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 acquir...
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| Main Authors: | , , |
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| Format: | Book |
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Elsevier,
2015-12-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | 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. |
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| Item Description: | 1347-8613 10.1016/j.jphs.2015.10.008 |