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Vol. 281, Issue 3, 1144-1153, 1997
Institute of Pharmacological Sciences (M.R., L.A., D.V., C.T.,
P.Q., R.P., R.F., A.C.),
Department of Medical Chemistry and
Biochemistry (P.F., E.S.), University of Milan, Milan, Italy; the
Departments of
Chemistry and Biochemistry (M.H.G.), University of
Washington, Seattle, and the
Department of Chemistry (P.M.), Clark
Atlanta University, Atlanta, Georgia
The mevalonate (MVA) pathway is involved in cell proliferation. We
investigated drugs acting at different enzymatic steps on rat aorta
smooth muscle cell (SMC) proliferation. Competitive inhibitors of
3-hydroxy-3-methylglutaryl coenzyme A reductase (0.1-10 µM)
dose-dependently decreased (up to 90%) SMC proliferation. This effect
was prevented by 100 µM MVA, 10 µM all-trans
farnesol (F-OH) and 5 µM all-trans geranylgeraniol
(GG-OH), precursors of protein prenyl groups, but not by
2-cis GG-OH, precursor of dolichols, squalene and
ubiquinone. The same inhibitory effect was obtained with
6-fluoromevalonate (1-50 µM), an inhibitor of MVA-pyrophosphate
decarboxylase. Partial recovery of cell proliferation was possible by
all-trans F-OH and all-trans GG-OH, but
not MVA. Squalestatin 1 (1-25 µM), a potent squalene synthase
inhibitor, blocked cholesterol synthesis and slightly inhibited (21%
decrease) SMC proliferation only at the highest tested concentration.
NB-598 (1-10 µM), a potent squalene epoxidase inhibitor, blocked
cholesterol synthesis without affecting SMC proliferation. Finally, the
benzodiazepine peptidomimetic BZA-5B (10-100 µM), a specific
inhibitor of protein farnesyltransferase, time- and dose-dependently
decreased SMC proliferation (up to 62%) after 9 days. This effect of
BZA-5B was prevented by MVA and all-trans GG-OH, but not
by all-trans F-OH. SMC proliferation was not affected by
the closely related compound BZA-7B, which does not inhibit protein
farnesyltransferase. Altogether, these findings focus the role of the
MVA pathway in cell proliferation and call attention to the involvement
of specific isoprenoid metabolites, probably through farnesylated and
geranylgeranylated proteins, in the control of this cellular event.
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