Curcumin analog EF24 induces apoptosis via ROS-dependent mitochondrial dysfunction in human colorectal cancer cells

• Published in: Cancer chemotherapy and pharmacology 2016-12, Vol.78 (6), p.1151-1161
• Main Authors: He, Guodong, Feng, Chen, Vinothkumar, Rajamanickam, Chen, Weiqian, Dai, Xuanxuan, Chen, Xi, Ye, Qingqing, Qiu, Chenyu, Zhou, Huiping, Wang, Yi, Liang, Guang, Xie, Yubo, Wu, Wei
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzylidene Compounds - pharmacology; Cancer Research; Caspases - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Curcumin - analogs & derivatives; Cytochromes c - metabolism; Humans; Medicine; Medicine & Public Health; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Oncology; Original Article; Pharmacology/Toxicology; Piperidones - pharmacology; Reactive Oxygen Species - metabolism
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-016-3172-x

Purpose Colorectal 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. Methods The 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 H 2 O 2 and pretreatment with an ROS scavenger, NAC. Results The 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. Conclusions Our 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.