The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats

Reif, Shimon; Weis, Boaz; Aeed, Hussein; Gana-Weis, Mali; Zaidel, Liliana; Avni, Yona; Romanelli, Roberto Giulio; Pinzani, Massimo; Kloog, Yoel; Bruck, Rafael

doi:10.1016/s0168-8278(99)80318-3

Cited by 47 publications

(43 citation statements)

References 30 publications

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“…The therapeutic potential of this action has already been demonstrated in vivo in experimentally induced liver cirrhosis in rats (15), where treatment with FTS was shown to decrease fibrosis and inflammation. FTS also appeared to reduce cellular levels of Ras in hepatic cell membranes in vivo.…”

Section: Discussionmentioning

confidence: 94%

“…These actions could occur as a direct result of Ras antagonism in monocytes, as Ras has a key role both in the signaling of migration by chemokines and in anti-apoptotic pathways. Indeed, Reif et al (15) have demonstrated that FTS can inhibit PDGF-induced cell migration. Alternatively the actions of FTS on Ras in mesangial cells could indirectly alter monocyte number by altering the mesangial cell secretion of key cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 99%

“…Acting in this way, FTS has been shown to inhibit the growth of Ha-Ras and K-Ras transformed rodent fibroblasts in vitro (13,14). FTS has also been shown in vivo to decrease inflammation and fibrosis scores in experimentally induced liver cirrhosis in rats, with a reduction in Ras levels in membranes extracted from rat livers treated with FTS being demonstrated relative to controls (15).…”

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confidence: 99%

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Ras Antagonist Farnesylthiosalicylic Acid (FTS) Reduces Glomerular Cellular Proliferation and Macrophage Number in Rat Thy-1 Nephritis

Clarke¹,

Kocher²,

Khwaja³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Targeting the Ras family of monomeric GTPases has been suggested as a therapeutic strategy in proliferative renal diseases. This article reports the effects of Ras antagonist farnesylthiosalicylic acid (FTS) in rat thy-1 nephritis, a model in which cytokine-driven glomerular cell proliferation and invasion is likely to involve Ras signaling pathways. FTS in vitro specifically inhibits the binding of Ras to discrete membrane sites, thereby downregulating several Ras-dependent signaling functions and accelerating Ras degradation. Forty-four Lewis rats were given nephritis by day zero injection of a monoclonal thy-1 antibody ER4 (2.5mg/kg body wt). Twentytwo rats were then treated with daily intraperitoneal injection of FTS (5 mg/kg body wt) until sacrifice, and the remaining control rats were given vehicle alone (C). Six rats from each group were sacrificed at day 1 to establish equal injury; other sacrifice points were day 7 and day 10. Bromo-deoxyuridine (BrdU) was injected 1 h before sacrifice, after which sections were used for immunohistochemistry, which included detection of Ras expression, BrdUϩ cells and macrophages/monocytes (ED1ϩ). Thy-1 nephritis was associated with an increase in glomerular expression of Ki-Ras and N-Ras isoforms, which was almost fully prevented by FTS. FTS treatment was associated with: (a) a 54% reduction in the mean number of BrdUϩ cells per glomerulus (P Ͻ 0.01), (b) a 50% reduction in macrophages/monocytes (ED1ϩ) per glomerulus (P Ͻ 0.01), and (c) a reduction in 24-h proteinuria at day 10 (P Ͻ 0.05). These results show that Ras inhibition can reduce both glomerular cell proliferation and glomerular macrophage cell number in the thy-1 model and justify further study of FTS as a potential therapeutic in proliferative nephritis.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ras Antagonist Farnesylthiosalicylic Acid (FTS) Reduces Glomerular Cellular Proliferation and Macrophage Number in Rat Thy-1 Nephritis

Clarke¹,

Kocher²,

Khwaja³

et al. 2003

Journal of the American Society of Nephrology

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“…12,13 In a model of hepatic cirrhosis involving cellular proliferation, this agent was also beneficial in attenuating hepatocyte damage. 14 In the present study, we tested the hypothesis that functional inhibition of Ras could attenuate early and advanced atherosclerotic lesion formation in the apolipoprotein-E (apoE)-deficient mouse model.…”

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confidence: 99%

Functional Inhibition of Ras by S - trans , trans -Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

George

Afek²,

Keren³

et al. 2002

Circulation

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Background-Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis. Methods and Results-We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E-deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-B expression were considerably reduced compared with controls. Conclusions-FTS

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“…Amiloride, an Na+/H+ exchanger inhibitor, decreases PDGF-induced proliferation and modulates the fibrogenic effect of oxidative stress in HSCs (229,230) and has also been shown to be effective in experimental liver fibrosis (231). Sfarnesylthiosalicylic acid, a ras antagonist, inhibits proliferation and migration of HSCs and reduces thioacetamide-induced liver fibrosis in rats (232). The semisynthetic analogue of fumagillin, TNP-470, inhibits HSC proliferation by blocking the cell cycle transition from G1 to S, prevents HSC activation, and attenuates the progression of liver fibrosis (233).…”

Section: Hsc As a Target Of Antifibrotic Drugsmentioning

confidence: 99%

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

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The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats

Cited by 47 publications

References 30 publications

Ras Antagonist Farnesylthiosalicylic Acid (FTS) Reduces Glomerular Cellular Proliferation and Macrophage Number in Rat Thy-1 Nephritis

Ras Antagonist Farnesylthiosalicylic Acid (FTS) Reduces Glomerular Cellular Proliferation and Macrophage Number in Rat Thy-1 Nephritis

Functional Inhibition of Ras by S - trans , trans -Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

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