A Novel Squalene Synthase inhibitor Combined with a Statin or Nitrogenous Biphosphonate in vitro

Simple item page
dc.contributor.authorWasko, Brian
dc.date.accessioned2021-06-28T15:30:30Z
dc.date.available2021-06-28T15:30:30Z
dc.date.issued2011
dc.description.abstractStatins 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 biphosphonates as potent and specific inhibitors of SQS, including tetrasodium salt of 9-biphenyl-4, dimethyl-nona-3, 7-dienyl-1, 1-biphosphonic 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 limited 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 SQS inhibitor with an HMGCR or FDPS inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletionlen_US
dc.identifier.citationWasko BM, Smits JP, Shull LW, Wiemer DF, and Hohl RJ. A novel squalene synthase inhibitor combined with a statin or nitrogenous bisphosphonate in vitro. J. Lipid Res. 2011 Nov;52(11):1957-64. PMID: 21903868.en_US
dc.identifier.urihttps://hdl.handle.net/10657.1/2565
dc.publisherJ. Lipid Res.en_US
dc.subjectsqualene synthase inhibitor, aminobisphosphonate, cholesterol, lovastatin, zoledronate, prenylation, farnesylation, geranylgeranylationen_US
dc.titleA Novel Squalene Synthase inhibitor Combined with a Statin or Nitrogenous Biphosphonate in vitroen_US
dc.typeArticleen_US

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
A Novel Squalene Synthase inhibitor combined with a statin or nitrogenous biphosoonate in vitro-LAPTOP-3HSIDR7K.pdf
Size:
8.59 KB
Format:
Adobe Portable Document Format
Description:
Download

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

College of Science and Engineering
Brian Wasko