title: β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma.
abstract: BACKGROUND
  The use of β-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether β-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma.
  
  
  METHODS
  Seven β-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma.
  
  
  RESULTS
  Three β-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. β-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, β-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, β-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01).
  
  
  CONCLUSIONS
  β-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, New South Wales 2031, Australia. e.pasquier@ccia.unsw.edu.au
authors.forename: E
authors.initials: E
authors.lastname: Pasquier
authors.forename: J
authors.initials: J
authors.lastname: Street
authors.forename: C
authors.initials: C
authors.lastname: Pouchy
authors.forename: M
authors.initials: M
authors.lastname: Carre
authors.forename: A J
authors.initials: AJ
authors.lastname: Gifford
authors.forename: J
authors.initials: J
authors.lastname: Murray
authors.forename: M D
authors.initials: MD
authors.lastname: Norris
authors.forename: T
authors.initials: T
authors.lastname: Trahair
authors.forename: N
authors.initials: N
authors.lastname: Andre
authors.forename: M
authors.initials: M
authors.lastname: Kavallaris
mesh_terms: D000008:Abdominal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009447:Neuroblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000319:Adrenergic beta-Antagonists; D020533:Angiogenesis Inhibitors