title: Inhibitory activity of ranibizumab, sorafenib, and pazopanib on light-induced overexpression of platelet-derived growth factor and vascular endothelial growth factor A and the vascular endothelial growth factor A receptors 1 and 2 and neuropilin 1 and 2.
abstract: BACKGROUND
  Cumulative light exposure is significantly associated with progression of age-related macular degeneration. Growth factors and growth factor receptor signaling are known to have a substantial impact on the development of age-related macular degeneration. This study explored the effects of ranibizumab, sorafenib, and pazopanib on vascular endothelial growth factor A (VEGF) receptors 1 and 2 and neuropilin 1 and 2 expression in human retinal pigment epithelial cells. In addition, their effects on light-induced overexpression of VEGF and platelet-derived growth factor were investigated.
  
  
  METHODS
  Primary human retinal pigment epithelial cells were exposed to white light and then treated with ranibizumab (0.125 mg/mL), sorafenib (1 μg/mL), or pazopanib (1 μg/mL). Viability of cells, expression of VEGF receptors 1 and 2 and neuropilin 1 and 2 and their mRNA, and secretion of VEGF and platelet-derived growth factor were investigated by reverse transcription-polymerase chain reactions, immunohistochemistry, and enzyme-linked immunosorbent assays.
  
  
  RESULTS
  Treatment with sorafenib or pazopanib reduced the expression of VEGF receptors 1 and 2 and neuropilin 1, and sorafenib also reduced neuropilin 2. Light exposure decreased cell viability and increased expression and secretion of VEGF and platelet-derived growth factor. Sorafenib and pazopanib significantly reduced light-induced overexpression and secretion of VEGF and platelet-derived growth factor. Ranibizumab reduced secreted VEGF in cell culture supernatants only.
  
  
  CONCLUSIONS
  Our in vitro results suggest that multikinase inhibitors have promising properties as a potential antiangiogenic treatment for age-related macular degeneration.
authors.affiliation: Department of Ophthalmology, Ludwig Maximilian University, Munich, Germany. marcus.kernt@med.uni-muenchen.de
authors.forename: Marcus
authors.initials: M
authors.lastname: Kernt
authors.forename: Sarah
authors.initials: S
authors.lastname: Thiele
authors.forename: Aljoscha S
authors.initials: AS
authors.lastname: Neubauer
authors.forename: Susanna
authors.initials: S
authors.lastname: Koenig
authors.forename: Christoph
authors.initials: C
authors.lastname: Hirneiss
authors.forename: Christos
authors.initials: C
authors.lastname: Haritoglou
authors.forename: Michael W
authors.initials: MW
authors.lastname: Ulbig
authors.forename: Anselm
authors.initials: A
authors.lastname: Kampik
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles; D008027:Light; D008875:Middle Aged; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism; D039921:Neuropilins / Q000235:genetics / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D001557:Benzenesulfonates; D007191:Indazoles; D039943:Neuropilin-2; D039921:Neuropilins; D010671:Phenylurea Compounds; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000069579:Ranibizumab