Sensitization of human bladder tumor cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis with a small molecule IAP antagonist

Thomas S Griffith; Tamara A Kucaba; Michael A O'Donnell; Jennifer Burns; Christopher Benetatos; Mark A McKinlay; Stephen Condon; Srinivas Chunduru

doi:10.1007/s10495-010-0535-3

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Sensitization of human bladder tumor cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis with a small molecule IAP antagonist

Journal article

Peer reviewed

Sensitization of human bladder tumor cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis with a small molecule IAP antagonist

Thomas S Griffith, Tamara A Kucaba, Michael A O'Donnell, Jennifer Burns, Christopher Benetatos, Mark A McKinlay, Stephen Condon and Srinivas Chunduru

Apoptosis (London), Vol.16(1), pp.13-26

01/2011

DOI: 10.1007/s10495-010-0535-3

PMID: 20734142

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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.

Intracellular Signaling Peptides and Proteins - pharmacology

Gene Expression - drug effects

Apoptosis - drug effects

Humans

Intracellular Signaling Peptides and Proteins - metabolism

Mitochondrial Proteins - genetics

Antineoplastic Combined Chemotherapy Protocols - pharmacology

X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors

Caspases - metabolism

TNF-Related Apoptosis-Inducing Ligand - pharmacology

Urinary Bladder Neoplasms - genetics

Mitochondrial Proteins - metabolism

Tumor Cells, Cultured

Intracellular Signaling Peptides and Proteins - genetics

Urinary Bladder Neoplasms - metabolism

Protein Structure, Tertiary

Recombinant Proteins - metabolism

Antineoplastic Combined Chemotherapy Protocols - metabolism

Signal Transduction

RNA, Small Interfering - pharmacology

Recombinant Proteins - genetics

Urinary Bladder Neoplasms - drug therapy

TNF-Related Apoptosis-Inducing Ligand - metabolism

Drug Synergism

Mitochondrial Proteins - pharmacology

Animals

X-Linked Inhibitor of Apoptosis Protein - metabolism

Protein Binding

Mice

TNF-Related Apoptosis-Inducing Ligand - genetics

RNA, Small Interfering - metabolism

Details

Title: Subtitle: Sensitization of human bladder tumor cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis with a small molecule IAP antagonist
Creators: Thomas S Griffith - Department of Urology, University of Iowa, 375 Newton Road, Iowa City, IA 52242-1089, USA. thomas-griffith@uiowa.edu
Tamara A Kucaba
Michael A O'Donnell
Jennifer Burns
Christopher Benetatos
Mark A McKinlay
Stephen Condon
Srinivas Chunduru
Resource Type: Journal article
Publication Details: Apoptosis (London), Vol.16(1), pp.13-26
Publisher: Netherlands
DOI: 10.1007/s10495-010-0535-3
PMID: 20734142
ISSN: 1360-8185
eISSN: 1573-675X
Grant note: CA109446 / NCI NIH HHS
Language: English
Date published: 01/2011
Academic Unit: Urology
Record Identifier: 9984051569602771

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