title: Sunitinib enhances neuronal survival in vitro via NF-κB-mediated signaling and expression of cyclooxygenase-2 and inducible nitric oxide synthase.
abstract: BACKGROUND
  Angiogenesis is tightly linked to inflammation and cancer. Regulation of angiogenesis is mediated primarily through activation of receptor tyrosine kinases, thus kinase inhibitors represent a new paradigm in anti-cancer therapy. However, these inhibitors have broad effects on inflammatory processes and multiple cell types. Sunitinib is a multitarget receptor tyrosine kinase inhibitor, which has shown promise for the treatment of glioblastoma, a highly vascularized tumor. However, there is little information as to the direct effects of sunitinib on brain-derived neurons. The objective of this study is to explore the effects of sunitinib on neuronal survival as well as on the expression of inflammatory protein mediators in primary cerebral neuronal cultures.
  
  
  METHODS
  Primary cortical neurons were exposed to various doses of sunitinib. The drug-treated cultures were assessed for survival by MTT assay and cell death by lactate dehydrogenase release. The ability of sunitinib to affect NF-κB, COX2 and NOS2 expression was determined by western blot. The NF-κB inhibitors dicoumarol, SN50 and BAY11-7085 were employed to assess the role of NF-κB in sunitinib-mediated effects on neuronal survival as well as COX2 and NOS2 expression.
  
  
  RESULTS
  Treatment of neuronal cultures with sunitinib caused a dose-dependent increase in cell survival and decrease in neuronal cell death. Exposure of neurons to sunitinib also induced an increase in the expression of NF-κB, COX2 and NOS2. Inhibiting NF-κB blunted the increase in cell survival and decrease in cell death evoked by sunitinib. Treatment of cell cultures with both sunitinib and NF-κB inhibitors mitigated the increase in COX2 and NOS2 caused by sunitinib.
  
  
  CONCLUSIONS
  Sunitinib increases neuronal survival and this neurotrophic effect is mediated by NF-κB. Also, the inflammatory proteins COX2 and NOS2 are upregulated by sunitinib in an NF-κB-dependent manner. These data are in agreement with a growing literature suggesting beneficial effects for inflammatory mediators such as NF-κB, COX2 and NOS2 in neurons. Further work is needed to fully explore the effects of sunitinib in the brain and its possible use as a treatment for glioblastoma. Finally, sunitinib may be useful for the treatment of a range of central nervous system diseases where neuronal injury is prominent.
authors.affiliation: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors.forename: Alma
authors.initials: A
authors.lastname: Sanchez
authors.forename: Debjani
authors.initials: D
authors.lastname: Tripathy
authors.forename: Xiangling
authors.initials: X
authors.lastname: Yin
authors.forename: Jinhua
authors.initials: J
authors.lastname: Luo
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Martinez
authors.forename: Paula
authors.initials: P
authors.lastname: Grammas
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000077210:Sunitinib
chemical_list: D007211:Indoles; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011758:Pyrroles; D007770:L-Lactate Dehydrogenase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D000077210:Sunitinib