Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients

Orphanet Journal of Rare Diseases

Luisa María Botella⁵  José María de Campos³  Mercedes Mota-Pérez¹  Ana Belén Perona-Moratalla²  Tomás Segura²  Gemma Serrano-Heras²  Karina Villar Gómez de las Heras¹  Virginia Albiñana⁴ 

[1] SSCC del Servicio de Salud de Castilla-La Mancha (SESCAM), Toledo, Spain;Unidad de Investigación, Complejo Universitario Hospital Albacete, Albacete, Spain;Servicio de Neurocirugía, Fundación Jiménez Díaz, Madrid, Spain;Centro de Investigaciones Biológicas, CSIC, Madrid, Spain;Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

关键词: Propranolol;    CNS tumors;    hemangioblastoma;    Hypoxia inducible factor;    pVHL;    von Hippel-Lindau disease (VHL);   

Others  :  1226224
DOI  :  10.1186/s13023-015-0343-5

 received in 2015-05-22, accepted in 2015-09-16,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Albiñana et al.

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