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首页> 外文期刊>Orphanet journal of rare diseases >Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients
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Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients

机译：普萘洛尔可降低von Hippel-Lindau患者血管母细胞瘤细胞的活力并诱导其凋亡

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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.
机译：背景Von Hippel-Lindau（VHL）病是一种罕见的肿瘤病，发病率为1：36,000，其特征是多种肿瘤的生长：中枢神经系统（CNS）和视网膜的血管母细胞瘤，肾癌，嗜铬细胞瘤，胰腺浆液性囊腺瘤和内淋巴囊肿。这些肿瘤不表达VHL蛋白（pVHL）。 pVHL泛素化缺氧诱导因子（HIF）蛋白，以被蛋白酶体降解;在没有VHL的情况下，HIF易位至细胞核以激活其靶基因的表达。迫切需要使用副作用减少的药物靶向VHL衍生的肿瘤，以避免重复进行中枢神经系统手术。最近的报道表明，普萘洛尔是一种用于治疗高血压以及其他心脏和神经系统疾病的β受体阻滞剂，是婴儿血管瘤（IH）的最佳选择。普萘洛尔可能是控制VHL疾病中血管母细胞瘤生长的有效方法，因为它在IH中显示出抗血管生成作用，并且对HIF水平有假设性影响。方法对HeLa 9X（HRE）缺氧反应元件细胞系和原发性成血管母细胞瘤细胞进行普萘洛尔处理，并评估其生存能力和凋亡。普萘洛尔处理后的HIF1-α和Hif-2α表达通过蛋白质印迹分析。进行定量PCR以研究HIF靶基因的mRNA表达。通过免疫测定法测量培养上清液中的血管内皮生长因子（VEGF）。结果普萘洛尔下调HeLa 9XHRE细胞中HIF依赖性转录。在低氧条件下，心得安可降低血管母细胞瘤细胞中HIF靶基因的表达，后者在长期治疗后会停止增殖并死亡。这些结果表明，普萘洛尔治疗促进了HIF蛋白表达的降低和HIF靶基因的相应下调，并在诱导细胞凋亡导致细胞死亡的同时抑制了细胞增殖。结论我们的结果表明，普萘洛尔可以减少HIF依赖性肿瘤的生长，因此可能是延迟VHL患者手术的有前途的治疗方法。

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