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

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.

• Authors: Claudio Scavelli, Giulia Di Pietro, Teresa Cirulli, Mauro Coluccia, Angela Boccarelli, Teresa Giannini, Giuseppe Mangialardi, Raffaello Bertieri, Addolorata Maria Luce Coluccia, Domenico Ribatti, Franco Dammacco, Angelo Vacca
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 12 Pt 1 Pg. 3256-62 (Dec 2007) ISSN: 1535-7163 [Print] United States
• PMID: 18089719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• DNA Primers
• Diphosphonates
• Imidazoles
• Vascular Endothelial Growth Factor A
• mevastatin
• Zoledronic Acid
• Lovastatin
• Receptors, Vascular Endothelial Growth Factor

Topics

• Adult
• Aged
• Base Sequence
• Blotting, Western
• Culture Media, Conditioned
• DNA Primers
• Diphosphonates (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• Imidazoles (pharmacology)
• Lovastatin (analogs & derivatives, pharmacology)
• Male
• Middle Aged
• Multiple Myeloma (blood supply)
• Neovascularization, Pathologic
• Phenotype
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Reverse Transcriptase Polymerase Chain Reaction
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)
• Zoledronic Acid