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R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma
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R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma
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Journal Article
R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma
2019
Overview
Propranolol is an approved non-selective β-adrenergic blocker that is first line therapy for infantile hemangioma. Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited. Here, we report successful treatment of pericardial edema with propranolol in a patient with Hypotrichosis-Lymphedema-Telangiectasia and Renal (HLTRS) syndrome, caused by a mutation in SOX18. Using a mouse pre-clinical model of HLTRS, we show that propranolol treatment rescues its corneal neo-vascularisation phenotype. Dissection of the molecular mechanism identified the R(+)-propranolol enantiomer as a small molecule inhibitor of the SOX18 transcription factor, independent of any anti-adrenergic effect. Lastly, in a patient-derived in vitro model of infantile hemangioma and pre-clinical model of HLTRS we demonstrate the therapeutic potential of the R(+) enantiomer. Our work emphasizes the importance of SOX18 etiological role in vascular neoplasms, and suggests R(+)-propranolol repurposing to numerous indications ranging from vascular diseases to metastatic cancer.
Publisher
eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
Subject
Adrenergic beta-Antagonists - administration & dosage
/ Adrenergic beta-Antagonists - pharmacology
/ Animals
/ Biochemistry, Molecular Biology
/ Cancer
/ Cardiology and cardiovascular system
/ Cornea
/ Enzyme Inhibitors - administration & dosage
/ Enzyme Inhibitors - pharmacology
/ Genetics
/ Humans
/ Hypotrichosis - drug therapy
/ Mice
/ Mutation
/ Patients
/ Propranolol - administration & dosage
/ Proteins
/ SOXF Transcription Factors - antagonists & inhibitors
