STRUCTURE-ACTIVITY-RELATIONSHIPS AMONG MONOTERPENE, INHIBITORS OF PROTEIN ISOPRENYLATION AND CELL-PROLIFERATION

The monoterpene d-limonene inhibits the post-translational isoprenylat ion of p21ras and other small G proteins, a mechanism that may contrib ute to its efficacy in the chemoprevention and therapy of chemically i nduced rodent cancers. In the present study, the relative abilities of 26 limonene-like monoterpenes to inhibit protein isoprenylation and c ell proliferation were determined. Many monoterpenes were found to be more potent than limonene as inhibitors of small G protein isoprenylat ion and cell proliferation. The relative potency of limonene-derived m onoterpenes was found to be: monohydroxyl = ester = aldehyde> thiol > acid = diol = epoxide > triol = unsubstituted. All monoterpenes that i nhibited protein isoprenylation did so in a selective manner, such tha t 21-26 kDa proteins were preferentially affected. Perillyl alcohol, o ne of the most potent terpenes, reduced 21-26 kDa protein isoprenylati on to 50% of the control level at a concentration of 1 mM, but had no effect on the isoprenylation of 67, 47 or 17 kDa proteins. In particul ar, p21ras farnesylation was inhibited 40% by 1 mM perillyl alcohol. A t the same concentration, perillyl alcohol completely inhibited the pr oliferation of human HT-29 colon carcinoma cells. The structure-activi ty relationships observed among the monoterpene isoprenylation inhibit ors support a role for small G proteins in cell proliferation, and sug gest that many limonene-derived monoterpenes warrant further investiga tion as antitumor agents.