Abstract
Urothelial carcinoma of the bladder accounts for approximately 5% of all cancer deaths in humans. The large majority of bladder tumors are non-muscle invasive at diagnosis, but even after local surgical therapy there is a high rate of local tumor recurrence and progression. Current treatments extend time to recurrence but do not significantly alter disease survival. The objective of the present study was to investigate the tumoricidal potential of combining the apoptosis-inducing protein TNF-related apoptosis-inducing ligand (TRAIL) with a small molecule inhibitor of apoptosis proteins (IAP) antagonist to interfere with intracellular regulators of apoptosis in human bladder tumor cells. Our results demonstrate that the IAP antagonist Compound A exhibits high binding affinity to the XIAP BIR3 domain. When Compound A was used at nontoxic concentrations in combination with TRAIL, there was a significant increase in the sensitivity of TRAIL-sensitive and TRAIL-resistant bladder tumor lines to TRAIL-mediated apoptosis. In addition, modulation of TRAIL sensitivity in the TRAIL-resistant bladder tumor cell line T24 with Compound A was reciprocated by XIAP small interfering RNA-mediated suppression of XIAP expression, suggesting the importance of XIAP-mediated resistance to TRAIL in these cells. These results suggest the potential of combining Compound A with TRAIL as an alternative therapy for bladder cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / metabolism
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Caspases / metabolism
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Drug Synergism
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Gene Expression / drug effects*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / pharmacology*
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Mice
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitochondrial Proteins / pharmacology*
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Protein Binding
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Protein Structure, Tertiary
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / pharmacology
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Tumor Cells, Cultured
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Urinary Bladder Neoplasms / drug therapy
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Urinary Bladder Neoplasms / genetics
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Urinary Bladder Neoplasms / metabolism
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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DIABLO protein, human
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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RNA, Small Interfering
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Recombinant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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X-Linked Inhibitor of Apoptosis Protein
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Caspases