Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts.
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.
Williams
Simon
S
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Pettaway
Curtis
C
Song
Rendu
R
Papandreou
Christos
C
Logothetis
Christopher
C
McConkey
David J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001897:Boronic Acids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex