Abstract：
There exist very limited non-hazardous therapeutic strategies except for surgical resection and lymphadenectomy against gastric cancer (GC) despite being the third leading cause of cancer deaths worldwide. This study proposes an innovative treatment approach against GC using a drug combination strategy that manipulates mitochondrial dynamics in conjunction with the induction of mitochondrial pathology-mediated cell death. Comparative analysis was done with gastric adenocarcinoma and normal cells by qPCR, western blot, microscopic immunocytochemistry, and live cell imaging. In this study, impairment of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission by Mdivi-1 created an imbalance in mitochondrial structural dynamics in indomethacin-treated AGS cells in which mitophagy-regulator protein PINK1 is downregulated. These drug combinations with the individual sub-lethal doses ultimately led to the activation of cell death machinery upregulating pro-apoptotic proteins like Bax, Puma, and Noxa. Interestingly, this combinatorial therapy did not affect normal gastric epithelial cells significantly and also no significant upregulation of death markers was observed. Moreover, the drug combination strategy also retarded cell migration and reduced stemness in GC cells. In summary, this study offers a pioneering specific therapeutic strategy for GC treatment, sparing normal cells providing opportunities for minimal drug-mediated toxicity utilizing mitochondria as a viable and specific target for anti-cancer therapy in gastric cancer.
摘要：
尽管是全球癌症死亡的第三大原因，但除了针对胃癌（GC）的手术切除和淋巴结切除术外，存在非常有限的非危险治疗策略。这项研究提出了一种针对GC的创新治疗方法，该方法使用药物组合策略来操纵线粒体动力学并诱导线粒体病理学介导的细胞死亡。通过qPCR对胃腺癌和正常细胞进行比较分析，westernblot,显微免疫细胞化学，和活细胞成像。在这项研究中,Mdivi-1对动力蛋白相关蛋白1（Drp1）介导的线粒体裂变的损害导致吲哚美辛处理的AGS细胞线粒体结构动力学失衡，其中线粒体自噬调节蛋白PINK1下调。这些药物与单个亚致死剂量的组合最终导致细胞死亡机制的激活，上调促凋亡蛋白如Bax，美洲狮,还有Noxa.有趣的是,这种联合治疗对正常胃上皮细胞没有显著影响,也没有观察到死亡标志物的显著上调.此外，药物组合策略还延迟了GC细胞的细胞迁移和干性降低。总之,这项研究为GC治疗提供了开创性的特定治疗策略，保留正常细胞，利用线粒体作为胃癌抗癌治疗的可行和特异性靶标，为最小的药物介导的毒性提供了机会。
