A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis.
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 0.06mg/injection) as well as tumor growth (65% at 0.006mg/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 (0.6mg/plug). In vitro, BP7033 inhibited proliferation of human umbilical vein endothelial cells (HUVEC) (IC(50) value 3x10(-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.
Hamma-Kourbali
Yamina
Y
Laboratoire d'Oncologie Cellulaire et Moléculaire, UPRES 2360, Université Paris 13, UFR SMBH, Bobigny, France.
Di Benedetto
Mélanie
M
Ledoux
Dominique
D
Oudar
Olivier
O
Leroux
Yves
Y
Lecouvey
Marc
M
Kraemer
Michel
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001592:Benzyl Alcohols / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D009389:Neovascularization, Pathologic; D009584:Nitrogen / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans / Q000494:pharmacology; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; C479078:BP 7033; D001592:Benzyl Alcohols; D004164:Diphosphonates; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D009584:Nitrogen