Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells.
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.
Carter
Bing Z
BZ
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gronda
Marcela
M
Wang
Zhiliang
Z
Welsh
Kate
K
Pinilla
Clemencia
C
Andreeff
Michael
M
Schober
Wendy D
WD
Nefzi
Adel
A
Pond
Gregory R
GR
Mawji
Imtiaz A
IA
Houghten
Richard A
RA
Ostresh
John
J
Brandwein
Joseph
J
Minden
Mark D
MD
Schuh
Andre C
AC
Wells
Richard A
RA
Messner
Hans
H
Chun
Kathy
K
Reed
John C
JC
Schimmer
Aaron D
AD
D000814:Aniline Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D003561:Cytarabine / Q000494:pharmacology; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein
D000814:Aniline Compounds; C500895:N-(6-((anilinocarbonyl)amino)-5-((anilinocarbonyl)((1-(4-cyclohexylbutyl)pyrrolidin-2-yl)methyl)amino)hexyl)-N-methyl-N'-phenylurea; D010671:Phenylurea Compounds; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003561:Cytarabine; D020169:Caspases