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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0023473,
umls-concept:C0162638,
umls-concept:C0205263,
umls-concept:C0205314,
umls-concept:C0679622,
umls-concept:C1261381,
umls-concept:C1704259,
umls-concept:C1705987,
umls-concept:C1879547,
umls-concept:C1957026
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pubmed:issue |
8
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pubmed:dateCreated |
2007-4-5
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pubmed:abstractText |
Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromosome-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 myelogenous 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 T315I mutant Bcr/Abl-expressing CML in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T315I mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML.
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pubmed:grant |
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pubmed:commentsCorrections |
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http://linkedlifedata.com/resource/pubmed/commentcorrection/17202319-9426204
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0006-4971
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pubmed:author |
|
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
109
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3470-8
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
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