Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

Shepard, Matthew J.; Bugarini, Alejandro; Edwards, Nancy A.; Lü, Jie; Zhang, Qi; Wu, Tianxia; Zhuang, Zhengping; Chittiboina, Prashant

doi:10.3171/2018.5.jns172879

Cited by 11 publications

(16 citation statements)

References 37 publications

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“…As shown in Figure 2 B, propranolol ( p = 0.0059) and ICI ( p = 0.0005) significantly decreased the amount of VEGF secreted by 786-O cells. This was also observed in ccRCC with both propranolol ( p = 0.014) and ICI ( p = 0.0028), at variance with the results published by Shepard et al [ 36 ], in which VEGF levels remained unchanged after 200 µM of propranolol treatment. Moreover, we also found a significant reduction of almost 20% in VEGF expression compared to the control, in three independent primary VHL-ccRCCs cultures treated with 100 µM of either propranolol or ICI.…”

Section: Resultssupporting

confidence: 78%

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Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel–Lindau Disease

Albiñana

Gallardo-Vara

Rojas-P

et al. 2020

JCM

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Von Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL−/− ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.

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Section: Resultssupporting

confidence: 78%

“…Both RCCs share a unique and common characteristic: a homozygous mutation in the VHL gene, which drives the stabilization of HIF protein in the resulting tumors, with HIF-2α being the predominant isoform. [ 36 ]. Hence, targeting HIF might have beneficial antitumor effects in both VHL and RCC patients.…”

Section: Discussionmentioning

confidence: 99%

Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel–Lindau Disease

Albiñana

Gallardo-Vara

Rojas-P

et al. 2020

JCM

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“…Although a recent publication supports our hypothesis that propranolol reduces hemangioblastoma growth,23 more studies are needed and with more patients to confirm these results, preferably with fewer previous invasive treatments (such as laser photocoagulation).…”

Section: Discussionsupporting

confidence: 59%

Evaluation of the safety and effectiveness of oral propranolol in patients with von Hippel-Lindau disease and retinal hemangioblastomas: phase III clinical trial

et al. 2019

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Backgroundvon Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by mutations in the VHL gene. Retinal hemangioblastoma is one of the most common tumours, and when it appears near the optic nerve, its treatment is challenging and risky. To date, no treatment has proven effective in changing the course of the disease. This study was designed to evaluate the safety and effectiveness of propranolol in controlling these tumours.MethodsSeven patients were included. All patients took a daily dose of 120 mg of propranolol for 1 year. Clinical variables were assessed at baseline, and at 1, 3, 6, 9 and 12 months. The primary endpoint of the study was the number and size of retinal hemangioblastomas. On every visit, retinal outcomes and blood biomarkers (such as vascular endothelial growth factor (VEGF) and miR210) were analysed.ResultsNumber and size of retinal hemangioblastomas remained stable in all patients. All of them had initially increased levels of VEGF and miR210. There was a gradual reabsorption of retinal exudation in two patients, correlating with a progressive decrease of both biomarkers. The only adverse effect reported was hypotension in one patient.ConclusionsPropranolol could be used to treat retinal hemangioblastomas in VHL patients, although more studies are needed to determine the ideal dose and long-term effect. VEGF and miR210 should be explored as biomarkers of disease activity. As far as we know, these are the first biomarkers proposed to monitor the VHL disease activity.Trial registration number2014-003671-30

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“…In this scenario, where surgery and pharmacological therapies show limited recovery and response for CNS VHL disease, an urgent requirement for new and more effective drugs with reduced side effects for these patients are demanded. www.nature.com/scientificreports www.nature.com/scientificreports/ Some previous studies from Shepard et al and our group have demonstrated that Propranolol, a non-specific β1-and β2-blocker, was efficient on in vitro treatment of CNS Hemangioblastomas primary cultures 19,21,52 . Basically, Propranolol was acting in two ways: i) decreasing cell viability by triggering apoptosis and ii) inhibiting the expression of HIF-dependent targets in VHL HB cells, where HIF-1α degradation is impaired 21 .…”

Section: Discussionmentioning

confidence: 89%

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Cuesta

Albiñana

Gallardo-Vara

et al. 2019

Sci Rep

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One of the major consequences of the lack of a functional VHL protein in von Hippel-Lindau disease, a rare cancer, is the constitutive activation of the HIF pathway. This activation ends up in the generation of Central Nervous System (CNS) Hemangioblastomas among other tumours along the lifespan of the patient. Nowadays, only surgery has been proven efficient as therapy since the systemic attempts have failed. Propranolol, a non-specific β1-and β2-adrenergic receptor antagonist, was recently designated as the first therapeutic (orphan) drug for VHL disease. Nevertheless, its β1 affinity provokes the decrease in blood pressure, being not recommended for low or regular blood pressure VHL patients. In order to overcome the β1-drawback, the properties of a high specific β2-adrenergic receptor blocker named ICI-118,551 have been studied. ICI-118,551 was able to decrease Hemangioblastomas cell viability in a specific manner, by triggering apoptosis. Moreover, ICI-118,551 also impaired the nuclear internalization of HIF-1α in Hemangioblastomas and hypoxic primary endothelial cells, reducing significantly the activation of HIF-target genes and halting the tumour-related angiogenic processes. In this work, we demonstrate the therapeutical properties of ICI-118,551 in VHL-derived CNS-Hemangioblastoma primary cultures, becoming a promising drug for VHL disease and other HIF-related diseases. Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited genetic disorder with an incidence of 1 per 36,000 individuals in the general population and is considered as a rare disease or rare cancer 1,2. Patients with VHL disease harbour a single mutation allele in the tumour suppressor gene VHL (3p25-p26). VHL protein (pVHL) controls the cytoplasmic levels of the Hypoxia Inducible Factor (HIF) complex. In normoxic conditions, pVHL binds to the previously hydroxylated prolyl residues of HIF-1α and HIF-2α, being ubiquitinated and targeted to the proteasome for rapid degradation. When patients suffer a spontaneous inactivation or loss of the second wild-type VHL allele (loss of heterozygosity), either there is no expression of the pVHL or the mutated form is not functional 3,4. Therefore, in the absence of functional pVHL, HIF-1α and HIF-2α subunits accumulate within the cytoplasm and translocate to the nucleus, triggering the hypoxia program by targeting hypoxia responsive genes, which are normally silenced in normoxia 5. HIF-1α and HIF-2α are involved in cell proliferation, angiogenesis, extracellular matrix degradation, vascular tone, and erythropoiesis, among other processes. Hence, cells from VHL tumours have a constitutively active HIF program (a pseudo-hypoxic state) due to the absence of functional pVHL 6,7. As a consequence of this pseudo-hypoxic state, the clinical manifestations of the disease include multiple benign and malignant tumours that appear throughout the lifespan of the patient: retinal hemangioblastoma,

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Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

Cited by 11 publications

References 37 publications

Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel–Lindau Disease

Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel–Lindau Disease

Evaluation of the safety and effectiveness of oral propranolol in patients with von Hippel-Lindau disease and retinal hemangioblastomas: phase III clinical trial

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

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