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

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

doi:10.1194/jlr.m016089

Cited by 27 publications

(26 citation statements)

References 45 publications

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“…If a buildup of farnesol is a causative factor, coadministration of statins can alleviate the liver toxicity by reducing the synthesis of FPP. A similar strategy has been proposed to avoid nonsterol isoprenoid depletion associated with treatment with statins ( 39 ). Judging from our results, the liver toxicity of SS inhibition is modest and self-limited even though the inhibition is complete.…”

Section: Discussionmentioning

confidence: 76%

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

Nagashima

Yagyu

Tozawa

et al. 2015

Journal of Lipid Research

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Mammals have developed sophisticated and complex systems to maintain cellular content of cholesterol, an essential component of cellular membranes and a precursor of bile acids and steroid hormones ( 1 ). In addition to dietary intake, cholesterol is supplied by de novo synthesis from acetate. Squalene synthase (SS; farnesyl-diphosphate farnesyltransferase, EC2.5.1.21) catalyzes the reductive head-to-head condensation of two molecules of farnesyl diphosphate (FPP) to form squalene, the fi rst committed intermediate in the cholesterol biosynthetic pathway ( 2, 3 ). SS contains ‫ف‬ 416 amino acids and is anchored to endoplasmic reticulum by a short C-terminal membrane-spanning domain, with its large N-terminal catalytic domain facing the cytosol, where water-soluble FPP and NADPH are present. Hepatic SS is highly regulated at the transcriptional level, not only by cellular cholesterol content ( 4 ) but also by proinfl ammatory cytokines: TNF-␣ and interleukin 1 ␤ ( 5 ). This enzyme has been an attractive target for cholesterol-lowering therapy because the inhibition of this step theoretically may not perturb the nonsterol pathway, which is a potential problem in the use of statins, inhibitors of HMG-CoA reductase Abstract Squalene synthase (SS) catalyzes the biosynthesis of squalene, the fi rst specifi c intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifi cally knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of suffi cient centripetal fl ow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were signifi cantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor ␣ target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specifi c ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing signifi cant mortality. -Nagashima, S

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Section: Discussionmentioning

confidence: 76%

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

Nagashima

Yagyu

Tozawa

et al. 2015

Journal of Lipid Research

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“…Although elucidation of the molecular mechanisms underlying the association of FDPS, FASN, as well as the nine other radioresistance-associated genes, with PC radioresistance has not yet been undertaken in this or previous works, previous studies indicating the necessity for cholesterol biosynthesis in the membrane association and activity of both mutant and wild-type KRAS in PC may explain our observations ( Ura et al , 1994 ). To this point, ZOL and cholesterol-lowering statins (that is, HMG-CoA reductase inhibitors) have been shown to decrease Ras prenylation or Ras protein levels in cells with mutant Ras ( Tassone et al , 2003 ; Marten et al , 2007 ; Wasko et al , 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation

et al. 2014

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Background:Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques.Methods:Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model.Results:Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model.Conclusions:Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

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“…It had been described that some isoprenoids containing the 1,1‐bisphoshonic unit, such as compound 85 , have the capacity to block SQS . More recently, isoprenoid 1,1‐bisphosphonates such as 86 – 89 were found to be able to inhibit SQS in the low nanomolar range, as illustrated in Figure …”

Section: Bisphosphonatesmentioning

confidence: 94%

“…[100,101] More recently,i soprenoid 1,1-bisphosphonates such as 86-89 were found to be able to inhibit SQS in the low nanomolar range, as illustrated in Figure 16. [102] Some linear amino 1,1-bisphosphonates were also found to behavea sv ery efficient inhibitors of T. cruzi SQS (TcSQS). For example, compound 71,w hich had been originally designed to block TcFPPS activity,b ecamea ne xtremelyp otent inhibitor of TcSQS at very low nanomolar concentrations, as shown in Figure 17.…”

Section: Bisphosphonates Targeting Squalene Synthasementioning

confidence: 99%

The Role of the Phosphorus Atom in Drug Design

2019

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Although the phosphorus atom is found in a variety of oxidation states, most of the phosphorus‐containing molecules of pharmacological importance possess phosphorus in the form of phosphonate or phosphinate functional groups, or in a major oxidation state as a phosphate group. The most common occurrence of phosphorus in drugs is either in prodrugs or in compounds for which the phosphorus atom plays a role in the biological activity, such as in modified nucleotides, in metabolically stable analogues of metabolites bearing phosphate groups, and as bioisosteric analogues of carboxyl groups.

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

Cited by 27 publications

References 45 publications

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation

The Role of the Phosphorus Atom in Drug Design

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