Journal article
Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease
Journal of neurosurgery, v 131(4), pp 1106-1114
01 Oct 2019
PMID: 30497198
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
OBJECTIVE Von Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by CNS hemangioblastomas (HBs) and clear cell renal cell carcinomas (RCCs) due to hypoxia-inducible factor activation (pseudohypoxia). Because of the lack of effective medical therapies for VHL, HBs and RCCs account for significant morbidity and mortality, ultimately necessitating numerous neurological and renal surgeries. Propranolol is an FDA-approved pan-beta adrenergic antagonist with antitumor effects against infantile hemangiomas (IHs) and possibly VHL HBs. Here, the authors investigated the antitumor efficacy of propranolol against pseudohypoxia-driven VHL-HBs and VHL-RCCs.
METHODS Patient-derived VHL-associated HBs (VHL-HBs) or 786-O-VHL-/-RCC cells were treated with clinically relevant concentrations of propranolol in vitro and assessed with viability assays, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. In vivo confirmation of propranolol antitumor activity was confirmed in athymic nude mice bearing 786-O xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) were analyzed for incidental propranolol intake. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis.
RESULTS Propranolol decreased HB and RCC viability in vitro with IC50 (half maximal inhibitory concentration) values of 50 mu M and 200 mu M, respectively. Similar to prior reports in infantile hemangiomas, propranolol induced apoptosis and paradoxically increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-O cells. While intracellular VEGF protein levels were not affected by propranolol treatment, propranolol decreased HIF expression in 786-O cells (7.6-fold reduction, p < 0.005). Propranolol attenuated tumor progression compared with control (33% volume reduction at 7 days, p < 0.005) in 786-O xenografted tumor-bearing mice. Three patients (harboring 25 growing CNS HBs) started propranolol therapy during the longitudinal VHL-HB study. HBs in these patients tended to grow slower (median growth rate 27.1 mm(3)/year vs 13.3 mm(3)/year) during propranolol treatment (p < 0.0004).
CONCLUSIONS Propranolol decreases VHL-HB and VHL-related RCC viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogates 786-O xenograft tumor progression in vivo, and retrospective clinical data suggest that propranolol curtails HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors.
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Details
- Title
- Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease
- Creators
- Matthew J. Shepard - National Institutes of HealthAlejandro Bugarini - National Institutes of HealthNancy A. Edwards - National Institute of Neurological Disorders and StrokeJie Lu - National Institute of Neurological Disorders and StrokeQi Zhang - National Institute of Neurological Disorders and StrokeTianxia Wu - National Institutes of HealthZhengping Zhuang - National Institutes of HealthPrashant Chittiboina - National Institute of Neurological Disorders and Stroke
- Publication Details
- Journal of neurosurgery, v 131(4), pp 1106-1114
- Publisher
- Amer Assoc Neurological Surgeons
- Number of pages
- 9
- Grant note
- National Institute for Neurological Diseases and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) ZIABC011773 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) National Institutes of Health Clinical Center in Bethesda, MD; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA ZIANS003053 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurology
- Web of Science ID
- WOS:000490249600015
- Scopus ID
- 2-s2.0-85072757899
- Other Identifier
- 991022155291804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Clinical Neurology
- Surgery