Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer

Pure and mixed isoprenoid end products of plant mevalonate metabolism trigger actions that suppress 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. These actions modulate HMG CoA reductase mRNA translation and the proteolytic degradation of HMG CoA reductase. Such post-transcriptional events, we propose, are activated directly by acyclic isoprenoids and indirectly by cyclic isoprenoids. Isoprenoids, acting secondarily to the dominant transcriptional effector of sterologenesis, modestly lower cholesterol levels, if and only if, sterologenesis is not repressed by a saturating imput of dietary cholesterol. An anomaly associated with tumor growth-a sterol feedback-resistant HMG CoA reductase activity-ensures a pool of sterologenic pathway intermediates. Such intermediates provide lipophilic anchors essential for membrane attachment and biological activity of growth hormone receptors, nuclear lamins A and B, and oncogenic ras. Tumor HMG CoA reductase retains high sensitivity to the isoprenoid-mediated secondary regulation. Repression of mevalonate synthesis by plant-derived isoprenoids reduces ras and lamin B processing, arrests cells in G1, and initiates cellular apoptosis. This unique tumor cell-specific sensitivity allows isoprenoids to be used for tumor therapy, an application emulating that of the statins, but one free of adverse effects. When evaluated at levels provided by a typical diet, isoprenoids individually have no impact on cholesterol synthesis and tumor growth. Nonetheless, isoprenoid-mediated activities are additive, and, sometimes synergistic. Therefore, the combined actions of the estimated 23,000 isoprenoid constituents of plant materials, acting in concert with other chemopreventive phytochemicals, may explain the lowered cancer risk associated with a diet rich in plant products. In contrast, that lowering of cancer risk does not correspond to supplemental intake of other dietary factors associated with fruits, vegetables, and cereal grains, namely fiber, beta-carotene, vitamin C, and vitamin E, and only weakly to supplemental folate.