p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells.

Abstract

Philadelphia chromosome positive chronic myeloid leukemia has a progressive course starting in a benign phase and terminating in a blastic phase. In this study, we show that human homolog double minute 2 (HDM2) inhibition, with MI-219-a novel compound, and consequently p53 stabilization induce chronic myeloid leukemia (CML) blast crisis cells to undergo apoptosis regardless of the presence of the T315I mutation in the BCR-ABL kinase domain. The response to MI-219 is associated with the downregulation of c-Myc and the induction of p21(WAF1). The p53 target and pro-apoptotic proteins PUMA, Noxa and Bax are induced, whereas full length Bid protein decreases with increased activity of pro-apoptotic cleaved Bid, and decrease of Mcl-1 is observed by increased caspase activity. CD95/FAS (FAS antigen) receptor is also induced by MI-219, indicating that both intrinsic and extrinsic apoptotic responses are transcriptionally induced. In addition, p53 protein accumulates in the mitochondrial fraction of treated cells involved in transcription-independent induction of apoptosis. We conclude that HDM-2 inhibition with MI-219 effectively induces p53-dependent apoptosis in most blast crisis CML cells, with or without BCR-ABL mutation(s).

• Authors: L F Peterson, E Mitrikeska, D Giannola, Y Lui, H Sun, D Bixby, S N Malek, N J Donato, S Wang, M Talpaz
• Journal: Leukemia (Leukemia) Vol. 25 Issue 5 Pg. 761-9 (May 2011) ISSN: 1476-5551 [Electronic] England
• PMID: 21350558 (Publication Type: Journal Article)

Chemical References

• Apoptosis Regulatory Proteins
• BAX protein, human
• BBC3 protein, human
• Indoles
• MI-291
• PMAIP1 protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Spiro Compounds
• TP53 protein, human
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Adult
• Aged
• Apoptosis
• Apoptosis Regulatory Proteins (metabolism)
• Blast Crisis (drug therapy, metabolism, pathology)
• Blotting, Western
• Female
• Flow Cytometry
• Genes, abl
• Humans
• Indoles (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism, pathology)
• Male
• Middle Aged
• Mutation (genetics)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Spiro Compounds (pharmacology)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (chemistry, genetics, metabolism)
• bcl-2-Associated X Protein (metabolism)