Synergistic cytotoxicity from combination of imatinib and platinum-based anticancer drugs specifically in Bcr-Abl positive leukemia cells

Imatinib,a multitargeted tyrosine kinase inhibitor,exhibits potent anticancer activity against leukemia harboring the bcr-abl oncogene and some solid tumors overexpressing c-kit and pdgfr. however,its clinical efficacy is severely compromised by the emergence of resistance primarily due to acquired mutations in the bcr-abl kinase domain. in this study,we showed that combination of imatinib with platinum (pt)-based anticancer agents,including cisplatin and oxaliplatin,exhibited synergistic cytotoxic effect specifically in bcr-abl+ human chronic myeloid leukemia cell line k562 but not in bcr-abl- rpmi8226 cells. importantly,the synergistic effect was also found to circumvent imatinib resistance in an imatinib-selected resistant subline k562 ima1.0. the combination treatment increased apoptosis and dna damage. mechanistic study revealed that increased inhibition of bcr-abl and downstream erk phosphorylation by the drug combination may contribute to the synergistic effect. © 2015 japanese pharmacological society. production and hosting by elsevier b.v.