Simvastatin, an Inhibitor of Cholesterol Biosynthesis, Shows a Synergistic Effect with N,N′-Bis(2-chloroethyl)-N-nitrosourea and β-Interferon on Human Glioma Cells¹

The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [³H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nm). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed to simvastatin completely restored the parameters evaluated, indicating that the drug specifically inhibited mevalonate synthesis. The effect of simvastatin in combination with β-interferon and N,N′-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nm, respectively. Subliminal concentrations of β-interferon or N,N′-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nm simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N′-bis(2-chloroethyl)-N-nitrosourea or β-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.