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The synergistic effects of oxaliplatin and piperlongumine on colorectal cancer are mediated by oxidative stress.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-08-08 , DOI: 10.1038/s41419-019-1824-6 WeiQian Chen 1 , WeiShuai Lian 1 , YiFeng Yuan 1 , MaoQuan Li 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-08-08 , DOI: 10.1038/s41419-019-1824-6 WeiQian Chen 1 , WeiShuai Lian 1 , YiFeng Yuan 1 , MaoQuan Li 1
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Oxaliplatin-based chemotherapy is recommended as the first-line therapeutic regimen for metastatic colorectal cancer. However, long-term and repeated oxaliplatin therapy leads to drug resistance and severe adverse events, which hamper its clinical application. Thus, chemosensitizers are urgently required for overcoming oxaliplatin resistance and toxicity. Here, the anticancer effects of oxaliplatin combined with piperlongumine (PL), a molecule promoting reactive oxygen species (ROS) generation, in colorectal cancer, were assessed. We demonstrated that oxaliplatin elevated cellular ROS amounts and showed synergistic anticancer effects with PL in colorectal cancer cells. These anticancer effects were mediated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress apoptotic-associated networks. Meanwhile, blockage of ROS production prevented apoptosis and fully reversed mitochondrial dysfunction and ER stress associated with the oxaliplatin/PL combination. Moreover, xenograft assays in mouse models highly corroborated in vitro data. In conclusion, this study provides a novel combination therapy for colorectal cancer, and reveals that manipulating ROS production might constitute an effective tool for developing novel treatments in colorectal cancer.
中文翻译：
奥沙利铂和胡椒长明对结直肠癌的协同作用是由氧化应激介导的。
推荐以奥沙利铂为基础的化疗作为转移性结直肠癌的一线治疗方案。然而，奥沙利铂长期、反复治疗会导致耐药性和严重的不良事件，阻碍了其临床应用。因此，迫切需要化学增敏剂来克服奥沙利铂耐药性和毒性。本研究评估了奥沙利铂与胡椒长明 (PL)（一种促进活性氧 (ROS) 生成的分子）联合治疗结直肠癌的抗癌作用。我们证明奥沙利铂可提高细胞 ROS 含量，并在结直肠癌细胞中与 PL 表现出协同抗癌作用。这些抗癌作用是由线粒体功能障碍和内质网（ER）应激凋亡相关网络介导的。同时，阻断 ROS 产生可防止细胞凋亡，并完全逆转与奥沙利铂/PL 组合相关的线粒体功能障碍和 ER 应激。此外，小鼠模型中的异种移植测定高度证实了体外数据。总之，这项研究为结直肠癌提供了一种新颖的联合疗法，并揭示了操纵ROS的产生可能成为开发结直肠癌新疗法的有效工具。
更新日期：2019-08-08
中文翻译：
奥沙利铂和胡椒长明对结直肠癌的协同作用是由氧化应激介导的。
推荐以奥沙利铂为基础的化疗作为转移性结直肠癌的一线治疗方案。然而，奥沙利铂长期、反复治疗会导致耐药性和严重的不良事件，阻碍了其临床应用。因此，迫切需要化学增敏剂来克服奥沙利铂耐药性和毒性。本研究评估了奥沙利铂与胡椒长明 (PL)（一种促进活性氧 (ROS) 生成的分子）联合治疗结直肠癌的抗癌作用。我们证明奥沙利铂可提高细胞 ROS 含量，并在结直肠癌细胞中与 PL 表现出协同抗癌作用。这些抗癌作用是由线粒体功能障碍和内质网（ER）应激凋亡相关网络介导的。同时，阻断 ROS 产生可防止细胞凋亡，并完全逆转与奥沙利铂/PL 组合相关的线粒体功能障碍和 ER 应激。此外，小鼠模型中的异种移植测定高度证实了体外数据。总之，这项研究为结直肠癌提供了一种新颖的联合疗法，并揭示了操纵ROS的产生可能成为开发结直肠癌新疗法的有效工具。
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