The free carboxyl group of the terminal farnesylcysteine or geranylgeranylcysteine in a large number of prenylated proteins is methylated by the prenylated protein methyltransferase (PPMTase), a unique enzyme among methyltransferases and this enzyme tightly associates with the particulate fractions in eukaryotic cells. Ras proteins are members of a family of GTPases that are essential components of receptor-mediated signaling cascades which regulate cell growth and differentiation and are also important components of signaling pathways that regulate cell death, cell shape and cell motility.
Salirasib (S-trans,trans-Farnesylthiosalicylic acid (FTS)), a novel farnesylated rigid carboxylic acid derivative, acts as a potent competitive inhibitor of PPMTase with Ki of 2.6 mM. Salirasib inhibited the growth of human Ha-ras-transformed Rat1 cells in vitro with EC50 of 7.5 μM[3]. In Panc-1 cells, FTS at a concentration of 25 – 100 mM reduced the amount of Ras in a dose-dependent manner[4]. Daily FTS treatment (5 mg/kg intraperitoneally) in Panc-1 xenografted mice markedly decreased tumor growth (after treatment for 18 days, tumor volume had increased by only 23 ± 30-fold in the FTS-treated group and by 127 ± 66-fold in controls)[4]. Salirasib reduced survivin expression in a time- and dose-dependent manner. After 48h of incubation with 150 mM of salirasib, mRNA levels of survivin decreased by 60, 70 and 45% in HepG2, Hep3B and Huh7, respectively[5]. 9L gliosarcoma cells established tumor-bearing rats were treated with convection enhanced drug delivery (CED) of salirasib (50 μM), at 10 days, average tumor growth rates (normalized in each rat to the initial tumor volume and then averaged over the group of rats) was1.61 ± 0.32 in salirasib-treated rats compared with 3.22 ± 0.55 in control[6].
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