title: Systems biology analysis unravels the complementary action of combined rosuvastatin and ezetimibe therapy.
abstract: OBJECTIVE
  Combination-drug therapy takes advantage of the complementary action of their individual components, thereby potentiating its therapeutic effect. Potential disadvantages include side effects that are not foreseen on basis of the data available from drug monotherapy. Here, we used a systems biology approach to understand both the efficacy and the side effects of a cholesterol-lowering drug-combination therapy on the basis of the biological pathways and molecular processes affected by each drug alone or in combination.
  
  
  RESULTS
  ApoE*3Leiden transgenic mice, a mouse model with human-like cholesterol-lowering drug responses, were treated with rosuvastatin and ezetimibe, alone and in combination. Analyses included functional responses, viz. effects on cardiovascular risk factors, inflammation, and atherosclerosis, and measurement of global gene expression, and identification of enriched biological pathways and molecular processes. Combination therapy reduced plasma cholesterol, plasma inflammation markers, and atherosclerosis stronger than the single drugs did. Systems biology analysis at the level of biological processes shows that the therapeutic benefit of combined therapy is largely the result of additivity of the complementary mechanisms of action of the two single drugs. Importantly, combination therapy also exerted a significant effect on 16 additional and mostly NF-κB-linked signaling processes, 11 of which tended to be regulated in a similar direction with monotherapy.
  
  
  CONCLUSIONS
  This study shows that gene expression analysis together with bioinformatics pathway analysis has the potential to help predict and identify drug combination-specific complementary and side effects.
authors.affiliation: TNO, Microbiology and Systems Biology, Zeist, The Netherlands. Lars.Verschuren@tno.nl
authors.forename: Lars
authors.initials: L
authors.lastname: Verschuren
authors.forename: Marijana
authors.initials: M
authors.lastname: Radonjic
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Wielinga
authors.forename: Thomas
authors.initials: T
authors.lastname: Kelder
authors.forename: Teake
authors.initials: T
authors.lastname: Kooistra
authors.forename: Ben
authors.initials: B
authors.lastname: van Ommen
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D012307:Risk Factors; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D049490:Systems Biology
chemical_list: D000924:Anticholesteremic Agents; D053318:Apolipoprotein E3; D001384:Azetidines; D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069438:Ezetimibe