Halofuginone: a potent inhibitor of critical steps in angiogenesis progression

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)

[1]  S. Badylak,et al.  Endothelial cell adherence to small intestinal submucosa: an acellular bioscaffold. , 1999, Biomaterials.

[2]  S. Ben‐Sasson,et al.  Anticancer drug targets: approaching angiogenesis. , 1999, The Journal of clinical investigation.

[3]  V. Brower.  Tumor angiogenesis—new drugs on the block , 1999, Nature Biotechnology.

[4]  M. Neeman,et al.  Inhibition of neovascularization and tumor growth, and facilitation of wound repair, by halofuginone, an inhibitor of collagen type I synthesis. , 1999, Neoplasia.

[5]  A. Hochberg,et al.  Inhibition of bladder carcinoma angiogenesis, stromal support, and tumor growth by halofuginone. , 1999, Cancer research.

[6]  A. Hochberg,et al.  Inhibition of matrix metalloproteinase-2 expression and bladder carcinoma metastasis by halofuginone. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[7]  W. Stetler-Stevenson,et al.  Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. , 1999, The Journal of clinical investigation.

[8]  H. Tsuzuki,et al.  Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor. , 1999, Cancer research.

[9]  J. Paul Robinson,et al.  Small Intestinal Submucosa: A Tissue-Derived Extracellular Matrix That Promotes Tissue-Specific Growth and Differentiation of Cells in Vitro , 1998 .

[10]  M. Pines,et al.  Halofuginone: a novel antifibrotic therapy. , 1998, General pharmacology.

[11]  S. Itohara,et al.  Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. , 1998, Cancer research.

[12]  M. Pines,et al.  Inhibition of glomerular mesangial cell proliferation and extracellular matrix deposition by halofuginone. , 1997, Kidney international.

[13]  C. S. Chen,et al.  Geometric control of cell life and death. , 1997, Science.

[14]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[15]  O. Halevy,et al.  Inhibition of collagen type I synthesis by skin fibroblasts of graft versus host disease and scleroderma patients: effect of halofuginone. , 1996, Biochemical pharmacology.

[16]  J. Folkman,et al.  A model of angiogenesis in the mouse cornea. , 1996, Investigative ophthalmology & visual science.

[17]  W. Risau.  Differentiation of endothelium , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  M. Benezra,et al.  Antiproliferative activity to vascular smooth muscle cells and receptor binding of heparin-mimicking polyaromatic anionic compounds. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[19]  L. Ellis,et al.  The implications of angiogenesis for the biology and therapy of cancer metastasis , 1994, Cell.

[20]  H. Schnaper,et al.  Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro , 1993, Journal of cellular physiology.

[21]  Shant Kumar,et al.  Angiogenic oligosaccharides of hyaluronan enhance the production of collagens by endothelial cells. , 1993, Journal of cell science.

[22]  O. Halevy,et al.  Halofuginone: an inhibitor of collagen type I synthesis. , 1993, Biochimica et biophysica acta.

[23]  D. Ingber.  Extracellular matrix and cell shape: Potential control points for inhibition of angiogenesis , 1991, Journal of cellular biochemistry.

[24]  P. Bornstein,et al.  Transcriptional activity of the alpha 1(I)-collagen promoter is correlated with the formation of capillary-like structures by endothelial cells in vitro. , 1991, The Journal of biological chemistry.

[25]  M. Pines,et al.  Increased skin tearing in broilers and reduced collagen synthesis in skin in vivo and in vitro in response to the coccidiostat halofuginone. , 1991, Poultry science.

[26]  M. Iruela-Arispe,et al.  Differential expression of extracellular proteins is correlated with angiogenesis in vitro. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[27]  R. Nicosia,et al.  Growth of microvessels in serum-free matrix culture of rat aorta. A quantitative assay of angiogenesis in vitro. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[28]  J. Schittny,et al.  Molecular architecture of basement membranes , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  J. Folkman.  What is the evidence that tumors are angiogenesis dependent? , 1990, Journal of the National Cancer Institute.

[30]  D. Ingber,et al.  Inhibition of angiogenesis through modulation of collagen metabolism. , 1988, Laboratory investigation; a journal of technical methods and pathology.

[31]  Y Iwamoto,et al.  A rapid in vitro assay for quantitating the invasive potential of tumor cells. , 1987, Cancer research.

[32]  Z. Werb,et al.  Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. , 1986, The Journal of biological chemistry.

[33]  L. Liotta,et al.  Partial purification and characterization of a neutral protease which cleaves type IV collagen. , 1981, Biochemistry.

[34]  D. Gospodarowicz,et al.  Clonal growth of bovine vascular endothelial cells: fibroblast growth factor as a survival agent. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Folkman,et al.  Anti‐Angiogenesis: New Concept for Therapy of Solid Tumors , 1972, Annals of surgery.

[36]  J. Folkman.  Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[37]  S. Badylak,et al.  Small intestinal submucosa: a substrate for in vitro cell growth. , 1998, Journal of biomaterials science. Polymer edition.

[38]  M. Pines,et al.  Inhibition of collagen synthesis, smooth muscle cell proliferation, and injury-induced intimal hyperplasia by halofuginone. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[39]  H. Kleinman,et al.  Regulation of capillary formation by laminin and other components of the extracellular matrix. , 1997, EXS.

[40]  L Santi,et al.  Inhibition of AIDS-Kaposi's sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy. , 1994, Oncology research.

[41]  C. Jackson,et al.  Type I collagen fibrils promote rapid vascular tube formation upon contact with the apical side of cultured endothelium. , 1991, Experimental cell research.

[42]  D. Gospodarowicz,et al.  The extracellular matrix and the control of proliferation of vascular endothelial and vascular smooth muscle cells. , 1980, Journal of supramolecular structure.