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Mol Cancer Ther. 2003;2:835-843
© 2003 American Association for Cancer Research

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

Simon Williams1, Curtis Pettaway1,2, Rendu Song2, Christos Papandreou3, Christopher Logothetis3 and David J. McConkey1

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

Requests for reprints: David McConkey, Department of Cancer Biology, Unit 173, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-8591; Fax: (713) 792-8747. E-mail: dmcconke{at}mdanderson.org

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.

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.

Grant support: A grant from the Department of Defense Prostate Cancer Research Program and developmental funds from the M.D. Anderson Prostate Cancer SPORE.

1 C. Papandreou and C. Logothetis, unpublished observations.

2 S. Williams and D. J. McConkey. The proteasome inhibitor bortezomib stabilizes a novel active form of p53 in human LNCaP-Pro5 prostate cancer cells, submitted for publication.

Received 5/ 5/03; revised 6/17/03; accepted 6/24/03.




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Copyright © 2003 by the American Association for Cancer Research.