apr-246 and benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone

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.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Caspase 2; Caspase 3; Caspase 9; Caspase Inhibitors; Cytochromes c; Drug Evaluation, Preclinical; Enzyme Activation; Enzyme Inhibitors; Genes, p53; Humans; Membrane Potential, Mitochondrial; Mitochondria; Quinuclidines; Tissue Distribution; Tumor Cells, Cultured