Newly synthesized bis-benzimidazole compound 8 induces apoptosis, autophagy and reactive oxygen species generation in HeLa cells

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• 作者：Naying Chu^a ; ^&dagger ; ; Guodong Yao^b ; ^&dagger ; ; Yuan Liu^a ; Maosheng Cheng^c ; Takashi Ikejima^b ; ^{ikejimat@vip.sina.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：C8 ; compound 8 ; hPBMC ; human peripheral blood mononuclear cells ; ROS ; reactive oxygen species ; ZVAD ; Z-V-A-D(OMe)-FMK ; MTT ; methylthiazolyldiphenyl-tetrazoliumbromide ; PI ; propidium iodide ; AO ; acridine orange ; MMP ; mitochondrial membrane potential ; FasL ; Fas ligand ; FADD ; Fas-associated death domain ; MDC ; monodansylcadaverine ; 3MA ; 3-methyladenine ; H2DCF-DA ; 2&prime ; 7&prime ; -dichlorofluorescin diacetate ; NAC ; N-acetylcysteine
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 September 2016
• 年：2016
• 卷：26
• 期：17
• 页码：4367-4371
• 全文大小：1169 K

文摘

Compound 8 (C8) is a newly synthesized bis-benzimidazole derivative and exerts significant anti-tumor activity in vitro. Previous studies demonstrated that C8 induced apoptosis and autophagy in human promyelocytic leukemia HL60 cells. However, cytotoxicity study on human peripheral blood mononuclear cells (hPBMC) showed that C8 exhibited less toxicity in normal cells. In this study, the molecular mechanism of C8 on human cervical carcinoma HeLa cells was investigated. The results showed that C8 inhibited the growth of HeLa cells and triggered both apoptotic and autophagic cell death. Subsequent experiment also indicated that reactive oxygen species (ROS) generation was induced in C8-treated HeLa cells. Since ROS scavenger decreased the ratio of apoptotic and autophagic cells, ROS generation contributed to C8-induced apoptosis and autophagy. Furthermore, inhibitors of apoptosis and autophagy also reduced ROS generation, respectively. Autophagy inhibition increased cell growth compared to C8-treated group and attenuated apoptotic cell death, indicating that C8-induced autophagy promoted apoptosis for cell death. However, the percentage of autophagic cells was enhanced when limiting apoptosis process. Taken together, C8 induced ROS-mediated apoptosis and autophagy in HeLa cells, autophagy promoted apoptosis but the former was antagonized by the latter. The data also gave us a new perspective on the anti-tumor effect of C8.