Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme a reductase

Tobert, Jonathan A.; Hitzenberger, G; Kukovetz, W. R.; Holmes, Ian; Jones, Keith

doi:10.1016/0021-9150(82)90070-3

Cited by 81 publications

(30 citation statements)

References 8 publications

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“…The hypocholesterolemic effects of two specific competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis HMG-COA reductase, compactin (23-25) and mevinolin (27)(28)(29), have been reported in normal subjects and in patients with heterozygous FH, but the dose-response relationships have only been examined in the former (28). In a multicenter trial, Tobert et al (28) examined the hypolipidemic effects of mevinolin given in doses of 6.25, 12.5, 25, and 50 mg twice daily to normal male volunteers.…”

Section: Discussionmentioning

confidence: 99%

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Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Illingworth¹,

Sexton²

1984

J. Clin. Invest.

175

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Section: Discussionmentioning

confidence: 99%

“…The recent development of two specific competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase, compactin (21)(22)(23)(24)(25) and mevinolin (26)(27)(28), has …”

Section: Introductionmentioning

confidence: 99%

Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Illingworth¹,

Sexton²

1984

J. Clin. Invest.

175

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“…The formation of mevalonate, which is catalyzed by 3-hydroxy-3-meth-ylglutaryl coenzyme A (HMG-CoA)' reductase, has long been regarded as the major regulatory step for de novo cholesterol biosynthesis (9-1 1). For this reason, competitive inhibitors of HMG-CoA reductase, such as compactin (ML 236B) (12) and mevinolin (MK803) (13), have received much attention as potential new therapeutic agents for treatment of hypercholesterolemia (14)(15)(16)(17)(18)(19)(20)(21). In addition to their cholesterol-lowering activity in vivo, these inhibitors ofmevalonate synthesis exhibit cytostatic activity when added to proliferating cells in tissue culture (22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Maltese¹,

Defendini²,

Green³

et al. 1985

J. Clin. Invest.

115

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3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, an essential precursor for isoprenoid compounds in mammalian cells. Recent studies have shown that mevinolin, a competitive inhibitor of the reductase, inhibits cell proliferation and induces differentiation in cultured C1300 (Neuro-2A) murine neuroblastoma cells. We now report that mevinolin can inhibit neuroblastoma growth in vivo. The specific activity of HMG-CoA reductase in subcutaneous neuroblastomas increased more than 20-fold between the fifth and eighth days after tumor inoculation, and remained elevated for the remainder of the tumor lifetime in mice. The increase in reductase activity was correlated with a marked increase in tumor DNA content and exponential increase in tumor weight. Using an in vitro assay to monitor the ability of mouse serum to suppress sterol synthesis, we determined that mevinolin was inactivated or cleared from the circulation within 3-6 h after a single subcutaneous injection. However, by using subcutaneous osmotic pumps to deliver a constant infusion of mevinolin, we were able to maintain adequate blood levels of the drug for 7 d. Mevinolin (5 mg/kg per h) suppressed tumor growth (wet weight) significantly when treatment was carried out between day 1 and day 8 or between day 5 and day 12 after tumor inoculation. Histopathological examination of tumors from mevinolin-treated mice revealed few or no mitotic figures and marked cellular degeneration. Measurements of incorporation of (3H)acetate into neuroblastoma sterols and ubiquinones 24 h after implantation of osmotic pumps showed that mevinolin produced a marked inhibition of isoprenoid synthesis in the tumors in vivo. The data suggest that, in addition to their demonstrated utility as cholesterol-lowering drugs, competitive inhibitors of HMG-CoA reductase may have considerable potential as novel antineoplastic agents.

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“…10 By uncertain mechanisms, this interrupts cellular proliferation, a phenomenon which has been exploited in studying cell division and proteins such as the cyclins. 11 Lovastatin has been suggested as a potential anticancer drug [12][13][14][15] and is known to perturb major signaling pathways by inhibiting isoprenylation of signal transduction proteins such as p21 ras.…”

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confidence: 99%

Mevalonate Prevents Lovastatin-Induced Apoptosis in Medulloblastoma Cell Lines

Wang

Macaulay²

1999

Can. j. neurol. sci.

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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 lovastatinarrested 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.RÉSUMÉ: Le mévalonate prévient l'apoptose induite par la lovastatine dans des lignées cellulaires de médulloblastome. Introduction: La 3-hydroxy-3-méthylglutaryl coenzyme a réductase (HMG-CoA réductase) est une enzyme clé, qui a un rôle d'étape cinétiquement limitante dans la voie du mévalonate et qui génère des précurseurs pour la biosynthèse du cholestérol et la production de dérivés non stéroïdiens du mévalonate impliqués dans certains processus de régulation de la croissance. Nous avons rapporté que la lovastatine, un inhibiteur compétitif de l'HMG-CoA réductase, non seulement inhibe la prolifération du médulloblastome in vitro, mais également induit presque complètement la mort cellulaire via l'apoptose. Cette étude explore certaines des voies qui pourraient être impliquées dans l'apoptose induite par la lovastatine. Méthodes: Les effets de l'exposition in vitro de lignées de cellules de médulloblastome à la lovastatine avec ou sans mévalonate ont été évalués par des études morphologiques, par cytométrie de flux, électrophorèse de l'ADN et analyse de Northern. Résultats: 1) Le mévalonate prévient l'apoptose quand les cellules sont coincubées avec la lovastatine ou quand il est administré à des cellules prétraitées par la lovastatine. 2) Le mévalonate rétablit le cycle cellulaire interrompu par la lovastatine, permettant une entrée en phase S. 3) Le mévalonate ne prévient pas l'apoptose induite par la lovastatine après un temps de prétraitement cri...

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Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme a reductase

Cited by 81 publications

References 8 publications

Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Mevalonate Prevents Lovastatin-Induced Apoptosis in Medulloblastoma Cell Lines

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