Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patientsReport as inadecuate




Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients - Download this document for free, or read online. Document in PDF available to download.

Orphanet Journal of Rare Diseases

, 10:118

First Online: 22 September 2015Received: 22 May 2015Accepted: 16 September 2015DOI: 10.1186-s13023-015-0343-5

Cite this article as: Albiñana, V., Villar Gómez de las Heras, K., Serrano-Heras, G. et al. Orphanet J Rare Dis 2015 10: 118. doi:10.1186-s13023-015-0343-5

Abstract

BackgroundVon 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.

MethodsHeLa 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.

ResultsPropranolol 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.

ConclusionsOur 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.

Keywordsvon Hippel-Lindau disease VHL pVHL Hypoxia inducible factor hemangioblastoma CNS tumors Propranolol AbbreviationsALK1Activin receptor like kinase 1

CNSCentral nervous system

DFODeferroxiamine

DMEMDulbecco’s modified Eagle medium

EOMAMouse hemangioendothelioma edothelial cells

EPOErythropoietin

FBSFetal bovine serum

FGFFibroblast growth factor

HIFHypoxia inducible factor

HREHypoxia responsive element

IHInfantile hemangioma

MMPMatrix metalloproteinases

pVHLVon Hippel Lindau protein

RPMIRoswell Park Memorial Institute

RT-PCRReverse transcription polymerase chain reaction

SDS-PAGESodium dodecyl sulfate-polyacrylamide gel electrophoresis

SOX-2 or SRY-box 2Sex-determining region Y-box

VEGFVascular endothelial growth factor

VHLVon Hippel-Lindau

José María de Campos deceased.

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Author: Virginia Albiñana - Karina Villar Gómez de las Heras - Gemma Serrano-Heras - Tomás Segura - Ana Belén Perona-Moratalla -

Source: https://link.springer.com/







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