1. Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML.
- Author
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Carter BZ, Mak DH, Schober WD, Koller E, Pinilla C, Vassilev LT, Reed JC, and Andreeff M
- Subjects
- Animals, Apoptosis Regulatory Proteins, Blast Crisis genetics, Carrier Proteins genetics, Carrier Proteins metabolism, Caspase 6 biosynthesis, Caspase 6 genetics, Cell Line, Tumor, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic genetics, Gene Expression Regulation, Leukemic drug effects, Gene Expression Regulation, Leukemic genetics, Gene Knockdown Techniques, Humans, Imidazoles pharmacology, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Leukemia, Myeloid, Acute genetics, Mice, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Piperazines pharmacology, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Proto-Oncogene Proteins c-mdm2 genetics, Proto-Oncogene Proteins c-mdm2 metabolism, Stromal Cells metabolism, Tumor Suppressor Protein p53 genetics, X-Linked Inhibitor of Apoptosis Protein genetics, Apoptosis, Blast Crisis metabolism, Leukemia, Myeloid, Acute metabolism, Signal Transduction, Tumor Suppressor Protein p53 metabolism, X-Linked Inhibitor of Apoptosis Protein metabolism
- Abstract
Activation of p53 by murine double minute (MDM2) antagonist nutlin-3a or inhibition of X-linked inhibitor of apoptosis (XIAP) induces apoptosis in acute myeloid leukemia (AML) cells. We demonstrate that concomitant inhibition of MDM2 by nutlin-3a and of XIAP by small molecule antagonists synergistically induced apoptosis in p53 wild-type OCI-AML3 and Molm13 cells. Knockdown of p53 by shRNA blunted the synergy, and down-regulation of XIAP by antisense oligonucleotide (ASO) enhanced nutlin-3a-induced apoptosis, suggesting that the synergy was mediated by p53 activation and XIAP inhibition. This is supported by data showing that inhibition of both MDM2 and XIAP by their respective ASOs induced significantly more cell death than either ASO alone. Importantly, p53 activation and XIAP inhibition enhanced apoptosis in blasts from patients with primary AML, even when the cells were protected by stromal cells. Mechanistic studies demonstrated that XIAP inhibition potentiates p53-induced apoptosis by decreasing p53-induced p21 and that p53 activation enhances XIAP inhibition-induced cell death by promoting mitochondrial release of second mitochondria-derived activator of caspases (SMAC) and by inducing the expression of caspase-6. Because both XIAP and p53 are presently being targeted in ongoing clinical trials in leukemia, the combination strategy holds promise for expedited translation into the clinic.
- Published
- 2010
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