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Research Articles: Therapeutics, Targets, and Development

Combination therapy with IFN- plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells

Departments of ¹ Cancer Biology, ² Urology, and ³ Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: David J. McConkey, Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Box 173, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8591; Fax: 713-792-8747. E-mail: dmcconke{at}mdanderson.org

Abstract

In a recent study, we showed that the proteasome inhibitor bortezomib sensitizes human bladder cancer cells to IFN-induced cell death. Here, we characterized the molecular mechanisms underlying the antitumoral effects of the combination in more detail. Bortezomib synergized with IFN- to promote apoptosis via a tumor necrosis factor–related apoptosis-inducing ligand–associated mechanism but did not inhibit production of proangiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) in human UM-UC-5 cells. In contrast, exposure to the combination did not increase the levels of apoptosis in human UM-UC-3 cells but did inhibit the production of basic fibroblast growth factor and vascular endothelial growth factor. Studies with tumor xenografts confirmed that combination therapy with bortezomib plus IFN- was effective in both models but that the effects were associated with differential effects on tumor necrosis factor–related apoptosis-inducing ligand–associated apoptosis (predominant in UM-UC-5) versus inhibition of angiogenesis (predominant in UM-UC-3). Together, our results show that combination therapy with IFN- plus bortezomib is effective but can work via different mechanisms (apoptosis versus angiogenesis inhibition) in preclinical models of human bladder cancer. [Mol Cancer Ther 2006;5(12):3032–41]

Grant support: M.D. Anderson Specialized Program of Research Excellence in Bladder Cancer grant P50 CA91846, Project 3.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ A. Papageorgiou, C. Dinney, and D.J. McConkey, manuscript submitted.

⁵ K. Zhu et al., in preparation.

⁶ Shrader et al., Mol Cancer Ther, in press.

Received 11/16/05; revised 9/27/06; accepted 10/30/06.