Pl. Crowell et al., STRUCTURE-ACTIVITY-RELATIONSHIPS AMONG MONOTERPENE, INHIBITORS OF PROTEIN ISOPRENYLATION AND CELL-PROLIFERATION, Biochemical pharmacology, 47(8), 1994, pp. 1405-1415
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.