Lovastatin is a potent inhibitor of meningioma cell proliferation: evidence for inhibition of a mitogen associated protein kinase.

摘要: Lovastatin inhibits 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase the rate limiting enzyme for synthesis of mevalonic acid, a precursor cholesterol, farnesyl and geranylgeranyl pyrophosphate isoprenoids. Recent studies suggest it also has growth inhibitory properties. Posttranslational or geranylgeranylation low molecular weight GTP-binding proteins such as RAS RHO are thought to be an essential step in activation phosphorylation cascades RAS–RAF-1–MEK-1–MAPK/ERK pathway which stimulate cell proliferation. In this study, we evaluated lovastatin effects on meningioma proliferation MEK-1–MAPK/ERK pathway. The effect was assessed eight human cultures stimulated by platelet derived factor (PDGF)-BB, cerebrospinal fluid (CSF), fetal bovine serum (FBS). Concomitant phosphorylation/activation mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) (MEK-1) MAPK/ERK were Western blot. Whether acts via mevalonate-dependent mechanism evaluated. Coadministration completely blocked PDGF-BB, CSF, FBS stimulation [3H]-thymidine incorporation inhibited PDGF-BB's stimulatory dose dependent manner. with its effects, reduced MEK-1/2 five meningiomas seven. mevalonate partially restored PDGF's mitogenic effect. is potent inhibitor may act part reducing Additional warranted assess whether similar HMG-CoA inhibitors represent new adjunctive chemotherapy recurrent meningiomas.