Document Detail


A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro.
MedLine Citation:
PMID:  21903868     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Brian M Wasko; Jacqueline P Smits; Larry W Shull; David F Wiemer; Raymond J Hohl
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-09-08
Journal Detail:
Title:  Journal of lipid research     Volume:  52     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-17     Completed Date:  2012-02-02     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1957-64     Citation Subset:  IM    
Affiliation:
Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA 52242, USA.
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MeSH Terms
Descriptor/Qualifier:
Cholesterol / biosynthesis
Diphosphonates / chemical synthesis,  chemistry,  pharmacology*
Drug Interactions
Enzyme Inhibitors / chemical synthesis,  chemistry,  pharmacology*
Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
Hep G2 Cells
Humans
Imidazoles / pharmacology*
Lovastatin / pharmacology*
Polyisoprenyl Phosphates / metabolism
Protein Prenylation / drug effects
RNA, Messenger / genetics,  metabolism
Receptors, LDL / genetics
Sesquiterpenes / metabolism
Structure-Activity Relationship
Substrate Specificity
Terpenes / metabolism
Chemical
Reg. No./Substance:
0/Diphosphonates; 0/Enzyme Inhibitors; 0/Imidazoles; 0/Polyisoprenyl Phosphates; 0/RNA, Messenger; 0/Receptors, LDL; 0/Sesquiterpenes; 0/Terpenes; 118072-93-8/zoledronic acid; 13058-04-3/farnesyl pyrophosphate; 57-88-5/Cholesterol; 6699-20-3/geranylgeranyl pyrophosphate; 75330-75-5/Lovastatin; EC 2.5.1.21/Farnesyl-Diphosphate Farnesyltransferase
Comments/Corrections

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