title: Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib.
abstract: BACKGROUND
  Prostate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested.
  
  
  METHODS
  We isolated and characterized three lines of endothelial cells from prostate cancer and we tested the effect of Sunitinib and Sorafenib, and the combined treatment with the anti-androgen Casodex, on their angiogenic functions.
  
  
  RESULTS
  Endothelial cells isolated from prostate tumors showed angiogenic properties and expression of androgen and vascular endothelial cell growth factor receptors. Sunitinib affected their proliferation, survival and motility while Sorafenib only showed a minor effect. At variance, Sunitinib and Sorafenib showed similar cytotoxic and anti-angiogenic effects on normal endothelial cells. Sorafenib and Sunitinib inhibited vascular endothelial cell growth factor receptor2 phosphorylation of prostate cancer endothelial cells, while they differentially modulated Akt phosphorylation as no inhibitory effect of Sorafenib was observed on Akt activation. The combined treatment of Casodex reverted the observed resistance to Sorafenib both on cell viability and on Akt activation, whereas it did not modify the response to Sunitinib.
  
  
  CONCLUSIONS
  Our study demonstrates a resistant behavior of endothelial cells isolated from prostate cancer to Sorafenib, but not Sunitinib. Moreover, it shows the benefit of a multi-target therapy combining anti-angiogenic and anti-hormonal drugs to overcome resistance.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fiorio Pla
authors.forename: Alessia
authors.initials: A
authors.lastname: Brossa
authors.forename: Michela
authors.initials: M
authors.lastname: Bernardini
authors.forename: Tullio
authors.initials: T
authors.lastname: Genova
authors.forename: Guillaume
authors.initials: G
authors.lastname: Grolez
authors.forename: Arnaud
authors.initials: A
authors.lastname: Villers
authors.forename: Xavier
authors.initials: X
authors.lastname: Leroy
authors.forename: Natalia
authors.initials: N
authors.lastname: Prevarskaya
authors.forename: Dimitra
authors.initials: D
authors.lastname: Gkika
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Torino, via Nizza 52, 10126 Torino, Italy. benedetta.bussolati@unito.it.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bussolati
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D000077157:Sorafenib; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D015415:Biomarkers; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib