Lovastatin and simvastatin are modulators of the proteasome

Lovastatin and simvastatin are HMG-CoA reductase inhibitors widely used as antihyperlipidemic drugs, which also display antiproliferative properties. In the present paper, we provide evidence that both lovastatin and simvasta tin are modulators of the purified bovine pituitary 20 S proteasome, since they mildly stimulate the chymotrypsin-like activity and inhibit the peptid ylglutamylpeptide hydrolyzing; activity without interfering with the trypsi n-like activity. However, those effects are only observed when the closed r ing forms of the drugs are used, while the opened ring form of lovastatin a cts as a mild inhibitor of the chymotrypsin like activity. The closed ring form of lovastatin is much more potent as a cytotoxic agent on the Colon-26 (C-26) colon carcinoma cell line than the opened ring form, which is only mildly cytostatic. Moreover, neither the cytotoxic effects nor the effects on 20 S proteasome activities are prevented by mevalonate. which by itself inhibits the trypsin-like activity of the proteasome. Neither the opened ri ng nor the closed ring form of lovastatin induces an accumulation of ubiqui tin-protein conjugates, which is observed after treatment with lactacystin, a selective proteasome inhibitor. In contrast with the opened ring form of lovastatin, the closed ring form induces the disappearance of detectable p 27(kip1) from C-26 cells. Altogether, our results indicate that the closed ring form of lovastatin induces cytotoxic effects independent of its HMG-Co A inhibiting activity, however, those effects are mediated by a complex mod ulation of proteasome activity rather than by inhibition of the 20 S protea some. (C) 2000 Elsevier Science Ltd. All rights reserved.