ubiquinone and perillyl-alcohol

The monoterpenes limonene and perillyl alcohol have been shown to induce the complete regression of rat mammary carcinomas by what appears to be a cytostatic and differentiation process. In order to evaluate the differentiating effects of the monoterpenes we tested the ability of perillyl alcohol to induce differentiation in a well-characterized neuroblastoma cell model. Perillyl alcohol was found to be a potent inducer of the neuroblastoma-derived cell line Neuro-2A. Several cellular effects of monoterpenes were ruled out as contributing to Neuro-2A differentiation including its cytostatic effect and its ability to inhibit ubiquinone (CoQ) syntheses.

Topics: Animals; Cell Differentiation; Cell Division; Cell Line; DNA; In Vitro Techniques; Mice; Monoterpenes; Neurites; Neuroblastoma; Terpenes; Tumor Cells, Cultured; Ubiquinone

We report the ability of Giardia lamblia to modify several of its cellular proteins by isoprenylation. Trophozoites cultured in the presence of [3H]mevalonate synthesized radiolabeled proteins of approx. 50 and 21-26 kDa. Chemical analysis indicated that farnesyl and geranylgeranyl isoprenoids comprised the majority of the radiolabel covalently associated with trophozoite proteins. In addition, antibodies to human p21ras immunoprecipitated mevalonate-labelled species of approx. 21 kDa. Inhibitors of several enzymatic steps of the mevalonate pathway dramatically affected Giardia metabolism. Protein isoprenylation and cell growth were blocked by compactin and mevinolin, competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in isoprenoid biosynthesis. In the presence of these inhibitors, Giardia growth was restored by the addition of mevalonate to the culture medium. In contrast, cell growth was blocked irreversibly by inhibitors of subsequent steps in the protein isoprenylation pathway. Trophozoite growth inhibition by limonene, perillic acid, perillyl alcohol and N-acetyl-S-farnesyl-L-cysteine was not reversed after the addition of mevalonate, dolichol, ubiquinone or cholesterol to the medium. These observations constitute the first description of protein isoprenylation in any protozoan and indicate that this post-translational modification is an important step in the regulation of the growth of this primitive eukaryote.

Topics: Acetylcysteine; Animals; Cholesterol; Cyclohexenes; Dolichols; Giardia lamblia; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Limonene; Lipid Metabolism; Lovastatin; Mevalonic Acid; Monoterpenes; Protein Prenylation; Proto-Oncogene Proteins p21(ras); Protozoan Proteins; Terpenes; Ubiquinone

Monoterpenes such as perillyl alcohol have been shown to cause the complete regression of advanced mammary carcinomas. Given the common origin of plant monoterpenes and many important molecules in mammalian mevalonate metabolism pathway, we investigated the effects of the monoterpene perillyl alcohol on mevalonate metabolism. NIH3T3 cells were labeled with [14C]mevalonolactone and lipids were analyzed. Perillyl alcohol inhibited ubiquinone synthesis and blocked the conversion of lathosterol to cholesterol. These two cellular effects of perillyl alcohol may contribute to the antitumor activity of the monoterpenes.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Carbon Radioisotopes; Cholesterol; Chromatography, High Pressure Liquid; Mevalonic Acid; Mice; Monoterpenes; Squalene; Terpenes; Ubiquinone