Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention

Abstract

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 inh...

Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

“…Although FPP lies upstream of GGPP in the mevalonate pathway, the addition of FPP would be unable to restore protein geranylgeranylation because a second molecule, isopentenyl PPi, is required for the conversion of FPP to GGPP. As isopentenyl PPi is also depleted by statin exposure, it would be unavailable to the statin-treated cell (49,50). These results, as well as the ability of GGTI-298 to induce apoptosis comparably with statins in sensitive tumor lines, build on previous reports (1,11,16,41) to clearly indicate the importance of protein geranylgeranylation in statininduced apoptosis.…”

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

“…Interestingly enough, this downregulation effect is observed in tissues that develop hormone-sensitive cancers responsive to T3 treatments such as prostate and breast. As a further example, malignant proliferation is associated with an increased HMG CoA reductase activity (Mo and Elson 2004) and T3 suppress the activity of this enzyme by either inhibition of reductase synthesis and accelerated degradation (Song and DeBose-Boyd 2006). Synergistic effects between statins and d-T3 or c-T3 have been demonstrated in in vitro anti-proliferative activity tests carried out in diverse tumor cells (McAnally et al 2007;Hussein and Mo 2009;Wali et al 2009a, b).…”

Posttranslational Protein Modifications

“…Related to inhibition of prenylation is the finding that a modest secondary benefit of cholesterol-lowering statins has been observed for a number of cancers driven by Ras expression (64). The chemotherapeutic rationale behind the benefit of statins is that because these drugs inhibit synthesis of isoprenoid precursors, a reduction of not just cholesterol but also farnesyl renders the tumorigenic cells susceptible to apoptosis due to diminished prenylation of Ras protein.…”