Journal
BLOOD
Volume 105, Issue 10, Pages 4043-4050Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2004-08-3168
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- NCI NIH HHS [CA-55164] Funding Source: Medline
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We tested the effects of small-molecule XIAP antagonists based on a polyphenylurea pharmacophore on cultured acute myelogenous leukemia (AML) cell lines and primary patient samples. X-linked inhibitor of apoptosis protein (XIAP) antagonist N-[(5R)-6-[(anilinocarbonyl)amino]-5-((anilinocarbonyl){[(2R)-1-(4-cyclohexyl-butyl)pyrrolidin-2-y vertical bar]methyl}amino)hexyl]-N-methyl-N'-phenylurea (1396-12), but not a structurally related control compound, induced apoptosis of primary leukemia samples with a lethal dose (LD50) of less than 10 mu M in 16 of 27 (60%) samples. In contrast XIAP antagonist 1396-12 was not lethal to the normal hematopoletic cells in short-term cytotoxicity assays. Response of primary AML specimens to XIAP inhibitor correlated with XIAP protein levels, with higher levels of XIAP associated with sensitivity. The XIAP antagonist 1396-12 induced activation of downstream caspases 3 and 7 prior to the activation of upstream caspase 8 and caspase 9. Apoptosis induction was also independent of B-cell lymphoma pro- tein-2 (Bcl-2) or caspase 8, indicative of a downstream effect on apoptotic pathways. Thus, polyphenylurea-based XIAP antagonsists directly induce apoptosis of leukemia cells and AML patient samples at low micromolar concentrations through a mechanism of action distinct from conventional chemotherapeutic agents. (c) 2005 by The American Society of Hematology.
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