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

Abstract	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.
Authors	Christina R Arnt, Mihnea V Chiorean, Michael P Heldebrant, Gregory J Gores, Scott H Kaufmann
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 46 Pg. 44236-43 (Nov 15 2002) ISSN: 0021-9258 [Print] United States
PMID	12218061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Antineoplastic Agents Apoptosis Regulatory Proteins Carrier Proteins DIABLO protein, human Inhibitor of Apoptosis Proteins Intracellular Signaling Peptides and Proteins Mitochondrial Proteins Peptides Proteins Recombinant Fusion Proteins X-Linked Inhibitor of Apoptosis Protein XIAP protein, human Etoposide Irinotecan Doxorubicin BIRC2 protein, human Ubiquitin-Protein Ligases CASP3 protein, human CASP7 protein, human CASP9 protein, human Caspase 3 Caspase 7 Caspase 9 Caspases Paclitaxel Camptothecin
Topics	Amino Acid Sequence Antineoplastic Agents (pharmacology) Apoptosis Apoptosis Regulatory Proteins Camptothecin (analogs & derivatives, pharmacology) Carrier Proteins (chemistry, metabolism) Caspase 3 Caspase 7 Caspase 9 Caspases (metabolism) Dose-Response Relationship, Drug Doxorubicin (pharmacology) Etoposide (pharmacology) Humans Immunoblotting Inhibitor of Apoptosis Proteins Intracellular Signaling Peptides and Proteins Irinotecan Mitochondrial Proteins (chemistry, metabolism) Molecular Sequence Data Paclitaxel (pharmacology) Peptides (chemistry, metabolism) Protein Binding Protein Structure, Tertiary Proteins (chemistry, metabolism) Recombinant Fusion Proteins (metabolism) Sequence Homology, Amino Acid Tumor Cells, Cultured Ubiquitin-Protein Ligases X-Linked Inhibitor of Apoptosis Protein

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