[Farnesyl transferase inhibitors: one target may be found in another].
Inserm U.563, Centre de Physiopathologie Toulouse Purpan, Département Innovation Thérapeutique et Oncologie Moléculaire, Institut Claudius Regaud, 20-24, rue du pont Saint-Pierre, 31052 Toulouse, France. Medecine sciences: M/S
(Impact Factor: 0.67).
03/2003; 19(2):211-6. DOI: 10.1051/medsci/2003192211
The fact that proteins such as Ras require farnesylation to induce malignant transformation prompted many investigators to design farnesyl transferase inhibitors (FTI) as novel anticancer drugs. FTIs inhibit the growth of ras transformed cells in vitro and induce tumor regression in ras dependent tumor in vivo. Moreover, FTIs inhibit tumor progression in human tumor xenograft models. Currently, FTIs are undergoing phase I and II trials in various cancer types. They show impressive antitumour efficacy and they lack toxicity. Despite these promising results, the development of such molecules in hindered by the absence of appropriate clinical endpoints and of surrogate biological markers. Indeed, it seems likely that Ras is not the critical target of FTIs and that inhibition of the farnesylation of proteins such as RhoB, might also contribute to the observed antitumour properties. Identification of targets that underlie their biological effect is essential in order to predict and evaluate their efficacy.
Available from: jpet.aspetjournals.org
- "Reducing the prenylation of proteins to treat NF1 has been recognized as a potential therapeutic approach. For example, the farnesyl transferase inhibitor (FTI) BMS-186511 (Mazieres et al., 2003) reduces proliferation of MPNST cell line ST88-14 (Yan et al., 1995), and FTI L-739,749 reduces proliferation of Nf-deficient mouse Schwann cells (Kim et al., 1997). A phase I clinical trial using FTI tipifarnib to treat plexiform neurofibromas was tolerated well in children, yet no objective responses were achieved (Widemann et al., 2006). "
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ABSTRACT: Neurofibromatosis type 1 (NF1) is a genetic disorder that is driven by the loss of neurofibromin (Nf) protein function. Nf contains a Ras-GTPase-activating protein domain, which directly regulates Ras signaling. Numerous clinical manifestations are associated with the loss of Nf and increased Ras activity. Ras proteins must be prenylated to traffic and functionally localize with target membranes. Hence, Ras is a potential therapeutic target for treating NF1. We have tested the efficacy of two novel farnesyl transferase inhibitors (FTIs), 1 and 2, alone or in combination with lovastatin, on two NF1 malignant peripheral nerve sheath tumor (MPNST) cell lines, NF90-8 and ST88-14. Single treatments of 1, 2, or lovastatin had no effect on Ras prenylation or MPNST cell proliferation. However, low micromolar combinations of 1 or 2 with lovastatin (FTI/lovastatin) reduced Ras prenylation in both MPNST cell lines. Furthermore, this FTI/lovastatin combination treatment reduced cell proliferation and induced an apoptotic response as shown by morphological analysis, procaspase-3/-7 activation, loss of mitochondrial membrane potential, and accumulation of cells with sub-G(1) DNA content. Little to no detectable toxicity was observed in normal rat Schwann cells following FTI/lovastatin combination treatment. These data support the hypothesis that combination FTI plus lovastatin therapy may be a potential treatment for NF1 MPNSTs.
Journal of Pharmacology and Experimental Therapeutics 08/2008; 326(1):1-11. DOI:10.1124/jpet.107.135830 · 3.97 Impact Factor
Available from: Tang Weihua
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ABSTRACT: The influences of Pr at Y- and Ba-sites on the superconductivity of YBa2Cu3Oy were studied comparatively. It is found that Pr at Y- and Ba-sites exhibit different Tc-depression behaviors. For the systems of Y1−xPrxBa2Cu3Oy, Y1−2xPrxCaxBa2Cu3Oy and YBa2−xPrxCu3Oy, the Tc vs. x relations can be fitted by the equations of Tc=92.3−105.9x2−81.7x, Tc=90−94.2x and Tc=90−567.7x2−7.52x, respectively. The parabolic term represents hole the filling effect, and the linear term describes depairing effect. The depression in superconductivity of Pr at Y-sites is due to both hole filling and depairing effects. However, Pr at Ba-sites seems to be due to hole filling only. The analysis of bond valence sums (BVS) suggests that the substitution of Pr for Ba affect indirectly through O4 sites on the hole concentration of CuO2 plane.
Physica C Superconductivity 04/1999; 315(1-2-315):59-65. DOI:10.1016/S0921-4534(99)00194-X · 0.94 Impact Factor
Available from: aseanfood.info
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ABSTRACT: Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, medicinal and cosmetic applications, especially nowadays in pharmaceutical, sanitary, cosmetic, agricultural and food industries. Because of the mode of extraction, mostly by distillation from aromatic plants, they contain a variety of volatile molecules such as terpenes and terpenoids, phenol-derived aromatic components and aliphatic components. In vitro physicochemical assays characterise most of them as antioxidants. However, recent work shows that in eukaryotic cells, essential oils can act as prooxidants affecting inner cell membranes and organelles such as mitochondria. Depending on type and concentration, they exhibit cytotoxic effects on living cells but are usually non-genotoxic. In some cases, changes in intracellular redox potential and mitochondrial dysfunction induced by essential oils can be associated with their capacity to exert antigenotoxic effects. These findings suggest that, at least in part, the encountered beneficial effects of essential oils are due to prooxidant effects on the cellular level.
Food and Chemical Toxicology 03/2008; 46(2):446-75. DOI:10.1016/j.fct.2007.09.106 · 2.90 Impact Factor
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