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Can J Neurol Sci. 1999 Nov;26(4):305-10.

Mevalonate prevents lovastatin-induced apoptosis in medulloblastoma cell lines.

Author information

1
Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.

Abstract

BACKGROUND:

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) is a key rate-limiting enzyme in the mevalonate pathway, which generates precursors for cholesterol biosynthesis and the production of non-steroidal mevalonate derivatives that are involved in a number of growth-regulatory processes. We have reported that lovastatin, a competitive inhibitor of HMG-CoA reductase, not only inhibits medulloblastoma proliferation in vitro, but also induces near-complete cell death via apoptosis. The present study explores some of the pathways which may be involved in lovastatin-induced apoptosis.

METHODS:

Medulloblastoma cell lines were exposed in vitro to lovastatin with or without mevalonate, and document the effects using morphology, flow cytometry. DNA electrophoresis and Northern analysis.

RESULTS:

1) Mevalonate prevents apoptosis when co-incubated with lovastatin, or when administered to lovastatin-pretreated cells. 2) Mevalonate restores the lovastatin-arrested cell cycle, allowing S phase entry. 3) Mevalonate does not prevent lovastatin-induced apoptosis after a critical duration of lovastatin pretreatment. For cell lines Daoy and UW228 this was 24 hours, and for D283 Med and D341 Med it was 48 hours. 4) Increases in HMG-CoA reductase mRNA levels induced by lovastatin are abrogated by co-incubation with lovastatin and mevalonate.

CONCLUSIONS:

These results confirm that lovastatin inhibition of this enzyme results in blockage of the mevalonate pathway, and that such a block is a critical step in the mechanism of lovastatin-induced apoptosis.

PMID:
10563217
DOI:
10.1017/s0317167100000433
[Indexed for MEDLINE]

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