Suppression of dolichol synthesis with isoprenoids and statins may potentiate the cancer-retardant efficacy of IGF-I down-regulation.
Agents that inhibit the synthesis of mevalonate or of downstream isoprenoids block the G1-S transition and induce apoptosis in many cell lines; these agents include statins, phenylacetate, and a range of cyclic and acyclic isoprenoids. This cytostatic effect is mediated primarily by decreased availability of dolichol; this deficit impedes the glycosylation of nascent IGF-I receptors, preventing their transfer to the cell surface. In most tissues as well as transformed cell lines, IGF-I activity is crucial for transition to S phase, and also prevents apoptosis. Thus, down-regulation of serum levels of free IGF-I - as may be achieved by caloric restriction, low-fat vegan diets, and various estrogen agonists/antagonists - may represent a useful strategy for preventing and controlling cancer; however, a compensatory up-regulation of tissue expression of IGF-I receptors limits the efficacy of such an approach. Concurrent use of agents that inhibit dolichol synthesis can be expected to prevent an increase in plasma membrane IGF-I receptors, thus potentiating the cancer-retardant efficacy of IGF-I down-regulation. Since dolichol and IGF-I appear to be essential for angiogenesis, these measures may also prove useful for control of pathogenic neovascularization.
McCarty
M F
MF
Pantox Laboratories, San Diego, California 92109, USA.
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D004286:Dolichols / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000517:prevention & control*; D009389:Neovascularization, Pathologic; D013403:Sugar Phosphates / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000924:Anticholesteremic Agents; D004286:Dolichols; D013403:Sugar Phosphates; D007334:Insulin-Like Growth Factor I; D008798:Mevalonic Acid