title: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, potentiate the anti-angiogenic effects of bevacizumab by suppressing angiopoietin2, BiP, and Hsp90α in human colorectal cancer.
abstract: BACKGROUND
  Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are commonly prescribed because of their therapeutic and preventive effects on cardiovascular diseases. Even though they have been occasionally reported to have antitumour activity, it is unknown whether statins have anti-angiogenic effect in human colorectal cancer (CRC).
  
  
  METHODS
  A total of 11 human CRC cell lines were used to test the effects of bevacizumab, statins, and bevacizumab plus statins on human umbilical vein endothelial cell (HUVEC) viability and invasion in vitro. To determine the molecular mechanism of statins as anti-angiogenic agents, we performed an angiogenesis antibody array and proteomics analysis and confirmed the results using immunoblot assay, HUVEC invasion rescue assay, and siRNA assay. The antitumoural effects of bevacizumab and statins were evaluated in xenograft models.
  
  
  RESULTS
  A conventional dose of statins (simvastatin 0.2 μM, lovastatin 0.4 μM, atorvastatin 0.1 μM, and pravastatin 0.4 μM) in combination with bevacizumab directly reduced the cell viability, migration, invasion, and tube formation of HUVECs. The culture media of the CRC cells treated with bevacizumab or statins were also found to inhibit HUVEC invasion by suppressing angiogenic mediators, such as angiopoietin2, binding immunoglobulin protein (BiP), and Hsp90α. The combined treatment with bevacizumab and simvastatin significantly reduced the growth and metastases of xenograft tumours compared with treatment with bevacizumab alone.
  
  
  CONCLUSIONS
  The addition of simvastatin at a dose used in patients with cardiovascular diseases (40-80 mg once daily) may potentiate the anti-angiogenic effects of bevacizumab on CRC by suppressing angiopoietin2, BiP, and Hsp90α in cancer cells. A clinical trial of simvastatin in combination with bevacizumab in patients with CRC is needed.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Samsung Medical Center, Seoul 135-710, Korea.
authors.forename: I
authors.initials: I
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Samsung Medical Center, Seoul 135-710, Korea.
authors.forename: C
authors.initials: C
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: W K
authors.initials: WK
authors.lastname: Kang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D019821:Simvastatin / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C586513:ANGPT2 protein, human; D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D061067:Antibodies, Monoclonal, Humanized; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D006360:Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068258:Bevacizumab; D019821:Simvastatin