Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ.

Inhibitor of apoptosis proteins (IAPs) interact with and inhibit caspases-3, -7, and -9. This interaction can be inhibited by Smac/DIABLO, a polypeptide released from mitochondria upon initiation of the apoptotic signaling process. Here we demonstrate that the first 4-8 N-terminal amino acids of Smac/DIABLO fused to the Drosophila antennapaedia penetratin ...
sequence, a carrier peptide, enhance the induction of apoptosis and long term antiproliferative effects of diverse antineoplastic agents including paclitaxel, etoposide, 7-ethyl-10-hydroxycamptothecin (SN-38), and doxorubicin in MCF-7 breast cancer cells. Similar effects were observed in additional breast cancer and immortalized cholangiocyte cell lines. Further analysis demonstrated that the Smac-penetratin fusion peptide crossed the cellular membrane, bound XIAP and cIAP1, displaced caspase-3 from cytoplasmic aggregates, and enhanced drug-induced caspase action in situ. These studies demonstrate that inhibition of IAP proteins can modulate the efficacy of antineoplastic agents.
Mesh Terms:
Amino Acid Sequence, Antineoplastic Agents, Apoptosis, Camptothecin, Carrier Proteins, Caspase 3, Caspase 7, Caspase 9, Caspases, Dose-Response Relationship, Drug, Doxorubicin, Etoposide, Humans, Immunoblotting, Inhibitor of Apoptosis Proteins, Intracellular Signaling Peptides and Proteins, Mitochondrial Proteins, Molecular Sequence Data, Paclitaxel, Peptides, Protein Binding, Protein Structure, Tertiary, Proteins, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Tumor Cells, Cultured, X-Linked Inhibitor of Apoptosis Protein
J. Biol. Chem.
Date: Nov. 15, 2002
Download Curated Data For This Publication
143518
Switch View:
  • Interactions 2