Disease relevance of Halofuginone

• Halofuginone given orally before fibrosis induction prevented the activation of most of the stellate cells and the remaining cells expressed low levels of collagen alpha1(I) gene, resulting in low levels of collagen [1].
• These results suggest that halofuginone may become an effective and novel mode of therapy in the treatment of liver fibrosis [1].
• Halofuginone also effectively suppresses tumor progression and metastasis in mice [2].
• 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 [2].
• Halofuginone treatment alone exerted no toxicity but significantly lessened radiation-induced fibrosis [3].

High impact information on Halofuginone

• Halofuginone inhibited the proliferation of other cell types of the fibrotic liver in vivo and inhibited collagen production and collagen alpha1(I) gene expression in the SV40-immortalized rat HSC-T6 cells in vitro [1].
• 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 [2].
• 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 [2].
• Halofuginone also suppresses extracellular matrix deposition and cell proliferation [4].
• We have previously demonstrated that halofuginone, a widely used alkaloid coccidiostat, is a potent inhibitor of collagen alpha1(I) and matrix metalloproteinase 2 gene expression [4].

Chemical compound and disease context of Halofuginone

• We conclude that halofuginone is a potent in vivo inhibitor of bleomycin-induced pulmonary fibrosis, and that it may potentially be used as a novel therapeutic agent for the treatment of this dysfunction [5].
• The chemoprophylactic effects of halofuginone lactate were tested against calf experimental cryptosporidiosis [6].
• Nicarbazin and halofuginone have been widely used as coccidiostats for the prevention and treatment of coccidiosis in poultry [7].
• In a placebo-controlled field study 152 suckling calves were treated daily against cryptosporidiosis either with sulfadimidine or with halofuginone (Halocur, Intervet) over 1 week [8].
• Field study of the efficacy of halofuginone and decoquinate in the treatment of cryptosporidiosis in veal calves [9].

Biological context of Halofuginone

• We attribute the profound antitumoral effect of halofuginone to its combined inhibition of the tumor stromal support, vascularization, invasiveness, and cell proliferation [4].
• RESULTS: Treatment of fibroblasts with 10(-8)M halofuginone enhanced basal and mitogen-mediated phosphorylation of c-Jun in culture [10].
• We previously demonstrated that this inhibitory property was related to the ability of halofuginone to disrupt transforming growth factor beta signal transduction [10].
• Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats [11].
• Similarly, halofuginone inhibited the phosphorylation of p38 MAPK and apoptosis in activated T cells (P = 0.0001 and 0.005, respectively) [12].

Anatomical context of Halofuginone

• Although halofuginone failed to prevent proliferative preneoplastic alterations in the bladder epithelium, it inhibited further progression of the chemically induced tumor into a malignant invasive stage [4].
• OBJECTIVE: The naturally occurring compound halofuginone has been shown to antagonize collagen synthesis by fibroblasts both in vitro and in vivo [10].
• Halofuginone blocked TGF-beta-induced delocalization of tight junction ZO-1, a marker of epidermal mesenchymal transition, in NMuMg mammary epithelial cells and suggest halofuginone may have in vivo anti-fibrogenesis characteristics [3].
• Inhibition of collagen synthesis, smooth muscle cell proliferation, and injury-induced intimal hyperplasia by halofuginone [13].
• Under the same conditions, halofuginone exerted a relatively small antiproliferative effect on the respective vascular endothelial cells [13].

Associations of Halofuginone with other chemical compounds

• The efficacy of halofuginone lactate against natural Cryptosporidium parvum infection in 150 neonatal market calves of a mixed Belgian breed was tested [14].
• METHODS: Partial hepatectomy (70%) was performed in thioacetamide-induced cirrhotic rats fed a halofuginone-containing diet [11].
• The antiproliferative effect of halofuginone was associated with inhibition of tyrosine phosphorylation of cellular proteins [15].
• A total of 1,435 isolates from 17 samples of cattle, poultry, human, and wild-animal wastes were obtained, and their ability to grow in the presence of four concentrations of five antibiotics (chlortetracycline, halofuginone, oxytetracycline, salinomycin, and streptomycin) was measured [16].
• Screening for the coccidiostats halofuginone and nicarbazin in egg and chicken muscle: development of an ELISA [7].

Gene context of Halofuginone

• The results detail the molecular effects of halofuginone on the TGF-beta signal pathway and show that halofuginone may lessen radiation-induced fibrosis in humans [3].
• Because von Hippel-Lindau (VHL)-associated tumors express high levels of VEGF, it was of interest to ascertain the potential usefulness of halofuginone for treatment of these tumors [17].
• Additionally, inhibition of Smad3 by overexpression of the inhibitory Smad7 protein or by treatment with the small molecule, halofuginone, dramatically reduces responses in animal models of kidney, lung, liver and radiation-induced fibrosis [18].
• Halofuginone inhibits NF-kappaB and p38 MAPK in activated T cells [12].
• CONCLUSION: Our findings illustrate the powerful down-regulatory property of c-Jun toward type I collagen and establish that halofuginone exerts its effect on collagen synthesis in a c-Jun-dependent manner [10].

Analytical, diagnostic and therapeutic context of Halofuginone

• In both systems, oral administration of halofuginone resulted in a profound anticancerous effect, even when the treatment was initiated at advanced stages of tumor development [4].
• Northern blotting showed that overexpression of c-Jun enhanced the ability of halofuginone to reduce collagen alpha2(I) messenger RNA levels in fibroblasts, whereas expression of the dominant-negative c-Jun abolished this effect [10].
• Topical administration of a halofuginone-containing cream for 20 days to TSK mice, which spontaneously develop dermal fibrosis, greatly increased the phosphorylated form of c-Jun in the skin; this was followed by a decrease in skin thickness and type I collagen messenger RNA expression [10].
• We also determined whether halofuginone had an effect on the phosphorylation state of c-Jun in the skin of TSK/+ mice via immunohistochemistry [10].
• METHODS: The phosphorylation state of c-Jun in the presence of halofuginone was examined via direct Western blotting, and the transcriptional activity of the activator protein 1 (AP-1) binding element via electrophoretic mobility shift assay and luciferase reporter assay [10].

References