Suppression of dolichol synthesis with isoprenoids and statins may potentiate the cancer-retardant efficacy of IGF-I down-regulation

Abstract 

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.

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