Synergic Interaction between Simvastatin and Antineoplastic Drugs on Glioma Cell Growth
The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase produces mevalonate, which is used for the synthesis of cholesterol and several non sterol products in animal cells (Goldstein, Brown, 1990). Inhibition of this enzyme triggers regulatory response that lowers the concentrations of low density lipoproteins (LDL) in blood. A major relationship exists between the cell growth processes and the mevalonate biosynthetic pathway. HMG-CoA reductase activity is high in rapidly growing cells; conversely, when mevalonate synthesis is strongly inhibited cell growth is blocked (Goldstein, Brown, 1990). Thus, it has been suggested that mevalonate may play an important role in cell proliferation. Several studies have demonstrated the need for growing cells of at least two products synthesized from mevalonate in order to proliferate, and the only one yet identified is cholesterol (Habenicht et al.1980; Goldstein, Brown, 1990). Mevalonate is an essential precursor of several important cellular constituents, including: cholesterol, involved in cell membrane maintenance; heme A and ubiquinone, involved in electron transport; dolychol, required for glycoprotein synthesis; and isopentyl adenine, present in some transfer RNAs (Goldstein, Brown, 1990). The most recently discovered products of the HMG-CoA reductase reaction are the prenylated proteins (Glomset et al.1990; Maltese et al.1990). These proteins are attached to the cytoplasm leaflets of cell membranes by virtue of covalently bound isoprenoid groups, either farnesyl (15 carbons) or geranyl-geranyl (20 carbons), both of which are derived from mevalonate. Examples include the growth-controlling ras proteins which are bound to the plasma membrane, and the traffic-directing rab proteins, which are bound to intracellular vesicles.
KeywordsCholesterol Interferon Neuroblastoma Thymidine Simvastatin
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- Maltese WA, Sheridan KM (1985) Differentiation of neuroblastoma cells induced by an inhibitor of mevalonate synthesis:relation of neurite outgrowth and acetylcolinesterase activity to changes in cell proliferation and blocked isoprenoid synthesis. J Cell Physiol 125: 540–558PubMedCrossRefGoogle Scholar
- Somna MR, Pagliarini P, Butti G, Paoletti R, Paoletti P, Fumagalli R (1992) Simvastatin, an inhibitor of cholesterol biosynthesis, shows synergistic effect with N, N’-Bis(2-chloroethyl)-N-nitrosourea and beta interferon on human glioma cells. sCancer Res 52: 1–9Google Scholar