Pools of
farnesyl diphosphate and other phosphorylated products of the
mevalonate pathway are essential to the post-translational processing and physiological function of
small G proteins, nuclear
lamins, and
growth factor receptors. Inhibitors of
enzyme activities providing those pools, namely, 3-hydroxy-3-methylglutaryl
coenzyme A (
HMG CoA) reductase and
mevalonic acid-
pyrophosphate decarboxylase, and of activities requiring substrates from the pools, the
prenyl protein transferases, have potential for development as novel chemotherapeutic agents. Their potentials as suggested by the clinical responses recorded in Phase I and II investigations of inhibitors of
HMG CoA reductase (the
statins), of
mevalonic acid-
pyrophosphate decarboxylase (
sodium phenylacetate and
sodium phenylbutyrate), and of farnesyl
protein transferase (
R115777,
SCH66336,
BMS-214662,
Tipifarnib,
L-778,123, and, prematurely,
perillyl alcohol) are dimmed by dose-limiting toxicities. These nondiscriminant growth-suppressive agents induce G1 arrest and initiate apoptosis and differentiation, effects attributed to modulation of cell signaling pathways either by modulating gene expression, suppressing the post-translational processing of signaling
proteins and
growth factor receptors, or altering
diacylglycerol signaling. Diverse
isoprenoids and the
HMG CoA reductase inhibitor,
lovastatin, modulate cell growth, induce cell cycle arrest, initiate apoptosis, and suppress cellular signaling activities.
Perillyl alcohol, the
isoprenoid of greatest clinical interest, initially was considered to inhibit farnesyl
protein transferase; follow-up studies revealed that
perillyl alcohol suppresses the synthesis of
small G proteins and
HMG CoA reductase. In sterologenic tissues,
sterol feedback control, mediated by
sterol regulatory element binding proteins (SREBPs) 1a and 2, exerts the primary regulation on
HMG CoA reductase activity at the transcriptional level. Secondary regulation, a nonsterol
isoprenoid-mediated fine-tuning of
reductase activity, occurs at the levels of
reductase translation and degradation.
HMG CoA reductase activity in
tumors is elevated and resistant to
sterol feedback regulation, possibly as a consequence of aberrant SREBP activities. Nonetheless,
tumor reductase remains sensitive to
isoprenoid-mediated post-transcriptional downregulation.
Farnesol, an acyclic
sesquiterpene, and farnesyl homologs,
gamma-tocotrienol and various farnesyl derivatives, inhibit
reductase synthesis and accelerate
reductase degradation. Cyclic
monoterpenes,
d-limonene,
menthol and
perillyl alcohol and
beta-ionone, a
carotenoid fragment, lower
reductase mass;
perillyl alcohol and
d-limonene lower
reductase mass by modulating translational efficiency. The elevated
reductase expression and greater demand for nonsterol products to maintain growth amplify the susceptibility of
tumor reductase to
isoprenoids, therein rendering
tumor cells more responsive than normal cells to
isoprenoid-mediated growth suppression. Blends of
lovastatin, a potent nondiscriminant inhibitor of
HMG CoA reductase, and
gamma-tocotrienol, a potent
isoprenoid shown to post-transcription-ally attenuate
reductase activity with specificity for
tumors, synergistically affect the growth of human DU145 and LNCaP prostate
carcinoma cells and pending extensive preclinical evaluation, potentially offer a novel chemotherapeutic strategy free of the dose-limiting toxicity associated with high-dose
lovastatin and other nondiscriminant
mevalonate pathway inhibitors.