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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Antineoplastic Agents / pharmacology
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Apoptosis
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Apoptosis Regulatory Proteins
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Camptothecin / analogs & derivatives*
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Camptothecin / pharmacology
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Carrier Proteins / chemistry*
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Carrier Proteins / metabolism
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Caspase 3
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Caspase 7
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Caspase 9
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Caspases / metabolism
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology
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Etoposide / pharmacology
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Humans
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Immunoblotting
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Irinotecan
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Mitochondrial Proteins / chemistry*
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Mitochondrial Proteins / metabolism
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Molecular Sequence Data
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Paclitaxel / pharmacology
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Peptides / chemistry
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Peptides / metabolism
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Protein Binding
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Protein Structure, Tertiary
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Proteins / chemistry*
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Proteins / metabolism
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Recombinant Fusion Proteins / metabolism
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Sequence Homology, Amino Acid
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Tumor Cells, Cultured
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Ubiquitin-Protein Ligases
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X-Linked Inhibitor of Apoptosis Protein
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Carrier Proteins
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DIABLO protein, human
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Peptides
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Proteins
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Recombinant Fusion Proteins
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Etoposide
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Irinotecan
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Doxorubicin
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BIRC2 protein, human
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Ubiquitin-Protein Ligases
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CASP3 protein, human
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CASP7 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 7
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Caspase 9
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Caspases
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Paclitaxel
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Camptothecin