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First published on April 15, 2008; DOI: 10.1124/mol.108.046045

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Received for publication February 4, 2008.
Revised April 8, 2008.
Accepted for publication April 11, 2008.

Fluvastatin synergistically improves the antiproliferative effect of everolimus on rat smooth muscle cells by altering p27kip1/cyclin E expression

Nicola Ferri 1*, Agnese Granata 1, Chiara Pirola 2, Francesca Torti 1, Pascal J Pfister 3, Richard Dorent 4, Alberto Corsini 1

1 University of Milan 2 University of MIlan 3 NicOx SA 4 Tenon Hospital

* Address correspondence to: E-mail: nicola.ferri{at}unimi.it

Abstract

Multiple intracellular signaling pathways stimulate quiescent smooth muscle cells (SMCs) to exit from G0 and reenter the cell cycle. Thus, a combination of two drugs with different mechanism of action may represent a suitable approach to control SMC proliferation, a prominent feature of in stent restenosis. In the present study, we investigated the effect of everolimus, an mTOR inhibitor, in combination with fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on proliferation of rat SMCs. The antiproliferative action of everolimus was amplified by 2.5 fold by the addition of subliminal concentrations of fluvastatin (5x10-7M), lowering the IC50 value from 2.5x10-9M to 1.0x10-9M. The increased antiproliferative effect of everolimus by fluvastatin was prevented in the presence of mevalonate, farnesol or geranylgeraniol, suggesting the involvement of prenylated proteins. Cell cycle analysis and [3H]-thymidine incorporation assay demonstrated that the two drugs synergistically interfered with the progression of G1 phase. In particular, the drug combination significantly upregulated p27Kip1 levels by 47.0%, suppressed cyclin E by 43.0%, and reduced retinoblastoma (Rb) hyperphosphorylation by 79.0%, compared to everolimus alone. Retroviral overexpression of cyclin E conferred a significant resistance of rat SMCs to the antiproliferative action of the drug combination, measured by cell counting, [3H]-thymidine incorporation and cell cycle analysis, with higher levels of hyperphosphorylated form of Rb. Taken together, these results demonstrated that everolimus acts synergistically with fluvastatin to inhibit SMC proliferation by altering the expression of cyclin E and p27kip1 which affect Rb phosphorylation and leading to G1 phase arrest.


Key words: Ras, Cdc42, rho, rac, other small G proteins, Overexpression, Cholesterol metabolism/lipoproteins




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