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Blood, 15 May 2005, Vol. 105, No. 10, pp. 4043-4050.
Prepublished online as a Blood First Edition Paper on February 1, 2005; DOI 10.1182/blood-2004-08-3168.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells
Bing Z. Carter,
Marcela Gronda,
Zhiliang Wang,
Kate Welsh,
Clemencia Pinilla,
Michael Andreeff,
Wendy D. Schober,
Adel Nefzi,
Gregory R. Pond,
Imtiaz A. Mawji,
Richard A. Houghten,
John Ostresh,
Joseph Brandwein,
Mark D. Minden,
Andre C. Schuh,
Richard A. Wells,
Hans Messner,
Kathy Chun,
John C. Reed, and
Aaron D. Schimmer
From the University of Texas MD Anderson Cancer Center, Houston, TX; the Ontario Cancer Institute, the Princess Margaret Hospital, the University Health Network, and the McLaughlin Center for Molecular Medicine, Toronto, Ontario, Canada; the Burnham Institute, and the Torrey Pines Institute for Molecular Studies, La Jolla, CA.
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-cyclohexylbutyl)pyrrolidin-2-yl]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 µM in 16 of 27 (60%) samples. In contrast, XIAP antagonist 1396-12 was not lethal to the normal hematopoietic 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 protein-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.
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