Department of Internal Medicine, Division of Cardiology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
Department of Internal Medicine, Division of Cardiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Environ Toxicol. 2024 Nov;39(11):4844-4858. doi: 10.1002/tox.24362. Epub 2024 Jun 17.
Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1β/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.
环境抗肿瘤药物，如索拉非尼，可能通过水再循环对人类造成风险，而索拉非尼使用者的心脏毒性风险增加是一个临床问题。因此，开发预防索拉非尼心脏毒性的策略是当务之急。恩格列净作为一种用于 2 型糖尿病控制的钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂，已被批准用于心力衰竭治疗。然而，其在索拉非尼心脏毒性实验模型中的心脏保护作用尚未见报道。实时定量 RT-PCR（qRT-PCR）、免疫印迹和免疫组织化学分析用于研究索拉非尼暴露对心脏 SGLT2 表达的影响。通过 Alamar blue 测定法研究了索拉非尼处理的心肌细胞中恩格列净对细胞活力的影响。免疫印迹分析用于描绘索拉非尼和恩格列净对心肌细胞中铁死亡/促炎信号的影响。使用组织学分析研究了 28 天索拉非尼±恩格列净治疗小鼠的心肌组织中铁死亡/DNA 损伤/纤维化/炎症。索拉非尼暴露显著促进了心肌细胞和小鼠心脏中 SGLT2 的上调。恩格列净治疗显著减轻了索拉非尼诱导的心肌细胞和小鼠心脏中的细胞毒性/DNA 损伤/纤维化。此外，在索拉非尼处理的心肌细胞和心肌组织中，恩格列净还阻断了谷胱甘肽过氧化物酶 4/xCT 依赖性铁死亡作为释放高迁移率族盒 1（HMGB1）的诱导剂。此外，恩格列净治疗还显著抑制了心肌细胞和心肌组织中索拉非尼促进的 NFκB/HMGB1 轴，抑制了恩格列净给药抑制索拉非尼刺激的促炎信号（TNF-α/IL-1β/IL-6）。最后，恩格列净治疗显著减轻了索拉非尼在小鼠心脏中促进的巨噬细胞募集。总之，恩格列净通过调节铁死亡/DNA 损伤/纤维化/炎症，可能成为索拉非尼暴露下人类的心脏保护剂。然而，需要进一步的临床证据来支持这一临床前发现。
