[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: 0.52). 03/2003; 19(2):211-6. DOI: 10.1051/medsci/2003192211
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the well established anti-cancer effect of farnesyltransferase inhibitor FTI-277, the neurotoxic effects of the agent are not yet clearly defined at the molecular and cellular levels. Here, we report the neurotoxic effects of FTI-277 and the involvement of reactive oxygen species (ROS) in FTI-induced neurotoxicity. Although there is no significant effect of FTI-277 for 2 days, long-term treatment of FTI-277 for 4 days induced dramatic reduction in outgrowth, maturation and branching of neuritis and considerable cytoxicity in a dose- and time-dependent manner in primary cultured rat embryo hippocampal neurons. Interestingly, FTI-277 for 4 days dramatically decreased expression of synapsin I, a crucial molecule involved in the neuronal growth and plasticity, and increased a cytotoxic G-protein RhoB of which ectopic expression induced the neurotoxicity in hippocampal neurons. Moreover, treatment with FTI-277 dramatically increased intracellular levels of ROS, which was sustained for 4 days; while blockage of ROS rescued FTI-277-induced neurotoxicity as well as both decrease of synapsin I and increase of RhoB. Taken together, these results provide the molecular insights for the mechanisms which might be of use aiming for avoiding neurotoxic side effects by FTI agent for a drug development for a clinical use.
    Biochemical and Biophysical Research Communications 10/2010; 403(1):91-6. DOI:10.1016/j.bbrc.2010.10.123 · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We describe here a piperazine alkyl derivative, NSC126188, which induced apoptosis of HeLa cells by upregulating RhoB expression. NSC126188 caused multi-septation of fission yeast and hypersensitized a ∆rho3 mutant, which implicates the involvement of functional human homolog RhoB. The treatment of cells with NSC126188 induced apoptosis and a dramatic increase in RhoB expression. In addition, RhoB knockdown using siRNA rescued cells from apoptosis, indicating a crucial role of RhoB in NSC126188-induced apoptosis. In a reporter assay using luciferase and EGFP under control of the RhoB promoter, NSC126188 increased both luciferase activity and the expression of EGFP, implicating transcriptional activation of RhoB by NSC126188. Furthermore, NSC126188 demonstrated in vivo anti-tumor activity, inhibiting tumor growth by 66.8% in a nude mouse xenograft using PC-3 human prostate cancer cells. These results suggest that NSC126188 is a potential lead compound and that upregulation of RhoB is associated with NSC126188-induced apoptosis.
    Investigational New Drugs 10/2011; 29(5):853-60. DOI:10.1007/s10637-010-9433-3 · 2.93 Impact Factor
  • [Show abstract] [Hide abstract]
    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 · 1.11 Impact Factor