Identification of Docetaxel as a Potential Drug to Promote HDL Biogenesis.
TL;DR: In this paper, the authors combined mutational and computational mapping methods to show that amino acid residues 442-539 in the mature DSC1 protein form an apoA-I binding site (AIBS) and carried out virtual screening of 10 million small molecules to estimate their binding affinities to the AIBS.
Abstract: Objective: Our recent studies showed that desmocollin 1 (DSC1) binds to apoA-I in order to inhibit apoA-I-mediated high density lipoprotein (HDL) biogenesis in atherosclerotic plaques. To promote HDL biogenesis in the plaque, here we search for small molecules that block apoA-I-DSC1 interactions. Approach and Results: We combined mutational and computational mapping methods to show that amino acid residues 442-539 in the mature DSC1 protein form an apoA-I binding site (AIBS). Using a crystal structure of the AIBS, we carried out virtual screening of 10 million small molecules to estimate their binding affinities to the AIBS, followed by the selection of 51 high-affinity binding molecules as potential inhibitors of apoA-I-DSC1 interactions. Among the 51, the chemotherapy drug docetaxel showed the highest potency in promoting apoA-I-mediated HDL biogenesis in primary human skin fibroblasts with the half-maximal effective concentration of 0.72 nM. In silico docking studies suggest that the taxane ring in docetaxel binds to the AIBS and that the carbon-13 sidechain of the taxane tightens/stabilizes the binding. The HDL biogenic effect of docetaxel was also observed in two predominant cell types in atherosclerosis, macrophages and smooth muscle cells. Importantly, docetaxel promoted HDL biogenesis at concentrations much lower than those required for inducing cytotoxicity. Conclusions: Determination of the AIBS in DSC1 and AIBS structure-based virtual screening allowed us to identify docetaxel as a strong HDL biogenic agent. With the remarkable potency in promoting HDL biogenesis, a chemotherapy drug docetaxel may be repurposed to enhance atheroprotective HDL functions.
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TL;DR: In this paper, the optimal cut-off values at baseline and fluctuation were determined using X-tile for non-small-cell lung cancer (NSCLC) patients undergoing radical resection and subsequent adjuvant chemotherapy.
Abstract: Background Cancer patients often exhibit chemotherapy-associated changes in serum lipid profiles, however, their prognostic value before and after adjuvant chemotherapy on survival among non-small-cell lung cancer (NSCLC) patients is unknown. Methods NSCLC patients undergoing radical resection and subsequent adjuvant chemotherapy from 2013 to 2017 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Fasted serum lipid levels were measured before and after chemotherapy. The optimal lipid cut-off values at baseline and fluctuation were determined using X-tile™. The fluctuations in serum lipid levels and disease-free survival (DFS) were assessed. Results Serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, apolipoprotein (Apo) A-I, and ApoB all significantly increased after adjuvant chemotherapy. X-tile determined 1.52 mmol/L of HDL-C and 0.74 g/L of ApoB as the optimal cut-off values before chemotherapy. Patients with HDL-C ≥ 1.52 mmol/L (median DFS: not reached vs. 26.30 months, P = 0.0005) and a decreased HDL-C level after adjuvant chemotherapy (median DFS: 80.43 vs. 26.12 months, P = 0.0204) had a longer DFS. An HDL-C level that increased by ≥ 0.32 mmol/L after chemotherapy indicated a worse DFS. A high baseline ApoB level were associated with a superior DFS. In the univariate analysis and the multivariate Cox analyses, a high baseline HDL-C level and a HDL-C reduction after adjuvant chemotherapy were independent indicators for superior DFS. High baseline HDL-C was related to N0-1 stage (χ2 = 6.413, P = 0.011), and HDL-C fluctuation was significantly correlated with specific chemotherapy regimens (χ2 = 5.002, P = 0.025). Conclusions Adjuvant chemotherapy increased various lipid levels in resected NSCLC patients. A higher HDL-C level before chemotherapy and a reduced HDL-C level after adjuvant chemotherapy were independent predictors of longer DFS in patients with curable NSCLC.
9 citations
TL;DR: In this paper , the authors investigated the efficacy of hydroxyurea in high-fat diet-fed ApoE-/- mice against atherosclerosis and examined the possible mechanism underlying treatment outcomes.
Abstract: Rationale: The efficacy and mechanism of hydroxyurea in the treatment of atherosclerosis have rarely been reported. The goal of this study was to investigate the efficacy of hydroxyurea in high-fat diet-fed ApoE-/- mice against atherosclerosis and examine the possible mechanism underlying treatment outcomes. Methods: ApoE-/- mice were fed a high-fat diet for 1 month and then administered hydroxyurea by gavage continuously for 2 months. Aortic root hematoxylin-eosin (H&E) staining and oil red O staining were used to verify the efficacy of hydroxyurea; biochemical methods and ELISA were used to detect changes in relevant metabolites in serum. 16S rRNA was used to detect composition changes in the intestinal bacterial community of animals after treatment with hydroxyurea. Metabolomics methods were used to identify fecal metabolites and their changes. Immunohistochemical staining and ELISA were used for the localization and quantification of intestinal NPC1L1. Results: We showed that aortic root HE staining and oil red O staining determined the therapeutic efficacy of hydroxyurea in the treatment of atherosclerosis in high-fat diet-fed ApoE-/- mice. Serological tests verified the ability of hydroxyurea to lower total serum cholesterol and LDL cholesterol. The gut microbiota was significantly altered after HU treatment and was significantly different from that after antiplatelet and statin therapy. Meanwhile, a metabolomic study revealed that metabolites, including stearic acid, palmitic acid and cholesterol, were significantly enriched in mouse feces. Further histological and ELISAs verified that the protein responsible for intestinal absorption of cholesterol in mice, NPC1L1, was significantly reduced after hydroxyurea treatment. Conclusions: In high-fat diet-fed ApoE-/- mice, hydroxyurea effectively treated atherosclerosis, lowered serum cholesterol, modulated the gut microbiota at multiple levels and affected cholesterol absorption by reducing NPC1L1 in small intestinal epithelial cells.
3 citations
TL;DR: For example, the authors showed that high-density lipoprotein cholesterol (HDL-C) levels in humans are associated with atherosclerotic cardiovascular disease (ASCVD), and that drugs that increase HDL-C have largely failed to prevent or treat ASCVD.
2 citations
TL;DR: In this article , the authors discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis, and show that the drug can significantly reduce dyslipidemia-induced LDL-A-I levels.
Abstract: The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to revisit the old HDL biogenesis hypothesis: HDL biogenesis reduces atherosclerosis. The location and function of DSC1 suggest that DSC1 is a druggable target for the promotion of HDL biogenesis, and the discovery of docetaxel as a potent inhibitor of the DSC1 sequestration of apolipoprotein A-I has provided us with new opportunities to test this hypothesis. The FDA-approved chemotherapy drug docetaxel promotes HDL biogenesis at low-nanomolar concentrations that are far lower than used in chemotherapy. Docetaxel has also been shown to inhibit atherogenic proliferation of vascular smooth muscle cells. In accordance with these atheroprotective effects of docetaxel, animal studies have shown that docetaxel reduces dyslipidemia-induced atherosclerosis. In the absence of HDL-directed therapies for atherosclerosis, DSC1 constitutes an important new target for the promotion of HDL biogenesis, and the DSC1-targeting compound docetaxel serves as a model compound to prove the hypothesis. In this brief review, we discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis.
1 citations
TL;DR: In this paper , the authors discuss the beginning, recent advances, challenges and future directions in developing ABCA1-directed therapies for ASCVD, as well as developing more specific and sophisticated strategies to upregulate ABCA-1 expression and activity.
Abstract: ATP-binding cassette transporter A1 (ABCA1) has been identified as the molecular defect in Tangier disease. It is biochemically characterized by absence of high-density lipoprotein cholesterol (HDL-C) in the circulation, resulting in the accumulation of cholesterol in lymphoid tissues. Accumulation of cholesterol in arteries is an underlying cause of atherosclerosis, and HDL-C levels are inversely associated with the presence of atherosclerotic cardiovascular disease (ASCVD). ABCA1 increases HDL-C levels by driving the generation of new HDL particles in cells, and cellular cholesterol is removed in the process of HDL generation. Therefore, pharmacological strategies that promote the HDL biogenic process by increasing ABCA1 expression and activity have been intensively studied to reduce ASCVD. Many ABCA1-upregulating agents have been developed, and some have shown promising effects in pre-clinical studies, but no clinical trials have met success yet. ABCA1 has long been an attractive drug target, but the failed clinical trials have indicated the difficulty of therapeutic upregulation of ABCA1, as well as driving us to: improve our understanding of the ABCA1 regulatory system; to develop more specific and sophisticated strategies to upregulate ABCA1 expression; and to search for novel druggable targets in the ABCA1-dependent HDL biogenic process. In this review, we discuss the beginning, recent advances, challenges and future directions in ABCA1 research aimed at developing ABCA1-directed therapies for ASCVD.
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TL;DR: The SRB assay provides a sensitive measure of drug-induced cytotoxicity, is useful in quantitating clonogenicity, and is well suited to high-volume, automated drug screening.
Abstract: We have developed a rapid, sensitive, and inexpensive method for measuring the cellular protein content of adherent and suspension cultures in 96-well microtiter plates. The method is suitable for ordinary laboratory purposes and for very large-scale applications, such as the National Cancer Institute's disease-oriented in vitro anticancer-drug discovery screen, which requires the use of several million culture wells per year. Cultures fixed with trichloroacetic acid were stained for 30 minutes with 0.4% (wt/vol) sulforhodamine B (SRB) dissolved in 1% acetic acid. Unbound dye was removed by four washes with 1% acetic acid, and protein-bound dye was extracted with 10 mM unbuffered Tris base [tris (hydroxymethyl)aminomethane] for determination of optical density in a computer-interfaced, 96-well microtiter plate reader. The SRB assay results were linear with the number of cells and with values for cellular protein measured by both the Lowry and Bradford assays at densities ranging from sparse subconfluence to multilayered supraconfluence. The signal-to-noise ratio at 564 nm was approximately 1.5 with 1,000 cells per well. The sensitivity of the SRB assay compared favorably with sensitivities of several fluorescence assays and was superior to those of both the Lowry and Bradford assays and to those of 20 other visible dyes. The SRB assay provides a colorimetric end point that is nondestructive, indefinitely stable, and visible to the naked eye. It provides a sensitive measure of drug-induced cytotoxicity, is useful in quantitating clonogenicity, and is well suited to high-volume, automated drug screening. SRB fluoresces strongly with laser excitation at 488 nm and can be measured quantitatively at the single-cell level by static fluorescence cytometry.
9,019 citations
TL;DR: Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
Abstract: Glide's ability to identify active compounds in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of “druglike” decoy ligands that have been selected to be representative of what we believe is likely to be found in the compound collection of a pharmaceutical or biotechnology company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that average measures for both “early” and “global” enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand−protei...
4,801 citations
TL;DR: Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
Abstract: A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
4,666 citations
University of Washington1, National Institutes of Health2, Institute for Health Metrics and Evaluation3, Sapienza University of Rome4, Mayo Clinic5, FIU Herbert Wertheim College of Medicine6, Cincinnati Children's Hospital Medical Center7, Boston University8, Essentia Health9, University of Douala10, University of British Columbia11, Medical University of Graz12, Telethon Institute for Child Health Research13, University of Milan14, Cedars-Sinai Medical Center15, Johns Hopkins University16, University of California, San Diego17, University of Michigan18, University of Edinburgh19, University of Texas Southwestern Medical Center20, Queen Mary University of London21, University of Alabama at Birmingham22, Harvard University23, Tufts Medical Center24, All India Institute of Medical Sciences25, Northwestern University26, University of Kentucky27, Casa Sollievo della Sofferenza28, Columbia University29, Icahn School of Medicine at Mount Sinai30, University of Sydney31, University of Cape Town32, Federal University of Rio de Janeiro33, University of Ibadan34, Case Western Reserve University35, Stanford University36, Universidade Federal de Minas Gerais37, The George Institute for Global Health38, Uppsala University39, Dresden University of Technology40, King Fahd Medical City41, Tulane University42, Imperial College London43
TL;DR: CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high- income countries.
3,315 citations
TL;DR: This study suggests that treating IGT patients with acarbose is associated with a significant reduction in the risk of cardiovascular disease and hypertension.
Abstract: ContextThe worldwide explosive increase in type 2 diabetes mellitus and its
cardiovascular morbidity are becoming major health concerns.ObjectiveTo evaluate the effect of decreasing postprandial hyperglycemia with
acarbose, an α-glucosidase inhibitor, on the risk of cardiovascular
disease and hypertension in patients with impaired glucose tolerance (IGT).Design, Setting, and ParticipantsInternational, multicenter double-blind, placebo-controlled, randomized
trial, undertaken in hospitals in Canada, Germany, Austria, Norway, Denmark,
Sweden, Finland, Israel, and Spain from July 1998 through August 2001. A total
of 1429 patients with IGT were randomized with 61 patients (4%) excluded because
they did not have IGT or had no postrandomization data, leaving 1368 patients
for a modified intent-to-treat analysis. Both men (49%) and women (51%) participated
with a mean (SD) age of 54.5 (7.9) years and body mass index of 30.9 (4.2).
These patients were followed up for a mean (SD) of 3.3 (1.2) years.InterventionPatients with IGT were randomized to receive either placebo (n = 715)
or 100 mg of acarbose 3 times a day (n = 714).Main Outcome MeasuresThe development of major cardiovascular events (coronary heart disease,
cardiovascular death, congestive heart failure, cerebrovascular event, and
peripheral vascular disease) and hypertension (≥140/90 mm Hg).ResultsThree hundred forty-one patients (24%) discontinued their participation
prematurely, 211 in the acarbose-treated group and 130 in the placebo group;
these patients were also followed up for outcome parameters. Decreasing postprandial
hyperglycemia with acarbose was associated with a 49% relative risk reduction
in the development of cardiovascular events (hazard ratio [HR], 0.51; 95%
confidence interval [CI]; 0.28-0.95; P = .03) and
a 2.5% absolute risk reduction. Among cardiovascular events, the major reduction
was in the risk of myocardial infarction (HR, 0.09; 95% CI, 0.01-0.72; P = .02). Acarbose was also associated with a 34% relative
risk reduction in the incidence of new cases of hypertension (HR, 0.66; 95%
CI, 0.49-0.89; P = .006) and a 5.3% absolute risk
reduction. Even after adjusting for major risk factors, the reduction in the
risk of cardiovascular events (HR, 0.47; 95% CI, 0.24-0.90; P = .02) and hypertension (HR, 0.62; 95% CI, 0.45-0.86; P = .004) associated with acarbose treatment was still statistically
significant.ConclusionThis study suggests that treating IGT patients with acarbose is associated
with a significant reduction in the risk of cardiovascular disease and hypertension.
1,632 citations