Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand.
Biochem Pharmacol. 2021 Oct;192:114743. doi: 10.1016/j.bcp.2021.114743. Epub 2021 Aug 26.
Doxorubicin (Dox) is widely used in chemotherapy regimens for several malignant conditions. Unfortunately, cumulative and irreversible cardiotoxicity of Dox is the most prominent adverse effect which limits its use. Several pharmacological interventions which exert antioxidant properties, including melatonin and metformin, have demonstrated beneficial effects against various cardiac pathological conditions. However, the exact molecular mechanisms underlying their cardioprotective effects are not completely understood. We hypothesized that treatment with either melatonin or metformin provides cardioprotection against Dox-induced cardiotoxicity through mitochondrial protection. Thirty-two male Wistar rats received 6 doses of either 0.9% normal saline solution (0.9% NSS, n = 8) or Dox (3 mg/kg, i.p., n = 24). The Dox-treated rats (n = 8/group) were co-treated with: 1) Vehicle (0.9% NSS), 2) Melatonin (10 mg/kg/day), and 3) Metformin (250 mg/kg/day) for 30 consecutive days via oral gavage. Following the treatment, left ventricular (LV) function, oxidative stress, inflammation, mitochondrial function, dynamics, biogenesis and bioenergetics, mitophagy, autophagy, and apoptosis were determined. Dox induced excessive oxidative stress, inflammation, autophagy, apoptosis, reduced mitochondrial function, dynamics balance, biogenesis, and bioenergetics leading to LV dysfunction. Treatment with either melatonin or metformin exerted equal measures of cardioprotection via reducing oxidative stress, inflammation, autophagy, apoptosis, and improved mitochondrial function, dynamics balance, biogenesis, and bioenergetics in the Dox-treated rats. Melatonin and metformin exerted both anti-cancer and cardioprotective properties, suggesting they have potential roles in concomitant therapy in cancer patients receiving Dox treatment.
多柔比星（Dox）广泛用于多种恶性疾病的化疗方案。不幸的是，Dox 的累积和不可逆的心脏毒性是最突出的不良反应，限制了其使用。几种发挥抗氧化特性的药理学干预措施，包括褪黑素和二甲双胍，已证明对各种心脏病理状况具有有益作用。然而，其心脏保护作用的确切分子机制尚不完全清楚。我们假设，褪黑素或二甲双胍的治疗通过线粒体保护提供对 Dox 诱导的心脏毒性的心脏保护作用。32 只雄性 Wistar 大鼠接受了 6 次 0.9%生理盐水溶液（0.9%NSS，n=8）或 Dox（3mg/kg，腹腔注射，n=24）中的任一组。Dox 处理的大鼠（n=8/组）分别用：1）载体（0.9%NSS）、2）褪黑素（10mg/kg/天）和 3）二甲双胍（250mg/kg/天）通过口服灌胃治疗 30 天。治疗后，测定左心室（LV）功能、氧化应激、炎症、线粒体功能、动力学、生物发生和生物能学、线粒体自噬、自噬和细胞凋亡。Dox 诱导过度的氧化应激、炎症、自噬、细胞凋亡、线粒体功能降低、动力学平衡、生物发生和生物能学，导致 LV 功能障碍。褪黑素或二甲双胍的治疗通过降低 Dox 处理大鼠的氧化应激、炎症、自噬、细胞凋亡，并改善线粒体功能、动力学平衡、生物发生和生物能学，发挥了同等程度的心脏保护作用。褪黑素和二甲双胍均具有抗癌和心脏保护特性，表明它们在接受 Dox 治疗的癌症患者的联合治疗中具有潜在作用。
