Effects of 2-aryl-1-cyano-1,2,3,4-tetrohydroisoquinolines on apoptosis induction mechanism in NB4 and MKN-45 cells

• Published in: Toxicology in vitro 2019-02, Vol.54, p.295-303
• Main Authors: Cao, Fang-Jun, Xu, Ming-Xuan, Zhou, Bo-Hang, Du, Yi-Si, Yao, Jun-Hu, Zhou, Le
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Aromatic compounds; Bcl-2 protein; Cancer; Caspase-3; Cell cycle; Cell Line, Tumor; Cells; Cytochrome; Cytochrome c; Cytochromes; Cytosol; Efflux; Flow cytometry; Humans; L-Lactate Dehydrogenase - metabolism; Malondialdehyde - metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Phosphorylation; Phosphotransferases - metabolism; Superoxide Dismutase - metabolism; Tetrahydroisoquinoline; Tetrahydroisoquinolines - pharmacology
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2018.10.007

Our previous study found that 2-aryl-1-cyano-1,2,3,4-tetrahydroisoquinolines (CATHIQs) have excellent anti-cancer activity and obvious apoptosis induction phenomenon. As our continuing research, this study further explored their underlying molecular mechanism of apoptosis induction in cancer cells. Flow cytometry analysis showed that the NB4 cells treated by 1-cyano-2-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline or the MKN-45 cells treated by 1-cyano-2-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline for 48 h were at early stage of apoptosis, and the cell cycle arrest was only slightly affected. Apoptosis rates of the cells significantly increase with the treatment concentration of the compounds. The compounds could significantly decrease the activities of SOD, raise the MDA level and promote the LDH leakage, suggesting that the excessive formation of ROS should be involved in the cell apoptosis. Western blot analysis showed that the compounds improved both Bax/Bcl-2 ratio and cleavages of procaspase-3, promoted efflux of cytochrome c to cytosol and phosphorylation of p38 and JNK, and attenuated phosphorylations of Akt and ERK. Together, inhibitions of PI3K/Akt and ERK and activation of p38 mediated the compounds-induced apoptosis through modulating the mitochondrial pathway and/or ROS production. [Display omitted] •The title compounds were able to induce apoptosis of the cancer cells NB4 and MKN-45.•The cell apoptosis was related with the excessive formation of ROS.•The cell apoptosis involved mitochondria pathway, MAPK pathway and PI3K/Akt pathway.•The title compounds are promising QBAs-like anticancer candidates.