A Systems Biology Strategy for Predicting Similarities and Differences of Drug Effects: Evidence for Drug-specific Modulation of Inflammation in Atherosclerosis

BackgroundSuccessful drug development has been hampered by a limited understanding of how to translate laboratory-based biological discoveries into safe and effective medicines. We have developed a generic method for predicting the effects of drugs on biological processes. Information derived from the chemical structure and experimental omics data from short-term efficacy studies are combined to predict the possible protein targets and cellular pathways affected by drugs.ResultsValidation of the method with anti-atherosclerotic compounds (fenofibrate, rosuvastatin, LXR activator T0901317) demonstrated a great conformity between the computationally predicted effects and the wet-lab biochemical effects. Comparative genome-wide pathway mapping revealed that the biological drug effects were realized largely via different pathways and mechanisms. In line with the predictions, the drugs showed differential effects on inflammatory pathways (downstream of PDGF, VEGF, IFNγ, TGFβ, IL1β, TNFα, LPS), transcriptional regulators (NFκB, C/EBP, STAT3, AP-1) and enzymes (PKCδ, AKT, PLA2), and they quenched different aspects of the inflammatory signaling cascade. Fenofibrate, the compound predicted to be most efficacious in inhibiting early processes of atherosclerosis, had the strongest effect on early lesion development.ConclusionOur approach provides mechanistic rationales for the differential and common effects of drugs and may help to better understand the origins of drug actions and the design of combination therapies.

[1]  K. Kostner,et al.  The withdrawal of torcetrapib from drug development: implications for the future of drugs that alter HDL metabolism , 2007, Expert opinion on investigational drugs.

[2]  Xiang Ou,et al.  Effect of T0901317 on Hepatic Proinflammatory Gene Expression in ApoE−/− Mice Fed a High-fat/high-cholesterol Diet , 2007, Inflammation.

[3]  E. Veltri,et al.  Tolerability and effects on lipids of ezetimibe coadministered with pravastatin or simvastatin for twelve months: results from two open-label extension studies in hypercholesterolemic patients. , 2008, Clinical therapeutics.

[4]  Tatiana Nikolskaya,et al.  Functional analysis of OMICs data and small molecule compounds in an integrated "knowledge-based" platform. , 2009, Methods in molecular biology.

[5]  P. Parini,et al.  Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice Published, JLR Papers in Press, November 1, 2005. , 2006, Journal of Lipid Research.

[6]  Milita Crisby,et al.  Rosuvastatin reduces caspase-3 activity and up-regulates alpha-secretase in human neuroblastoma SH-SY5Y cells exposed to A beta. , 2004, Neuroscience letters.

[7]  Mike Tyers,et al.  Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast , 2008, PLoS genetics.

[8]  Robert Kleemann,et al.  Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. , 2004, Blood.

[9]  Robert Barouki,et al.  Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. , 2003, Molecular pharmacology.

[10]  B. Staels,et al.  Liver X receptor modulators: effects on lipid metabolism and potential use in the treatment of atherosclerosis. , 2009, Biochemical pharmacology.

[11]  Alberto Zambon,et al.  Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR–&agr; Activators: Clinical and Experimental Evidence , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[12]  L. Hartmann,et al.  Selective estrogen-receptor modulators -- mechanisms of action and application to clinical practice. , 2003, The New England journal of medicine.

[13]  Angela M. Siesky,et al.  Hepatic peroxisomal fatty acid β-oxidation is regulated by liver X receptor α , 2005 .

[14]  Robert Krysiak,et al.  Monocyte Release of Tumor Necrosis Factor-α and Interleukin-1β in Primary Type IIa and IIb Dyslipidemic Patients Treated With Statins or Fibrates , 2005, Journal of cardiovascular pharmacology.

[15]  T. Ashburn,et al.  Drug repositioning: identifying and developing new uses for existing drugs , 2004, Nature Reviews Drug Discovery.

[16]  W. Koenig,et al.  Fenofibrate Reduces Atherogenesis in ApoE*3Leiden Mice: Evidence for Multiple Antiatherogenic Effects Besides Lowering Plasma Cholesterol , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[17]  Angela M. Siesky,et al.  Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha. , 2005, Endocrinology.

[18]  Robert Kleemann,et al.  Rosuvastatin Reduces Atherosclerosis Development Beyond and Independent of Its Plasma Cholesterol–Lowering Effect in APOE*3-Leiden Transgenic Mice: Evidence for Antiinflammatory Effects of Rosuvastatin , 2003, Circulation.

[19]  Timothy M Willson,et al.  Crystal structure of the PXR-T1317 complex provides a scaffold to examine the potential for receptor antagonism. , 2007, Bioorganic & medicinal chemistry.

[20]  Yuri Nikolsky,et al.  Systems biology approaches to the study of cardiovascular drugs. , 2010, Methods in molecular biology.

[21]  Michael J. Keiser,et al.  Relating protein pharmacology by ligand chemistry , 2007, Nature Biotechnology.

[22]  Robert Kleemann,et al.  Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. , 2003, Blood.

[23]  Barbara Karten,et al.  Expression of ABCG1, but Not ABCA1, Correlates with Cholesterol Release by Cerebellar Astroglia* , 2006, Journal of Biological Chemistry.

[24]  Thomas Zander,et al.  Application of T cell-based transcriptomics to identify three candidate biomarkers for monitoring anti-TGFβR therapy , 2010, Pharmacogenetics and genomics.

[25]  S. Yusuf,et al.  Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. , 2001, Circulation.

[26]  Sean Ekins,et al.  Computational prediction of human drug metabolism , 2005, Expert opinion on drug metabolism & toxicology.

[27]  Robert Kleemann,et al.  Negative Regulation of Human Fibrinogen Gene Expression by Peroxisome Proliferator-activated Receptor α Agonists via Inhibition of CCAAT Box/Enhancer-binding Protein β* , 2001, The Journal of Biological Chemistry.

[28]  Peter Tontonoz,et al.  Liver X Receptor-dependent Repression of Matrix Metalloproteinase-9 Expression in Macrophages* , 2003, The Journal of Biological Chemistry.

[29]  Robert Kleemann,et al.  Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB-C/EBP-β complex formation , 2003 .

[30]  Robert Kleemann,et al.  Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3–Leiden Transgenic Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[31]  N Latruffe,et al.  Effect of peroxisomes proliferators and hypolipemic agents on mitochondrial inner membrane linked D-3-hydroxybutyrate dehydrogenase (BDH). , 1995, Biochemistry and molecular biology international.

[32]  Y. Zhang,et al.  Improvement of inflammatory responses associated with NF-κB pathway in kidneys from diabetic rats , 2008, Inflammation Research.

[33]  T. Kooistra,et al.  Mouse models for atherosclerosis and pharmaceutical modifiers. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[34]  François Mach,et al.  Inflammation and Atherosclerosis , 2004, Herz.

[35]  Daniel R. Jeske,et al.  Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice. , 2007, Gastroenterology.

[36]  Susumu Goto,et al.  Systems biology approaches and pathway tools for investigating cardiovascular disease. , 2009, Molecular bioSystems.

[37]  Age K Smilde,et al.  Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: a combined transcriptomics and metabolomics analysis , 2007, Genome Biology.

[38]  B Staels,et al.  Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta. , 2001, The Journal of biological chemistry.

[39]  M. Crisby,et al.  Rosuvastatin reduces caspase-3 activity and up-regulates α-secretase in human neuroblastoma SH-SY5Y cells exposed to Aβ , 2004, Neuroscience Letters.

[40]  T. Kooistra,et al.  HMG-CoA reductase inhibitors: effects on chronic subacute inflammation and onset of atherosclerosis induced by dietary cholesterol. , 2005, Current drug targets. Cardiovascular & haematological disorders.

[41]  Robert Kleemann,et al.  Global Suppression of IL-6-induced Acute Phase Response Gene Expression after Chronic in Vivo Treatment with the Peroxisome Proliferator-activated Receptor-α Activator Fenofibrate* , 2004, Journal of Biological Chemistry.