title: Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma.
abstract: Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective β-adrenergic receptor antagonist propranolol hydrochloride. Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, and not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express β2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.
authors.affiliation: Departments of Pediatrics and Medical Biophysics, University of Toronto.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Wolter
authors.forename: Nikolaus E
authors.initials: NE
authors.lastname: Wolter
authors.forename: Alvaro
authors.initials: A
authors.lastname: Blanch
authors.forename: Teresa
authors.initials: T
authors.lastname: Partridge
authors.forename: Lynn
authors.initials: L
authors.lastname: Cheng
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Morgenstern
authors.forename: Monika
authors.initials: M
authors.lastname: Podkowa
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001342:Autonomic Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D004268:DNA-Binding Proteins; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009423:Nervous System Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins; D011433:Propranolol / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D000319:Adrenergic beta-Antagonists; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011943:Receptors, Adrenergic, beta; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D011433:Propranolol