Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats

Bruck, R.

doi:10.1053/jhep.2001.21408

Cited by 128 publications

(122 citation statements)

References 57 publications

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“…48 However, portal-tract fibrogenesis was not a prominent feature in this model, and was better induced following treatment with b-estradiol or epidermal growth factor (EGF). The finding of TAA inducing predominantly parenchymal fibrosis is in keeping with our previously published work 49 in which immunohistochemistry demonstrated parenchymal deposition of fibrous tissue following TAA administration.…”

Section: Figuresupporting

confidence: 91%

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

Ohayon

Mawasi

Pevzner

et al. 2008

Laboratory Investigation

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Section: Figuresupporting

confidence: 91%

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

Ohayon

Mawasi

Pevzner

et al. 2008

Laboratory Investigation

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“…In hepatic fibrosis, halofuginone inhibited the activation of liver stellate cells, which is characterized by their transformation from quiescent, vitamin A -storing cells to highly proliferative, aSMA-positive cells that synthesize large amounts of collagen type I (25). The high levels of transgelin gene expression in the Wilms' tumor xenografts and the high levels of aSMA-positive fibroblasts in prostate cancer and Wilms' tumor control, untreated xenografts were inhibited by halofuginone, but not by the respective chemotherapies (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Samples were stained with Sirius red for collagen. In situ hybridization for collagen a1(I) was done as previously described (25). The primers used for preparing the transgelin (SMA22a) probe were F-GGCCAACA-AGGGTCCATCCTAT and R-AGGACATTGGCTTCCAA-GGACA.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

“…In animal models of fibrosis (adhesions, cGvHD, radiation-induced fibrosis, and pulmonary fibrosis), administration of halofuginone prevented the increase in collagen a1(I) gene expression and collagen synthesis. In the liver, halofuginone inhibited the synthesis of collagen type I and aSMA, resulting in inhibition of stellate cell activation and liver fibrosis (25). Human clinical efficacy was shown by topical dermal administration of halofuginone in patients with scleroderma and cGvHD (21).…”

Section: Introductionmentioning

confidence: 99%

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

Sheffer

Leon

Pinthus

et al. 2007

Molecular Cancer Therapeutics

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Stromal myofibroblasts play an important role in tumor progression. The transition of fibroblasts to myofibroblasts is characterized by expression of smooth muscle genes and profuse synthesis of extracellular matrix proteins. We evaluated the efficacy of targeting fibroblast-to-myofibroblast transition with halofuginone on tumor progression in prostate cancer and Wilms' tumor xenografts. In both xenografts, low doses of halofuginone treatment, independent of the route of administration, resulted in a trend toward inhibition in tumor development. Moreover, halofuginone synergizes with low dose of docetaxel in prostate cancer and vincristine and dactinomycin in Wilms' tumor xenografts, resulting in significant reduction in tumor volume and weight comparable to the effect observed by high doses of the respective chemotherapies.

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“…This may reflect the other immunological functions of this cytokine: animals that overexpress interferon-γ in the liver exhibit a diffuse inflammatory infiltrate (Toyonaga et al, 1994). Other compounds that block stellate cell activation include endothelin antagonists (Rockey and Chung, 1996;Cho et al, 2000), pentoxifylline Preaux et al, 1997), halofuginone (Pines et al, 1997;Bruck et al, 2001), fumagillin (Wang et al, 2000) and inhibitors of angiotensin II (Yoshiji et al, 2001). Natural products also have yielded candidate compounds, based on studies in culture and in experimental models of fibrosis.…”

Section: Inhibition Of Stellate Cell Activationmentioning

confidence: 99%

Chronic liver injury, TGF-β, and cancer

Bissell

2001

Exp Mol Med

155

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Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-β) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-β and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-β to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-β antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-β.

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Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats

Cited by 128 publications

References 57 publications

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

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

Chronic liver injury, TGF-β, and cancer

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