Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells.

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 microM 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.

• Authors: 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
• Journal: Blood (Blood) Vol. 105 Issue 10 Pg. 4043-50 (May 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15687241 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aniline Compounds
• N-(6-((anilinocarbonyl)amino)-5-((anilinocarbonyl)((1-(4-cyclohexylbutyl)pyrrolidin-2-yl)methyl)amino)hexyl)-N-methyl-N'-phenylurea
• Phenylurea Compounds
• Proteins
• Proto-Oncogene Proteins c-bcl-2
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• Cytarabine
• Caspases

Topics

• Aniline Compounds (pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cytarabine (pharmacology)
• Female
• Humans
• Leukemia, Myeloid, Acute (metabolism, pathology)
• Male
• Middle Aged
• Phenylurea Compounds (pharmacology)
• Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Tumor Cells, Cultured
• X-Linked Inhibitor of Apoptosis Protein