A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis

• Published in: Biochemical and biophysical research communications 2003-10, Vol.310 (3), p.816-823
• Main Authors: Hamma-Kourbali, Yamina, Di Benedetto, Mélanie, Ledoux, Dominique, Oudar, Olivier, Leroux, Yves, Lecouvey, Marc, Kraemer, Michel
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Benzyl Alcohols - chemistry; Benzyl Alcohols - pharmacology; Bisphosphonate; Cell Division; Cell Line, Tumor; Cells, Cultured; Collagen - pharmacology; Diphosphonates - chemistry; Diphosphonates - pharmacology; Dose-Response Relationship, Drug; Drug Combinations; Endothelial cells; Endothelium, Vascular - pathology; Female; Humans; In Vitro Techniques; Inhibitory Concentration 50; Laminin - pharmacology; Life Sciences; Mice; Mice, Nude; MMP-2; Models, Chemical; Neoplasm Transplantation; Neoplasms - drug therapy; Neovascularization, Pathologic; Nitrogen - pharmacology; Protein Processing, Post-Translational; Proteoglycans - pharmacology; Time Factors; Umbilical Veins - cytology; VEGF
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2003.09.083

Bisphosphonates (BP) are powerful inhibitors of bone resorption and are widely used in the treatment of patients with metastasis-induced osteolysis. In the present study, we show that a novel non-nitrogen-containing BP (BP7033) that exhibits antitumor activity is a potent inhibitor of both in vivo and in vitro angiogenesis. When administered to mice, BP7033 inhibited tumoral angiogenesis (65% at 0.06 mg/injection) as well as tumor growth (65% at 0.006 mg/injection) in a tumor model of A431 cells xenografted in nude mice, with no sign of toxicity. Additionally, in vivo angiogenesis induced by vascular endothelial growth factor-containing Matrigel implants was reduced by 90% in the presence of BP7033 (0.6 mg/plug). In vitro, BP7033 inhibited proliferation of human umbilical vein endothelial cells (HUVEC) (IC 50 value 3 × 10 −4 M) and completely prevented the formation of capillary-like tubules by HUVEC in Matrigel. Moreover, treatment of A431 cells by BP7033 induced an inhibition of Ras processing and a decrease in the secretion of both vascular endothelial growth factor and matrix metalloproteinase-2, two well-known stimulators of the proliferation and migration of endothelial cells. These findings indicate that this new BP compound has marked antiangiogenic properties and thus represents a promising candidate for treatment of malignant diseases with an angiogenic component.