Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, P.O. Box: 56189-53141, Ardabil, Iran.
Department of Toxicology and Pharmacology, Faculty of Pharmacy, Damghan Islamic Azad University, Damghan, Iran.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Aug;393(8):1447-1457. doi: 10.1007/s00210-020-01853-x. Epub 2020 Mar 14.
Heart failure was subsequently noted in 2-4% of patients on bevacizumab (BEV). Whereas mitochondria play an important role in myocardial tissue homeostasis, deterioration in mitochondrial function will eventually lead to cardiomyocyte cell death and consequently cardiovascular dysfunction. Therefore, the aim of our study is to search the effects of BEV on isolated rat heart mitochondria and cardiomyocytes, and survey the effect of curcumin as a mitochondrial protective and cardioprotective agent. Rat heart mitochondria and cardiomyocytes were isolated from adult rat heart ventricular. By using biochemical and flow cytometry evaluations, the parameters of mitochondrial toxicity including succinate dehydrogenase (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse, reactive oxygen species (ROS) formation and lipid peroxidation (LP), and cellular assays such as cytotoxicity and MMP collapse were evaluated. Results revealed that BEV (up to 50 μg/ml) induced a concentration- and time-dependent rise in mitochondrial ROS formation, MMP collapse, mitochondrial swelling, LP, and inhibition of SDH in rat heart mitochondria. Our results showed that curcumin (10-100 μM) significantly ameliorated BEV-induced mitochondrial toxicities. Also, our results in cellular assays confirmed amelioration effect of curcumin against BEV toxicity. These results indicate that the cardiotoxic effects of BEV are associated with mitochondrial dysfunction and ROS formation, which finally ends in MMP collapse and mitochondrial swelling as the "point of no return" in the cascade of events leading to apoptosis. Also, results of this study suggest that probably the combination therapy of BEV and curcumin could decrease mitochondrial effects of this drug.
贝伐珠单抗（BEV）治疗后有 2-4%的患者出现心力衰竭。虽然线粒体在心肌组织稳态中起着重要作用，但线粒体功能的恶化最终将导致心肌细胞死亡，进而导致心血管功能障碍。因此，我们的研究目的是探讨 BEV 对分离的大鼠心肌线粒体和心肌细胞的影响，并研究姜黄素作为线粒体保护和心脏保护剂的作用。从成年大鼠心脏心室中分离大鼠心肌线粒体和心肌细胞。通过生化和流式细胞术评估，评估线粒体毒性的参数，包括琥珀酸脱氢酶（SDH）活性、线粒体肿胀、线粒体膜电位（MMP）崩溃、活性氧（ROS）形成和脂质过氧化（LP），以及细胞测定，如细胞毒性和 MMP 崩溃。结果表明，BEV（高达 50μg/ml）在大鼠心肌线粒体中诱导浓度和时间依赖性的线粒体 ROS 形成、MMP 崩溃、线粒体肿胀、LP 和 SDH 抑制增加。我们的结果表明，姜黄素（10-100μM）显著改善了 BEV 诱导的线粒体毒性。此外，我们在细胞测定中的结果证实了姜黄素对 BEV 毒性的改善作用。这些结果表明，BEV 的心脏毒性作用与线粒体功能障碍和 ROS 形成有关，这最终导致 MMP 崩溃和线粒体肿胀，成为导致细胞凋亡的级联事件中的“不归点”。此外，本研究结果表明，BEV 和姜黄素的联合治疗可能会降低该药物的线粒体作用。
