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.