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HMG CoA reductase inhibitors, NSAIDs and risk of glioma.

ABSTRACT: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) have shown inverse associations with cancer risks, but the results have been inconsistent. As there are no previous published data in brain tumors, we conducted a case-control study to investigate statin therapy and risk of glioma. We further evaluated the use of nonsteriodal anti-inflammatory drugs (NSAIDs) and risk of these tumors. We recruited newly diagnosed glioma cases and frequency matched controls at Columbia University and the University of California San Francisco. Standardized questions on statins and NSAIDs were used at both institutions. Intakes of these drugs were defined as >6 months of at least twice weekly use versus less than this amount or never use. From July 2007 to January 2010, we recruited a total of 517 cases and 400 controls. Simvastatin and lovastatin showed significant inverse associations with glioma (odds ratio [OR] = 0.49, 95% confidence interval [CI] 0.30, 0.81 and OR = 0.47, 95% CI 0.24, 0.93, respectively). For NSAIDs, aspirin use was also inversely related to glioma risk (OR = 0.68, 95% CI 0.49, 0.96). Both statins and NSAIDs showed significant inverse trends between the duration of drug use and glioma risk (trend tests p = 0.03 and p = 0.02, respectively), and drug intake for >120 months demonstrated the most significant associations for both types of medication. The inverse association between statin therapy and risk of glioma supports the roles of Ras/Rho GTPases or inflammatory cytokines in gliomagenesis, and a similar relationship between NSAIDs and glioma highlights the importance of cyclo-oxygenase 2 in glioma pathogenesis.

SUBMITTER: Ferris JS

PROVIDER: S-EPMC3394887 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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HMG CoA reductase inhibitors, NSAIDs and risk of glioma.

Ferris Jennifer S JS McCoy Lucie L Neugut Alfred I AI Wrensch Margaret M Lai Rose R

International journal of cancer 20120404 6

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) have shown inverse associations with cancer risks, but the results have been inconsistent. As there are no previous published data in brain tumors, we conducted a case-control study to investigate statin therapy and risk of glioma. We further evaluated the use of nonsteriodal anti-inflammatory drugs (NSAIDs) and risk of these tumors. We recruited newly diagnosed glioma cases and frequency matched controls at Columbia ...[more]

PMID: 22419506

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Project description:HMG-CoA reductase (HMGR) is the target of statins, cholesterol-lowering drugs prescribed to millions of patients worldwide. More recent research indicates that HMGR could be a useful target in the development of antimicrobial agents. Over the last seven decades, researchers have proposed a series of increasingly complex reaction mechanisms for this biomedically important enzyme. The maturation of the mechanistic proposals for HMGR have paralleled advances in a diverse set of research areas, such as molecular biology and computational chemistry. Thus, the development of the HMGR mechanism provides a useful case study for following the advances in state-of-the-art methods in enzyme mechanism research. Similarly, the questions raised by these mechanism proposals reflect the limitations of the methods used to develop them. The mechanism of HMGR, a four-electron oxidoreductase, is unique and far more complex than originally thought. The reaction contains multiple chemical steps, coupled to large-scale domain motions of the homodimeric enzyme. The first proposals for the HMGR mechanism were based on kinetic and labeling experiments, drawing analogies to the mechanism of known dehydrogenases. Advances in molecular biology and bioinformatics enabled researchers to use site-directed mutagenesis experiments and protein sequencing to identify catalytically important glutamate, aspartate, and histidine residues. These studies, in turn, have generated new and more complicated mechanistic proposals. With the development of protein crystallography, researchers solved HMGR crystal structures to reveal an unexpected lysine residue at the center of the active site. The many crystal structures of HMGR led to increasingly complex mechanistic proposals, but the inherent limitations of the protein crystallography left a number of questions unresolved. For example, the protonation state of the glutamate residue within the active site cannot be clearly determined from the crystal structure. The differing protonation state of this residue leads to different proposed mechanisms for the enzyme. As computational analysis of large biomolecules has become more feasible, the application of methods such as hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to the HMGR mechanism have led to the most detailed mechanistic proposal yet. As these methodologies continue to improve, they prove to be very powerful for the study of enzyme mechanisms in conjunction with protein crystallography. Nevertheless, even the most current mechanistic proposal for HMGR remains incomplete due to limitations of the current computational methodologies. Thus, HMGR serves as a model for how the combination of increasingly sophisticated experimental and computational methods can elucidate very complex enzyme mechanisms.

Project description:BackgroundHypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. ?-Hydroxy ?-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates' requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup.MethodsOut of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II.ResultsThe molecular docking of amentoflavone (GOLD score 70.54, ?G calc. = -?10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ?G calc. = -?6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-?-D-glucopyranosyl (6'???1?)-O-?-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use.ConclusionThis computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.

Project description:BackgroundThe relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality.Methods and findingsThis cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins. In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%). A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens.ConclusionsStatin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.

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HMG CoA reductase inhibitors, NSAIDs and risk of glioma.

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HMG CoA reductase inhibitors, NSAIDs and risk of glioma.

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