title: Inhibition of the renin-angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells.
abstract: BACKGROUND
  The renin-angiotensin system (RAS) promotes angiogenesis and growth of neoplastic cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer. Tissue factor (TF), for its involvement in tumor growth, angiogenesis, and metastasis is considered a hallmark of cancer progression. In this study we evaluated whether RAS blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA-MB-231 cell line.
  
  
  METHODS
  Cell TF activity was assessed by one stage clotting time, TF and VEGF antigens and mRNA levels by ELISA and RT-PCR, respectively. AT(1) was detected by flow-cytometry and angiotensin-II levels by EIA.
  
  
  RESULTS
  Captopril reduced in a concentration-dependent way both the strong constitutive TF activity (983.2±55.2 vs. 686.7±135.1U/5×10(5) cells with 10μg/ml captopril) and antigen (32.3±5.9 vs. 13.2±6.6ng/ml) in MDA-MB-231. Similar results were observed with enalapril. AT1 was present on cell membrane and losartan, a competitive inhibitor of AT1, reduced TF expression to a degree similar as that exerted by ACE inhibitors. Moreover, captopril and losartan downregulated the constitutive mRNA TF expression by ~35%. Similar results were observed with anti-AT1 and angiotensin II antibodies. In addition, the constitutive VEGF antigen and mRNA levels were reduced in the presence of captopril or losartan, and an anti-VEGF antibody downregulated cell TF activity by ~40%.
  
  
  CONCLUSIONS
  These results could, at least in part, contribute to the discussion about the possible effects of ACE inhibitors and AT1 receptor antagonists in malignancy, and offer new clues to support their use for tumor control.
authors.affiliation: Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Napoleone
authors.forename: Antonella
authors.initials: A
authors.lastname: Cutrone
authors.forename: Daniela
authors.initials: D
authors.lastname: Cugino
authors.forename: Concetta
authors.initials: C
authors.lastname: Amore
authors.forename: Angelomaria
authors.initials: A
authors.lastname: Di Santo
authors.forename: Licia
authors.initials: L
authors.lastname: Iacoviello
authors.forename: Giovanni
authors.initials: G
authors.lastname: de Gaetano
authors.forename: Maria Benedetta
authors.initials: MB
authors.lastname: Donati
authors.forename: Roberto
authors.initials: R
authors.lastname: Lorenzet
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002216:Captopril / Q000494:pharmacology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004656:Enalapril / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004656:Enalapril; D013925:Thromboplastin; D002216:Captopril