A novel synthetic novobiocin analog,FM-Nov17,induces DNA damage in CML cells through generation of reactive oxygen species

Objectives to 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). methods mtt 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. results fm-nov17 significantly inhibited the proliferation of k562 cells,with an ic50 of 58.28 ± 0.304 μm,and k562/g01 cells,with an ic50 of 62.36 ± 0.136 μm. 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. conclusions fm-nov17-induces dna damage and mitochondria-dependent cellular apoptosis in cml cells. the process is mediated by the generation of ros. © 2015 institute of pharmacology,polish academy of sciences. published by elsevier sp. z o.o. all rights reserved.