期刊
BLOOD
卷 109, 期 8, 页码 3470-3478出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-02-005579
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资金
- NCI NIH HHS [P01 CA 46939] Funding Source: Medline
Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromo.. some-positive leukemia, but resistance develops in all phases of the disease. Bcr/Abl point mutations and other alterations reduce the kinase inhibitory activity of imatinib mesylate; thus, agents that target Bcr/Abl through unique mechanisms may be needed. Here we describe the activity of WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myrelogenous leukemia (CML) cells. Loss of Bcr/Abl protein correlated with the onset of apoptosis and reduced phosphorylation of Bcr/Abl substrates. WP1130 did not affect Hsp90/Hsp70 ratios within the cells and did not require the participation of the proteasomal pathway for loss of Bcr/Abl protein. WP1130 was more effective in reducing leukemic versus normal hematopoietic colony formation and strongly inhibited colony formation of cells derived from patients with T3151 mutant Bcr/Abl-expressing CML in blast crisis. WP1130 suppressed the growth of K562 hetero-transplanted tumors as well as both wildtype Bcr/Abl and T3151 mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T3151 mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML.
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