• Nanwen Zhang, Lisen Huang, Jue Tian, Xianling Chen, Fang Ke, Ming Zheng, Jianhua Xu, and Lixian Wu.
• Dept. of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Institute of Materia Medica, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China.
• Pharmacol Rep. 2016 Apr 1; 68 (2): 423-8.

ObjectivesTo investigate the cytotoxicity of FM-Nov17 against chronic myeloid leukemia (CML) cells, we explored its underlying mechanisms mediating the induction of DNA damage and apoptotic cell death by reactive oxygen species (ROS).MethodsMTT assays were used to measure the proliferation-inhibition ratio of K562 and K562/G01 cells. Flow cytometry (FCM) was used to test the level of extracellular ROS, DNA damage, cell cycle progression and apoptosis. Western blotting was used to verify the amount of protein.ResultsFM-Nov17 significantly inhibited the proliferation of K562 cells, with an IC50 of 58.28±0.304μM, and K562/G01 cells, with an IC50 of 62.36±0.136μM. FM-Nov17 significantly stimulated the generation of intracellular ROS, followed by the induction of DNA damage and the activation of the ATM-p53-r-H2AX pathway and checkpoint-related signals Chk1/Chk2, which led to increased numbers of cells in the S and G2/M phases of the cell cycle. Furthermore, FM-Nov17 induced apoptotic cell death by decreasing mitochondrial membrane potential and activating caspase-3 and PARP. The above effects were all prevented by the ROS scavenger N-acetylcysteine.ConclusionsFM-Nov17-induces DNA damage and mitochondria-dependent cellular apoptosis in CML cells. The process is mediated by the generation of ROS.Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

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