Potent suppression of proliferation of a10 vascular smooth muscle cells by combined treatment with lovastatin and 3-allylfarnesol, an inhibitor of protein farnesyltransferase.
Statins, which inhibit 3-hydroxy-3-methylglutaryl-CoA reductase and thus the synthesis of cholesterol, are remarkably effective in the treatment of cardiovascular disease. In addition to their favorable effect on lipid profile, these drugs may also prevent the proliferation of vascular smooth muscle that is characteristic of atherosclerosis. We hypothesize that statins prevent the post-translational prenylation, and thus inhibit the function, of critical small GTPases in vascular smooth muscle cells. We have therefore assayed the effect of lovastatin on both the growth of A10 vascular smooth muscle cells and the status of their Ras and RhoB proteins. We find that < or =1 microM lovastatin potently inhibits the proliferation of A10 cultures, and higher concentrations (> or =3 microM) induce apoptosis. We have also tested the effect of 3-allylfarnesol (3-alFOH), an inhibitor of farnesyl transferase (FTI). The data show that although > or =10 microM 3-alFOH is required for a cytostatic effect, the action of 3 microM 3-alFOH can be greatly potentiated by even nanomolar levels of lovastatin. We also find that lovastatin and 3-alFOH exhibit synergism to cause the up-regulation and relocalization of RhoB from the membrane to cytosolic compartments. This relocalization of RhoB, which is presumed to reflect an inhibition of its prenylation, correlates with the proapoptotic activities of combined 3-alFOH and lovastatin treatment. These data suggest that RhoB may be a valuable pharmacological target in cardiovascular disease, and that combinations of statins and certain FTIs may be of value in treatment of disorders that are characterized by excess cell proliferation.
Mattingly
Raymond R
RR
Department of Pharmacology, Wayne State University, Detroit, Michigan 48201, USA. r.mattingly@wayne.edu
Gibbs
Richard A
RA
Menard
Raymond E
RE
Reiners
John J
JJ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007700:Kinetics; D008148:Lovastatin / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D013997:Time Factors; D014162:Transfection
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases