Synergistic apoptosis induction in leukemic cells by miR-15a/16-1 and arsenic trioxide

MicroRNAs (miRNAs) are small noncoding RNAs that regulate target gene expression through translation repression or messenger RNA degradation. MiR-15a and 16-1 form a cluster at the chromosomal region 13q14, which is frequently deleted or down-regulated in chronic lymphocytic leukemia. Arsenic trioxide (As2O3, ATO) has been successfully applied to treat acute promyelocytic leukemia (APL). Its combination with other drugs presented therapeutic activities in hematologic and solid tumors. Here we investigated the potential synergy between miR-15a/16-1 and ATO on Bcr-Abl positive leukemic K562 cells. In this study, we found that combination of miR-15a/16-1 and ATO synergistically induced growth inhibition and apoptosis in K562 cells. The apoptosis, at least in part, through regulating mitochondrial function including the release of cytochrome c and loss of mitochondrial transmembrane potential, also activation of caspase-3 and degradation of poly-adenosine diphosphate-ribose polymerase. However, the expression of Bcr-Abl was not affected by ATO and/or miR-15a/16-1. Moreover, apoptotic synergy between miR-15a/16-1 and ATO was observed in Bcr-Abl negative leukemic cell lines and primary leukemic cells. Taken together, these findings suggested that the combined regiment of miR-15a/16-1 and ATO might be a potential therapeutic remedy for the treatment of leukemia. (C) 2010 Elsevier Inc. All rights reserved.