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 alpha1(I) and matrix metalloproteinase 2 (MMP-2) gene expression. Halofuginone also effectively suppresses tumor progression and metastasis in mice. These results together with the well-documented role of extracellular matrix (ECM) components and matrix degrading enzymes in formation of new blood vessels led us to investigate the effect of halofuginone on the angiogenic process. In a variety of experimental 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 deposition of subendothelial ECM. The most conclusive anti-angiogenic activity of halofuginone was demonstrated 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 promising drug for further evaluation in the treatment of a wide range of diseases associated with pathological angiogenesis.

Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect

“…In prostate cancer and Wilms' tumor xenografts, halofuginone, but not the respective chemotherapies, affected collagen a1(I) gene expression and collagen content. These results are consistent with our previous findings that halofuginone inhibited collagen type I synthesis in various preclinical studies in which excess of collagen was the hallmark of the disease (20,21), and halofuginone-dependent inhibition of collagen type I synthesis was correlated with reduction in tumor progression (26,27). In addition, only halofuginone inhibited the synthesis of Cygb/STAP, which is known to regulate collagen synthesis under the control of TGF-h (18,19), a finding that is consistent with the notion that halofuginone acts through the inhibition of Smad2/3 phosphorylation downstream of TGF-h (22 -24).…”

“…Cygb/STAP expression is upregulated under hypoxia and is regulated by the hypoxiainducible factor 1 (19), which regulates angiogenesis and is overexpressed in human cancers and their metastases (34). The inhibition of angiogenesis by halofuginone, in general (26), and of prostate cancer and Wilms' tumor xenografts, in particular (28,29), may suggest the involvement, at least in part, of hypoxia-inducible factor 1 -dependent Cygb/STAP overexpression in angiogenesis and tumor progression.…”

“…Human clinical efficacy was shown by topical dermal administration of halofuginone in patients with scleroderma and cGvHD (21). Halofuginone-dependent inhibition of collagen type I synthesis was associated with inhibition of microvessel formation in vitro and in vivo and resulted in decreased tumor growth in multiple murine models (26), including transplantable and chemically induced bladder carcinoma, glioma, von-Hippel-Lindau-associated pheochromocytoma (27), prostate cancer (28), and Wilms' tumor (29).…”

Diminished corneal angiogenesis in gelatinase A‐deficient mice

“…In this report, we demonstrated that the angiogenetic response induced by bFGF is markedly reduced in mice lacking a functional gelatinase A gene compared with that of wildtype animals. Our data con¢rm the results reported by Elkin et al [12] who showed that halofuginone, an inhibitor of collagen K1(I) and gelatinase A gene expression, almost completely suppressed bFGF-induced angiogenesis in vivo and inhibited endothelial capillary tube formation in vitro.…”

Type I collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma

“…18 The antiangiogenic effect of halofuginone has been described in several angiogenesis-dependent xenografts models. [18][19][20] For the first time, our data demonstrate that proangiogenic effect of Col(I) expression contributes to the angiogenic switch that subsequently facilitates the progression of microinvasive to deeply invasive tumors in a de novo melanoma model. …”