title: Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients.
abstract: BACKGROUND
  Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumors: hemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma, pheochromocytomas, pancreatic serous cystadenoma, and endolymphatic sac tumors. These tumors do not express VHL protein (pVHL). pVHL ubiquitinates hypoxia inducible factor (HIF) protein for degradation by the proteasome; in the absence of VHL, HIF translocates to the nucleus to activate the expression of its target genes. Targeting VHL-derived tumors with drugs that have reduced side effects is urgent to avoid repeat CNS surgeries. Recent reports have shown that propranolol, a β-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control hemangioblastoma growth in VHL disease because of its antiangiogenic effects demonstrated in IH and the hypothetical impact on HIF levels.
  
  
  METHODS
  HeLa 9X (HRE) hypoxia responsive element cell line and primary hemangioblastoma-derived cells were subjected to propranolol treatment and cell viability and apoptosis were evaluated. HIF1-α and Hif-2α expression after propranolol treatment was analyzed by western blotting. Quantitative PCR was performed to study the mRNA expression of HIF target genes. Vascular endothelial growth factor (VEGF) was measured in culture supernatants by immunoassay.
  
  
  RESULTS
  Propranolol downregulated HIF-dependent transcription in HeLa 9XHRE cells. Under hypoxic conditions, propranolol decreased the expression of HIF target genes in hemangioblastoma cells, which stopped proliferating and died following long-term treatment. These results suggests that propranolol treatment promoted reduced HIF protein expression and corresponding downregulation of HIF target genes, and inhibited cell proliferation in parallel with induction of cell death by apoptosis.
  
  
  CONCLUSIONS
  Our results suggest that propranolol could reduce the growth of HIF-dependent tumors and may thus be a promising treatment to delay surgery in VHL patients.
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, Madrid, Spain. vir_albi_di@yahoo.es.
authors.forename: Virginia
authors.initials: V
authors.lastname: Albiñana
authors.affiliation: SSCC del Servicio de Salud de Castilla-La Mancha (SESCAM), Toledo, Spain. kvillar@jccm.es.
authors.forename: Karina
authors.initials: K
authors.lastname: Villar Gómez de Las Heras
authors.affiliation: Unidad de Investigación, Complejo Universitario Hospital Albacete, Albacete, Spain. gemmas@sescam.jccm.es.
authors.forename: Gemma
authors.initials: G
authors.lastname: Serrano-Heras
authors.affiliation: Unidad de Investigación, Complejo Universitario Hospital Albacete, Albacete, Spain. tomass@sescam.jccm.es.
authors.forename: Tomás
authors.initials: T
authors.lastname: Segura
authors.affiliation: Unidad de Investigación, Complejo Universitario Hospital Albacete, Albacete, Spain. abperona@sescam.jccm.es.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Perona-Moratalla
authors.affiliation: SSCC del Servicio de Salud de Castilla-La Mancha (SESCAM), Toledo, Spain. mmota@jccm.es.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Mota-Pérez
authors.affiliation: Servicio de Neurocirugía, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: de Campos
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, Madrid, Spain. cibluisa@cib.csic.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. cibluisa@cib.csic.es.
authors.forename: Luisa María
authors.initials: LM
authors.lastname: Botella
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D018325:Hemangioblastoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011433:Propranolol / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000188:drug therapy / Q000473:pathology*
chemical_list: D000319:Adrenergic beta-Antagonists; D011433:Propranolol