Abstract
p53 mutations occur frequently in human tumors. The low-molecular-weight compound PRIMA-1(MET) reactivates mutant p53, induces apoptosis in human tumor cells and inhibits tumor xenograft growth in vivo. Here, we show that PRIMA-1(MET) induces mutant p53-dependent mitochondria-mediated apoptosis through activation of caspase-2 with subsequent cytochrome c release and further activation of downstream caspase-9 and caspase-3. Inhibition of caspase-2 by a selective inhibitor and/or siRNA prevents cytochrome c release on PRIMA-1(MET) treatment and causes a significant reduction in PRIMA-1(MET)-induced cell death. Our findings highlight a chain of cellular events triggered by PRIMA-1(MET) that lead to apoptotic cell death. This should facilitate further development and optimization of efficient PRIMA-1(MET)-based anticancer drugs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Caspase 2 / metabolism*
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Caspase Inhibitors
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Cytochromes c / metabolism
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Drug Evaluation, Preclinical
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Genes, p53 / physiology
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Mitochondria / drug effects*
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Quinuclidines / pharmacology*
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Tissue Distribution / drug effects
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Tumor Cells, Cultured
Substances
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Amino Acid Chloromethyl Ketones
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Antineoplastic Agents
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Aza Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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Caspase Inhibitors
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Enzyme Inhibitors
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Quinuclidines
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Cytochromes c
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Caspase 2
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Caspase 3
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Caspase 9
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2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
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eprenetapopt