Refractoriness to conventional chemotherapy is a major challenge in the treatment of advanced ovarian cancer (OC). There is increasing evidence that mitochondrial priming correlates with cisplatin response in various cancers. Notably, Bim and Bid, two of the proapoptotic BH3-only proteins, are recognized as the most effective inducers of mitochondrial priming in OC. In this study, we constructed two tumor-specific oncolytic adenoviruses (Ads) coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid), respectively, and performed gain-of-function assays in nine OC cell lines. Ad-tBid exhibited significant antitumor efficacy than the controls. On addition of Ad-tBid pretreatment, mito-primed cells displayed more sensitivity to cisplatin both in vitro and ex vivo. We also found that Ad-tBid induced mitochondrial apoptosis in a Bak-dependent manner. Furthermore, a combined cisplatin plus Ad-tBid therapy markedly inhibited tumor growth in a subcutaneous xenotransplanted tumor model. In mice bearing peritoneal disseminated OC, intraperitoneal administration of Ad-tBid potentiated the antitumor effect of cisplatin. Our findings suggest that Ad-tBid enhances cisplatin response in OC cells, establishing the potential treatment of advanced OC via a combination of cisplatin and Ad-tBid.

中文翻译：

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截断的投标通过激活卵巢癌中的线粒体凋亡途径调节顺铂反应。

对常规化疗的难治性是晚期卵巢癌 (OC) 治疗的主要挑战。越来越多的证据表明线粒体启动与各种癌症中的顺铂反应相关。值得注意的是，Bim 和 Bid 是两种仅 BH3 促凋亡蛋白，被认为是 OC 中最有效的线粒体启动诱导剂。在这项研究中，我们构建了两种分别编码 Bim (Ad-Bim) 或截短的 Bid (Ad-tBid) 的肿瘤特异性溶瘤腺病毒 (Ads)，并在九个 OC 细胞系中进行了功能获得测定。Ad-tBid 表现出比对照显着的抗肿瘤功效。添加 Ad-tBid 预处理后，线粒体引发的细胞在体外和体外均对顺铂表现出更高的敏感性。我们还发现 Ad-tBid 以 Bak 依赖性方式诱导线粒体凋亡。此外，顺铂联合 Ad-tBid 疗法显着抑制了皮下异种移植肿瘤模型中的肿瘤生长。在携带腹膜播散性 OC 的小鼠中，Ad-tBid 的腹膜内给药增强了顺铂的抗肿瘤作用。我们的研究结果表明 Ad-tBid 增强了 OC 细胞中的顺铂反应，通过顺铂和 Ad-tBid 的组合建立了晚期 OC 的潜在治疗方法。