title: Synergistic cytotoxicity from combination of imatinib and platinum-based anticancer drugs specifically in Bcr-Abl positive leukemia cells.
abstract: 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.
authors.affiliation: Department of Chemistry, The Chinese University of Hong Kong, Sha Tin, N.T., Hong Kong Special Administrative Region. Electronic address: weiym@link.cuhk.edu.hk.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wei
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Sha Tin, N.T., Hong Kong Special Administrative Region. Electronic address: kennethto@cuhk.edu.hk.
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.affiliation: Department of Chemistry, The Chinese University of Hong Kong, Sha Tin, N.T., Hong Kong Special Administrative Region. Electronic address: scfau-yeung@cuhk.edu.hk.
authors.forename: Steve C F
authors.initials: SC
authors.lastname: Au-Yeung
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D016313:Genes, abl / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000633:toxicity*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D002945:Cisplatin
keywords: Bcr-Abl; Cisplatin; DNA damage; Imatinib; Oxaliplatin