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

Angela Papageorgiou, Ashish Kamat, William F. Benedict, Colin Dinney, David J. McConkey

Research output: Contribution to journalArticle

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-α 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 interieukin-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-α 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-α plus bortezomib is effective but can work via different mechanisms (apoptosis versus angiogenesis inhibition) in preclinical models of human bladder cancer.

Original languageEnglish (US)
Pages (from-to)3032-3041
Number of pages10
JournalMolecular cancer therapeutics
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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