New benzimidazole acridine derivative induces human colon cancer cell apoptosis in vitro via the ROS-JNK signaling pathway

• Published in: Acta pharmacologica Sinica Vol. 36; no. 9; pp. 1074 - 1084
• Main Authors: Chen, Kang, Chu, Bi-zhu, Liu, Feng, Li, Bin, Gao, Chun-mei, Li, Lu-lu, Sun, Qin-sheng, Shen, Zhi-fa, Jiang, Yu-yang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2015; Nature Publishing Group
• Subjects: Acridines - chemistry; Acridines - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biomedical and Life Sciences; Biomedicine; Caspases - metabolism; Cell Line, Tumor; Colon - drug effects; Colon - metabolism; Colon - pathology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; HCT116 Cells; Humans; Immunology; Internal Medicine; JNK Mitogen-Activated Protein Kinases - metabolism; Medical Microbiology; Original; original-article; Pharmacology/Toxicology; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Vaccine; 体外培养; 体外诱导; 信号通路; 吖啶; 细胞凋亡; 结肠癌; 苯并咪唑; 衍生物; anticancer drug; benzimidazole acridine; colon cancer; ROS; death receptor-5; JNK1; apoptosis
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2015.44

Aim： To investigate the mechanisms underlying anticancer action of the benzimidazole acridine derivative N-{（1H-benzo[d]imidazol-2-yl） methyl}-2-butylacridin-9-amine （8m） against human colon cancer cells in vitro. Methods： Human colon cancer cell lines SW480 and HCT116 were incubated in the presence of 8m, and then the cell proliferation and apoptosis were measured. The expression of apoptotic/signaling genes and proteins was detected using RT-PCR and Western blotting. ROS generation and mitochondrial membrane depolarization were visualized with fluorescence microscopy. Results： 8m dose-dependently suppressed the proliferation of SW480 and HCT116 cells with ICso values of 6.77 and 3.33 pmol/L, respectively. 8m induced apoptosis of HCT116 cells, accompanied by down-regulation of Bcl-2, up-regulation of death receptor-5 （DR5）, truncation of Bid, cleavage of PARP, and activation of caspases （including caspase-8 and caspase-9 as well as the downstream caspases-3 and caspase-7）. Moreover, 8m selectively activated JNK and p38 without affecting ERK in HCT116 cells. Knockout of JNK1, but not p38, attenuated 8m-induced apoptosis. In addition, 8m induced ROS production and mitochondrial membrane depolarization in HCT116 cells. Pretreatment with the antioxidants N-acetyl cysteine or glutathione attenuated 8m-induced apoptosis and JNK activation in HCT116 cells. Conclusion： The new benzimidazole acridine derivative, 8m exerts anticancer activity against human colon cancer cells in vitro by inducing both intrinsic and extrinsic apoptosis pathways via the ROS-JNK1 pathway.