Halofuginone: a potent inhibitor of critical steps in angiogenesis progression

ABSTRACT We have previously demonstrated that halofuginone, a low molecular weight quinazolinone alkaloid, is a potent inhibitor of collagen α1(I) and matrix metalloproteinase 2 (MMP‐2) gene expres¬sion. Halofuginone also effectively suppresses tu¬mor progression and metastasis in mice. These re¬sults together with the well‐documented role of extracellular matrix (ECM) components and matrix degrading enzymes in formation of new blood ves¬sels led us to investigate the effect of halofuginone on the angiogenic process. In a variety of experimen¬tal system, representing sequential events in the angiogenic cascade, halofuginone treatment resulted in profound inhibitory effect. Among these are the abrogation of endothelial cell MMP‐2 expression and basement membrane invasion, capillary tube formation, and vascular sprouting, as well as depo¬sition of subendothelial ECM. The most conclusive anti‐angiogenic activity of halofuginone was demon‐strated in vivo (mouse corneal micropocket assay) by showing a marked inhibition of basic fibroblast growth factor (bFGF) ‐induced neovascularization in response to systemic administration of halofuginone, either i.p. or in the diet. The ability of halofuginone to interfere with key events in neovascularization, together with its oral bioavailability and safe use as an anti‐parasitic agent, make it a promis¬ing drug for further evaluation in the treatment of a wide range of diseases associated with pathological angiogenesis.—Elkin, M., Miao, H.‐Q., Nagler, A., Aingorn, E., Reich, R., Hemo, I., Dou, H.‐L., Pines, M., Vlodavsky, I. Halofuginone: a potent inhibitor of critical steps in angiogenesis progression. FASEB J. 14, 2477–2485 (2000)