Authors: Thomas S Griffith Tamara A Kucaba Michael A O’Donnell Jennifer Burns Christopher Benetatos Mark A McKinlay Stephen Condon Srinivas Chunduru
Publish Date: 2010/08/24
Volume: 16, Issue: 1, Pages: 13-26
Abstract
Urothelial carcinoma of the bladder accounts for approximately 5 of all cancer deaths in humans The large majority of bladder tumors are nonmuscle 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 apoptosisinducing protein TNFrelated apoptosisinducing 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 TRAILsensitive and TRAILresistant bladder tumor lines to TRAILmediated apoptosis In addition modulation of TRAIL sensitivity in the TRAILresistant bladder tumor cell line T24 with Compound A was reciprocated by XIAP small interfering RNAmediated suppression of XIAP expression suggesting the importance of XIAPmediated 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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