Curcumin analog EF24 induces apoptosis via ROS-dependent mitochondrial dysfunction in human colorectal cancer cells
Curcumin analog EF24 induces apoptosis via ROS-dependent mitochondrial dysfunction in human colorectal cancer cells
复制标题
姜黄素类似物 EF24 通过 ROS 依赖性线粒体功能障碍诱导人结直肠癌细胞凋亡
DOI：
10.1007/s00280-016-3172-x
复制
发表时间：
2016-12-01
影响因子：
3
通讯作者：
Wu, Wei
中科院分区：
文献类型：
--
作者：
He, Guodong;Feng, Chen;Wu, Wei
结直肠癌是世界上最常见的恶性肿瘤，死亡率高。迫切需要具有最小不良副作用的改进的治疗策略。在这项研究中，EF 24，一种新的类似物的天然化合物姜黄素的抗肿瘤作用进行了评估，在大肠癌cells.MethodsThe抗肿瘤活性EF 24对人结肠癌细胞系（HCT-116，SW-620，HT-29）的细胞周期阻滞，细胞凋亡和线粒体功能的措施进行了测定。ROS在EF 24诱导的抗肿瘤活性的贡献进行了评估，通过测量H2 O2和预处理与ROS清除剂，NAC.ResultsThe研究结果表明，EF 24治疗剂量依赖性地抑制细胞活力，并导致细胞周期停滞在G2/M期在所有测试的结肠癌细胞系。此外，我们证明EF 24处理通过增强HCT-116和SW-620细胞中ROS的细胞内积累而有效地诱导凋亡，但在HT-29细胞中具有中等效果。我们发现EF 24处理降低了结肠癌细胞中的线粒体膜电位，导致线粒体细胞色素c的释放。EF 24还诱导caspase 9和3的活化，导致Bcl-2蛋白表达和Bcl-2/Bax比值降低。活性氧清除剂NAC预处理可抑制EF 24诱导的细胞死亡、凋亡、细胞周期阻滞和线粒体功能障碍，提示EF 24的抗肿瘤作用可能与上游活性氧的产生有关。结论EF 24可能通过增加结肠癌细胞内活性氧的积累，导致线粒体膜的破坏，从而激活内源性凋亡信号通路。因此，EF 24可能是结肠癌治疗应用的潜在候选者。
PurposeColorectal cancer is the most commonly diagnosed malignancy with high mortality rates worldwide. Improved therapeutic strategies with minimal adverse side effects are urgently needed. In this study, the anti-tumor effects of EF24, a novel analog of the natural compound curcumin, were evaluated in colorectal cancer cells.MethodsThe anti-tumor activity of EF24 on human colon cancer lines (HCT-116, SW-620, and HT-29) was determined by measures of cell cycle arrest, apoptosis, and mitochondrial function. The contribution of ROS in the EF24-induced anti-tumor activity was evaluated by measures of H2O2and pretreatment with an ROS scavenger, NAC.ResultsThe findings indicated that EF24 treatment dose-dependently inhibited cell viability and caused cell cycle arrest at G2/M phase in all the tested colon cancer cell lines. Furthermore, we demonstrated that EF24 treatment induced apoptosis effectively via enhancing intracellular accumulation of ROS in both HCT-116 and SW-620 cells, but with moderate effects in HT-29 cells. We found that EF24 treatment decreased the mitochondrial membrane potential in the colon cancer cells, leading to the release of mitochondrial cytochrome c. Also, EF24 induced activation of caspases 9 and 3, causing decreased Bcl-2 protein expression and Bcl-2/Bax ratio. Pretreatment with NAC, a ROS scavenger, abrogated the EF24-induced cell death, apoptosis, cell cycle arrest, and mitochondrial dysfunction, suggesting an upstream ROS generation which was responsible for the anticancer effects of EF24.ConclusionsOur findings support an anticancer mechanism by which EF24 enhanced ROS accumulation in colon cancer cells, thereby resulting in mitochondrial membrane collapse and activated intrinsic apoptotic signaling. Thus, EF24 could be a potential candidate for therapeutic application of colon cancer.