Department of Biochemistry, Faculty of Science, University of Tabuk, 71491, Tabuk, Saudi Arabia.
Division of Biochemistry, Faculty of Science, Tanta University, Tanta City, 31512, Egypt.
Sci Rep. 2023 Dec 20;13(1):22782. doi: 10.1038/s41598-023-49578-0.
Chemoresistance and chemotherapy-related ovarian damage are well-reported in breast cancer (BC) young patients. Herein, the inhibition of the mitochondrial fission was invested to explore its chemosensitizing role in Paclitaxel (PTX)-resistant cells, and its ability to restore the ovarian integrity in mice receiving PTX or cisplatin chemotherapy. To establish these aims, PTX-resistance was generated in BC cells, which were treated with PTX in combination with Drp1 deficiency, via mdivi-1, or Drp1-specific siRNA transfection. Furthermore, the alterations in the ovarian structure and the endocrine-related hormones were explored in mice receiving repetitive doses of PTX or cisplatin. We found that combining PTX with mdivi-1 improved cell responsiveness to PTX, induced apoptosis- and autophagy-mediated cell death, and relieved cellular oxidative stress. Additionally, the expression of PCNA1 and cyclin B1 genes were downregulated, meanwhile, p53, p21, and mitochondrial fusion proteins (Mfu1&Mfu2) were increased. The in vivo investigations in mice demonstrated that PTX induced gonadotoxic damage similar to cisplatin, whereas dual treatment of mice with PTX+ mdivi-1 failed to restore their normal follicular count and the circulating levels of E2 and AMH hormones. These results suggested that combining Drp1 inhibition with PTX resensitized breast cancer cells to PTX but failed to offer enough protection against chemotherapy-related gonadotoxicity.
化疗耐药和化疗相关的卵巢损伤在乳腺癌（BC）年轻患者中已有报道。在此，我们研究了线粒体分裂的抑制作用，以探索其在紫杉醇（PTX）耐药细胞中的化疗增敏作用，以及其在接受 PTX 或顺铂化疗的小鼠中恢复卵巢完整性的能力。为了实现这些目标，我们在 BC 细胞中产生了 PTX 耐药性，通过 mdivi-1 联合 Drp1 缺乏、或 Drp1 特异性 siRNA 转染，用 PTX 处理这些细胞。此外，我们还在接受重复剂量的 PTX 或顺铂治疗的小鼠中研究了卵巢结构的改变和与内分泌相关的激素变化。我们发现，将 PTX 与 mdivi-1 联合使用可提高细胞对 PTX 的反应性，诱导凋亡和自噬介导的细胞死亡，并减轻细胞氧化应激。此外，PCNA1 和 cyclin B1 基因的表达下调，同时 p53、p21 和线粒体融合蛋白（Mfu1 和 Mfu2）增加。在接受重复剂量的 PTX 或顺铂治疗的小鼠的体内研究表明，PTX 诱导的性腺毒性损伤与顺铂相似，而用 PTX+mdivi-1 双重处理小鼠未能恢复其正常的卵泡计数和 E2 和 AMH 激素的循环水平。这些结果表明，抑制 Drp1 与 PTX 联合使用可使乳腺癌细胞对 PTX 重新敏感，但不能为化疗相关的性腺毒性提供足够的保护。
