有或无糖尿病的癌症患者心力衰竭的发生率。链脲佐菌素（STZ）诱导的糖尿病大鼠口服达格列净预处理 6 周，随后腹腔注射 Dox 4 周。应用连续超声心动图评估心功能。对于体外分析，将高糖培养的心肌细胞用 10 μM 的达格列净处理，然后用 1 μM 的 Dox 暴露。测量细胞凋亡和内质网（ER）应激相关蛋白的表达。在所研究的患者中，患有糖尿病的患者发生重大不良心血管事件（包括心力衰竭的发展）的风险更高。在糖尿病大鼠中，达格列净减少了心脏纤维化，并显著改善了心脏功能。达格列净可有效抑制高糖条件下 Dox 诱导的心肌细胞凋亡和活性氧。在机制上，我们表明达格列净降低了 Bax 和 cleaved caspase 3 的心脏表达，但增加了 Bcl-2。达格列净还显著降低了包括 GRP78、PERK、eIF-2α、ATF-4 和 CHOP 在内的与 ER 应激相关的蛋白。我们的研究首次表明，达格列净减轻了糖尿病患者中 Dox 诱导的心肌细胞凋亡。这些结果表明，达格列净可用于预防接受 Dox 治疗的糖尿病癌症患者的心脏毒性。
