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Research Articles: Therapeutics, Targets, and Development

Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma

¹ Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, ² Section of General Pathology, and ³ Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy; and ⁴ Novartis Pharma, Origgio, Italy

Requests for reprints: Angelo Vacca, Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare, 11, I-70124 Bari, Italy. Phone: 39-80-559-34-44; Fax: 39-80-559-21-89. E-mail: a.vacca{at}dimo.uniba.it

Abstract

Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma. [Mol Cancer Ther 2007;6(12):3256–62]

Grant support: Associazione Italiana per la Ricerca sul Cancro, Ministry of Universities and Research (MUR, PRIN Projects 2005, Project CARSO no. 72/2), Ministry of Health, Progetto Oncologia 2006, Humanitas Mirasole S.P.A., Novartis Pharma, and fellowships from Fondazione Italiana per la Ricerca sul Cancro (A.M.L. Coluccia and T. Cirulli).

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.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 5/ 3/07; revised 9/21/07; accepted 10/24/07.