| Monoterpenes have chemopreventive and chemotherapeutic activities in a number of animal tumor models including rat mammary cancer models. Monoterpenes are generated in plant cells through mevalonate metabolism and have the potential to interfere with this pathway in animal cells. Inhibitors of farnesyl-protein transferase, one of the enzymes in this pathway, have been shown to prevent and treat tumors in animal models. Two monoterpenes, limonene and perillyl alcohol (POH), are currently in anticancer clinical trials. In order to understand the mechanism(s) of monoterpenes' antitumor activity so that more potent agents can be developed or identified, I studied the effects of monoterpenes on mevalonate metabolism. In the initial studies using cell lines, I found that monoterpenes inhibited small G protein isoprenylation, coenzyme Q (CoQ) synthesis and cholesterol synthesis. In NIH3T3 cells, the target enzymes for the observed inhibitions were type I and II geranylgeranyl-protein transferases, lathosterol 5-desaturase, and one or several enzymes in the CoQ synthesis branch of the pathway. In primary cultured rat mammary epithelial cell (RMEC) studies, both POH and its in vivo metabolites inhibited CoQ and cholesterol syntheses. However, POH did not inhibit protein isoprenylation while its metabolites did. Lastly, with the development of a novel method, I studied the effect of an anticancer dose of dietary POH on the mevalonate pathway in in situ RMEC, which are the origin of mammary carcinomas in rat mammary cancer models. Dietary POH modestly inhibited small G protein isoprenylation, including Ras prenylation by farnesyl-protein transferase and RhoA prenylation by type I geranylgeranyl-protein transferase, and CoQ synthesis. Dietary POH also raised the levels of Ras, RhoA and Rab6 proteins in these cells. These monoterpene-induced alterations are likely to be primary and may lead to those terminal biological events that are associated with the regressing mammary tumors such as inhibition of cell cycling, and the induction of differentiation and apoptosis. Further experimentations are necessary to evaluate the importance of these changes in in situ RMEC as they relate to the anticancer activities of monoterpenes. |
