Smac mimetic reverses resistance to TRAIL and chemotherapy in human urothelial cancer cells

Adam R. Metwalli, Sanaz Khanbolooki, Goodwin Jinesh, Debasish Sundi, Jay B. Shah, Marissa Shrader, Woonyoung Choi, Laura M. Lashinger, Srinivas Chunduru, David J. McConkey, Mark McKinlay, Ashish M. Kamat

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Inhibitors of apoptosis proteins (IAPs) have been shown to contribute to resistance of neoplastic cells to chemotherapy and to biologic antineoplastic agents. Consequently, new agents are being developed targeting this family of proteins. In a panel of bladder cancer cell lines, we evaluated a Smac mimetic that antagonizes several IAPs for its suitability for bladder cancer therapy. Results: Single-agent compound-A had little effect, but compound-A augmented TRAIL- and chemotherapy-induced apoptosis. Immunoblotting showed that combination treatment with compound-A and TRAIL resulted in cleavage of procaspase-3 and procaspase-7, activation of which irreversibly commits cells to apoptosis. Immunoprecipitation of XIAP showed displacement of active caspase-3 fragments from XIAP, supporting the proposed mechanism of action. Furthermore, siRNA-mediated silencing of XIAP similarly sensitized these cells to apoptosis. Experimental design: A panel of seven bladder cancer cell lines were evaluated for sensitivity to the Smac mimetic compound-A alone, TRAIL alone, chemotherapy alone, compound-A plus TRAIL and compound-A plus chemotherapy by DNA fragmentation analysis. IAP levels and caspase activation were examined by western blotting. Release of caspase-3 from X-linked inhibitor of apoptosis protein (XIAP), the most effective IAP, was assessed by immunoprecipitation and western blotting. Finally, siRNA knockdown of XIAP was correlated with the sensitivity of cells to apoptosis induced by compound-A plus TRAIL by DNA fragmentation and western blotting. Conclusion: Our results suggest that targeting of XIAP with the Smac mimetic compound-A has the potential to augment the effects of a variety of chemotherapeutic and biologic therapies in bladder cancer.

Original languageEnglish (US)
Pages (from-to)885-892
Number of pages8
JournalCancer Biology and Therapy
Volume10
Issue number9
DOIs
StatePublished - Nov 1 2010
Externally publishedYes

Keywords

  • Bladder cancer
  • Chemotherapy
  • IAP antagonist
  • Smac mimetic
  • TRAIL

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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