期刊
CANCER RESEARCH
卷 66, 期 22, 页码 10959-10966出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-1216
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资金
- NCI NIH HHS [P30 CA16672, CA100632] Funding Source: Medline
Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Ab1 fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Ab1 kinase inhibitor imatinib against chronic-phase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Ab1 protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Ab1-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Ab1 transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Ab1 protein level. Imatinib directly inhibited the kinase activity of Bcr-Ab1. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Ab1 were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors.
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