Erastin synergizes with cisplatin via ferroptosis to inhibit ovarian cancer growth in vitro and in vivo
Erastin synergizes with cisplatin via ferroptosis to inhibit ovarian cancer growth in vitro and in vivo
复制标题
Erastin 通过铁死亡与顺铂协同抑制卵巢癌的体外和体内生长
DOI：
10.1111/jog.14779
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发表时间：
2021-04-21
影响因子：
1.6
通讯作者：
Yi, Xiaofang
中科院分区：
文献类型：
--
作者：
Cheng, Qi;Bao, Lingjie;Yi, Xiaofang
目的 基于顺铂的化疗是卵巢癌的一线治疗方法。然而，卵巢癌经常出现对顺铂治疗的获得性耐药或严重的副作用，因此迫切需要有效的联合疗法来克服这些障碍。在本研究中，我们旨在揭示erastin和顺铂(CDDP)之间通过在体外和体内诱导铁死亡来抑制卵巢癌细胞生长的协同作用。方法我们进行了CCK-8测定来检测单独的erastin或与顺铂联合使用时的细胞活力，并通过蛋白质印迹分析提供了进一步的证实。使用透射电子显微镜和流式细胞仪分析来描述铁死亡的特征。此外，还构建了卵巢癌肿瘤异种移植物以验证体内效果。结果CDDP诱导卵巢癌细胞系中多种细胞死亡模式，包括铁死亡。从机制上讲，erastin 会引发铁死亡并增加活性氧 (ROS) 的水平，从而增强顺铂的细胞毒性作用。基于 CDDP 和erastin 的联合治疗似乎在体外和体内最大限度地提高了卵巢癌的治疗效果，同时最大限度地减少了副作用。结论总的来说，我们的结果表明，erastin 与顺铂协同作用，抑制卵巢癌细胞的生长，这可能是通过 ROS 介导的机制来操纵的，增强顺铂治疗，并为克服顺铂治疗耐药性提供了一种新策略。
Aim Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment or serious side effects often occurs in ovarian cancer, and thus, there is an urgent need for effective and combined therapies to overcome such obstacles. In the present study, we aimed to uncover synergistic effects between erastin and cisplatin (CDDP) in inhibiting ovarian cancer cell growth by inducing ferroptosis in vitro and in vivo.Methods We performed a CCK-8 assay to detect cell viability in response to erastin alone or in combination with cisplatin and provided further confirmation by western blotting analysis. Transmission electron microscopy and flow cytometry analysis were used to depict the characteristics of ferroptosis. In addition, an ovarian cancer tumor xenograft was built to verify the effects in vivo.Results CDDP induced multiple modes of cell death-including ferroptosis in ovarian cancer cell lines. Mechanistically, erastin triggered ferroptosis and increased the levels of reactive oxygen species (ROS) so as to augment the cytotoxic effect of cisplatin. Combination therapy based on CDDP and erastin appeared to maximize the therapeutic effects while minimizing side effects in ovarian cancer both in vitro and in vivo.Conclusion Collectively, our results indicate that erastin works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.