Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts

Simon Williams, Curtis Pettaway, Rendu Song, Christos Papandreou, Christopher Logothetis, David J. McConkey

Research output: Contribution to journalArticle

Abstract

Bortezomib (Velcade, PS-341) is a dipeptide boronate inhibitor of the 26S proteasome developed for use in cancer therapy. Here we examined the effects of bortezomib on apoptosis and angiogenesis in derivatives of two popular human prostate cancer cell lines (LNCaP-Pro5 and PC3M-Pro4). Bortezomib strongly inhibited proliferation in both cell lines in vitro , but the PC3M-Pro4 cells were significantly more sensitive than the LNCaP-Pro5 cells to bortezomib-induced apoptosis. The compound also significantly inhibited the growth of LNCaP-Pro5 and LNCaP-Pro4 tumor xenografts, but the mechanisms involved in tumor growth inhibition differed in the two models. Bortezomib-treated LNCaP-Pro5 tumors displayed reduced microvessel densities and vascular endothelial cell growth factor secretion and high levels of endothelial cell apoptosis consistent with angiogenesis inhibition. In contrast, PC3M-Pro4 tumors were poorly vascularized at baseline, and bortezomib failed to induce significant changes in microvessel density, angiogenic factor secretion, or endothelial cell death in this model. Rather, growth inhibition in the PC3M-Pro4 tumors was associated with direct increases in tumor cell death. Together, our results confirm that bortezomib is active in preclinical models of human prostate cancer, but its effects on apoptosis versus angiogenesis are cell type dependent.

Original languageEnglish (US)
Pages (from-to)835-843
Number of pages9
JournalMolecular cancer therapeutics
Volume2
Issue number9
StatePublished - Sep 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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