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, Aaron D. Schimmer

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4043-4050
Number of pages8
JournalBlood
Volume105
Issue number10
DOIs
StatePublished - May 15 2005
Externally publishedYes

Fingerprint

Dive into the research topics of 'Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells'. Together they form a unique fingerprint.

Cite this