A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro

Brian M Wasko; Jacqueline P Smits; Larry W Shull; David F Wiemer; Raymond J Hohl

doi:10.1194/jlr.M016089

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A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro

Journal article

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A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro

Brian M Wasko, Jacqueline P Smits, Larry W Shull, David F Wiemer and Raymond J Hohl

Journal of lipid research, Vol.52(11), pp.1957-1964

11/2011

DOI: 10.1194/jlr.M016089

PMCID: PMC3196227

PMID: 21903868

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Abstract

Statins and nitrogenous bisphosphonates (NBP) inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR) and farnesyl diphosphate synthase (FDPS), respectively, leading to depletion of farnesyl diphosphate (FPP) and disruption of protein prenylation. Squalene synthase (SQS) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis. Herein, we have identified novel bisphosphonates as potent and specific inhibitors of SQS, including the tetrasodium salt of 9-biphenyl-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic acid (compound 5). Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells. At high concentrations, lovastatin and zoledronate impaired protein prenylation and decreased cell viability, which limits their potential use for cholesterol depletion. When combined with lovastatin, compound 5 prevented lovastatin-induced FPP depletion and impairment of protein farnesylation. Compound 5 in combination with the NBP zoledronate completely prevented zoledronate-induced impairment of both protein farnesylation and geranylgeranylation. Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone. The combination of an SQS inhibitor with an HMGCR or FDPS inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion.

Protein Prenylation - drug effects

Receptors, LDL - genetics

Sesquiterpenes - metabolism

Lovastatin - pharmacology

Humans

RNA, Messenger - genetics

Enzyme Inhibitors - pharmacology

Substrate Specificity

Imidazoles - pharmacology

Structure-Activity Relationship

Enzyme Inhibitors - chemical synthesis

RNA, Messenger - metabolism

Polyisoprenyl Phosphates - metabolism

Hep G2 Cells

Drug Interactions

Terpenes - metabolism

Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors

Diphosphonates - chemistry

Enzyme Inhibitors - chemistry

Diphosphonates - chemical synthesis

Cholesterol - biosynthesis

Diphosphonates - pharmacology

Details

Title: Subtitle: A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro
Creators: Brian M Wasko - Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA 52242, USA
Jacqueline P Smits
Larry W Shull
David F Wiemer
Raymond J Hohl
Resource Type: Journal article
Publication Details: Journal of lipid research, Vol.52(11), pp.1957-1964
DOI: 10.1194/jlr.M016089
PMID: 21903868
PMCID: PMC3196227
NLM abbreviation: J Lipid Res
ISSN: 0022-2275
eISSN: 1539-7262
Publisher: United States
Grant note: T32 GM067795 / NIGMS NIH HHS
Language: English
Date published: 11/2011
Academic Unit: Neuroscience and Pharmacology; Chemistry; Internal Medicine
Record Identifier: 9983985936202771

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