Department of Obstetrics and Gynecology, Lamphun Hospital, Lamphun 51000, Thailand; Neurophysiology Unit, 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.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Biochem Pharmacol. 2021 Jun;188:114587. doi: 10.1016/j.bcp.2021.114587. Epub 2021 Apr 29.
The standard chemotherapy regimens of ovarian cancer are platinum-based chemotherapy (carboplatin and paclitaxel) and bevacizumab (BEV). However, the effects of BEV alone or combined with carboplatin and paclitaxel on mitochondrial dynamics, mitochondrial function, mitophagy, apoptosis, inflammation and vascular endothelial growth factor (VEGF) in human ovarian cancer mitochondria and cells have not yet been investigated. Therefore, we aimed to test the hypothesis that 1) platinum-based chemotherapy and BEV equally damage isolated mitochondria from human ovarian cancers, and ovarian cancer cells through inducing mitochondrial dynamics dysregulation, mitochondrial dysfunction, increased mitophagy and apoptosis, as well as altered inflammation and VEGF; and 2) combined therapies exert greater damage than monotherapy. Each isolated human ovarian cancer mitochondria (n = 16) or CaOV3 cells (n = 6) were treated with either platinum-based chemotherapy (carboplatin 10 μM and paclitaxel 5 μM), BEV (2 mg/mL) or combined platinum-based chemotherapy and BEV for 60 min or 24 h, respectively. Following the treatment, mitochondrial dynamics, mitochondrial function, mitophagy, apoptosis, cytotoxicity, inflammation and VEGF were determined. Platinum-based chemotherapy caused ovarian cancer mitochondria and cell damage through mitochondrial dysfunction, increased cell death with impairment of membrane integrity, and enhanced VEGF reduction, while BEV did not. BEV caused deterioration of ovarian cancer mitochondria and cells through mitochondrial-dependent apoptosis, but it had no effect on cell viability. Interestingly, combined platinum-based chemotherapy and BEV treatments had no addictive effects on all parameters except mitochondrial maximal respiration, when compared to monotherapy. Collectively, these findings suggest that platinum-based chemotherapy and BEV caused human ovarian cancer mitochondrial and cell damage through different mechanisms.
卵巢癌的标准化疗方案是铂类化疗（卡铂和紫杉醇）和贝伐单抗（BEV）。然而，尚未研究 BEV 单独或与卡铂和紫杉醇联合应用对人卵巢癌细胞线粒体中线粒体动力学、线粒体功能、线粒体自噬、细胞凋亡、炎症和血管内皮生长因子（VEGF）的影响。因此，我们旨在检验以下假设：1）铂类化疗和 BEV 通过诱导线粒体动力学失调、线粒体功能障碍、增加线粒体自噬和细胞凋亡以及改变炎症和 VEGF，对人卵巢癌线粒体和细胞造成同等的损伤；2）联合治疗比单药治疗造成更大的损伤。分别用铂类化疗（卡铂 10 μM 和紫杉醇 5 μM）、BEV（2 mg/mL）或联合铂类化疗和 BEV 处理 16 个人源卵巢癌细胞线粒体或 6 个人源卵巢癌细胞 CaOV3，分别处理 60 min 或 24 h。处理后，测定线粒体动力学、线粒体功能、线粒体自噬、细胞凋亡、细胞毒性、炎症和 VEGF。铂类化疗通过线粒体功能障碍导致卵巢癌细胞线粒体和细胞损伤，导致细胞膜完整性受损的细胞死亡增加和 VEGF 减少，而 BEV 则没有。BEV 通过线粒体依赖性细胞凋亡导致卵巢癌细胞线粒体和细胞恶化，但对细胞活力没有影响。有趣的是，与单药治疗相比，联合铂类化疗和 BEV 治疗除了最大线粒体呼吸之外，对所有参数均无相加作用。总之，这些发现表明，铂类化疗和 BEV 通过不同的机制导致人卵巢癌细胞线粒体和细胞损伤。
