Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 129, Issue 4, Pages 210-215Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1016/j.jphs.2015.10.008
Keywords
Imatinib; Cisplatin; Oxaliplatin; Bcr-Abl; DNA damage
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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. (C) 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.
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