HMG-CoA reductase inhibitors (statins) as anticancer drugs (review).
Apart from their lipid lowering activity, HMG-CoA reductase inhibitors (statins) impair numerous cellular functions associated with metastasis, e.g. gene expression, angiogenesis, cell adhesion, cell motility and invasiveness. Furthermore, statins have impact on apoptotic cell death and modulate cellular susceptibility to cell killing by anticancer drugs and ionizing radiation. Part of the effects provoked by statins are due to the inhibition of the prenylation of low molecular weight GTPases, in particular Ras and Rho, which play key roles in signaling evoked by stimulation of cell surface receptors. C-terminal lipid modification of Ras/Rho GTPases is essential for their correct intracellular localization and function. By depletion of the cellular pool of isoprene precursor molecules, statins reduce the level of membrane-bound active Ras/Rho proteins, thereby impairing corresponding functions. Since broad clinical experience already exists for statins, their incorporation into established tumor-therapeutic regimens would be realizable in a rather short period of time. Here, data available at present arguing for the usefulness of statins in anticancer therapy are summarized and discussed.
Fritz
Gerhard
G
Department of Toxicology, University of Mainz, D-55131 Mainz, Germany. fritz@uni-mainz.de
D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death; D049109:Cell Proliferation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D011839:Radiation, Ionizing; D020703:ras GTPase-Activating Proteins / Q000187:drug effects / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020703:ras GTPase-Activating Proteins; D020741:rho GTP-Binding Proteins