Sensitization of human bladder tumor cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis with a small molecule IAP antagonist |
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Authors: | Thomas S Griffith Tamara A Kucaba Michael A O’Donnell Jennifer Burns Christopher Benetatos Mark A McKinlay Stephen Condon Srinivas Chunduru |
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Institution: | (1) Department of Urology, 3204 MERF, University of Iowa, 375 Newton Road, Iowa City, IA 52242-1089, USA;(2) TetraLogic Pharmaceuticals, 365 Phoenixville Pike, Malvern, PA 19355, USA |
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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. |
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