title: Sorafenib inhibits neuroblastoma cell proliferation and signaling, blocks angiogenesis, and impairs tumor growth.
abstract: BACKGROUND
  More effective therapy for children with high-risk neuroblastoma is desperately needed. Preclinical studies have shown that neuroblastoma tumor growth can be inhibited by agents that block angiogenesis. We hypothesized that drugs which target both neuroblastoma cells and tumor angiogenesis would have potent anti-tumor activity. In this study we tested the effects of sorafenib, a multi-kinase inhibitor, on neuroblastoma cell proliferation and signaling, and in mice with subcutaneous human neuroblastoma xenografts or orthotopic adrenal tumors.
  
  
  METHODS
  Mice with subcutaneous neuroblastoma xenografts or orthotopic adrenal tumors were treated with sorafenib, and tumor growth rates were measured. Blood vessel architecture and vascular density were evaluated histologically in treated and control neuroblastoma tumors. The in vitro effects of sorafenib on neuroblastoma proliferation, cell cycle, and signaling were also evaluated.
  
  
  RESULTS
  Sorafenib inhibited tumor growth in mice with subcutaneous and orthotopic adrenal tumors. Decreased numbers of cycling neuroblastoma cells and tumor blood vessels were seen in treated versus control tumors, and the blood vessels in the treated tumors had more normal architecture. Sorafenib treatment also decreased neuroblastoma cell proliferation, attenuated ERK signaling, and enhanced G(1) /G(0) cell cycle arrest in vitro.
  
  
  CONCLUSIONS
  Our results demonstrate that sorafenib inhibits the growth of neuroblastoma tumors by targeting both neuroblastoma cells and tumor blood vessels. Single agent sorafenib should be evaluated in future phase II neuroblastoma studies.
authors.affiliation: Departments of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Nisha C
authors.initials: NC
authors.lastname: Kakodkar
authors.forename: Radhika R
authors.initials: RR
authors.lastname: Peddinti
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Guerrero
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chlenski
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yang
authors.forename: Helen R
authors.initials: HR
authors.lastname: Salwen
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D009447:Neuroblastoma / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib