Lovastatin-induced apoptosis is modulated by geranylgeraniol in a neuroblastoma cell line.

Abstract

Mevalonic aciduria (MA), the most severe form of mevalonate kinase deficiency (MKD), is still an orphan drug disease and the pathogenetic mechanisms underlying neuronal dysfunction is still poorly understood. In our study we have investigated the apoptotic mechanism mediated by the exposure of the cultured neuroblastoma cell line, SH-SY5Y, to lovastatin in absence or in presence of the isoprenoid, geranylgeraniol, with the aim of unraveling the pathogenesis of MA. Lovastatin, blocks the mevalonate pathway inhibiting the 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR), an enzyme of the mevalonate pathway upstream the mevalonate kinase enzyme, reproducing biochemical features similar to those found in MKD. We demonstrate that apoptosis in neuronal lovastatin treated-cells is induced by the mitochondrial pathway, with caspase-9 as the initiator and caspase-3 as the effector caspase. The presence of geranylgeraniol modulates both the caspase-9 and caspase-3 activity in a dose-dependent way, confirming that this isoprenoid enters the mevalonate pathway, is metabolized and finally is able to by-pass the statin biochemical block reconstituting the mevalonate pathway. According to our findings, it should not be the time course adopted that modulates the apoptotic response but rather the isoprenoid itself. Being aware that our results have been obtained using a biochemical model of MKD, and not cells from patients with the disease, we believe our findings increase the knowledge of MA pathogenesis, and may possibly contribute to the development of novel therapeutic strategies.

• Authors: Annalisa Marcuzzi, Valentina Zanin, Elisa Piscianz, Paola Maura Tricarico, Josef Vuch, Martina Girardelli, Lorenzo Monasta, Anna Monica Bianco, Sergio Crovella
• Journal: International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience (Int J Dev Neurosci) Vol. 30 Issue 6 Pg. 451-6 (Oct 2012) ISSN: 1873-474X [Electronic] United States
• PMID: 22759742 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Diterpenes
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lovastatin
• geranylgeraniol
• Caspases

Topics

• Analysis of Variance
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Diterpenes (pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Lovastatin (pharmacology)
• Neuroblastoma (pathology)
• Time Factors