Propranolol exhibits activity against hemangiomas independent of beta blockade

• Type of Material: Article
• Authors: Maiko Sasaki, Emory University; Paula E. North, Children's Hospital of Wisconsin; Justin Elsey, Emory University; Jeffrey Bubley, Emory University; Shikha Rao, Emory University; Yoonhee Jung, Emory University; Shengnan Wu, Georgia State University; Ming-Hui Zou, Georgia State University; Brian Pollack, Emory University; Jayanth Kumar, Stritch School of Medicine; Hartej Singh, Emory University; Jack Arbiser, Emory University
• Language: English
• Date: 2019-11-01
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41698-019-0099-9
• Title of Journal or Parent Work: NPJ Precision Oncology
• Volume: 3
• Start Page: 27
• End Page: 27
• Grant/Funding Information: J.L.A. was supported in part by NIH RO1 AR47901.; Additional support was provided by the National Center for Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.
• Keywords: METHYLTRANSFERASE BHMT; INFANTILE HEMANGIOMA; EXPRESSION; Life Sciences & Biomedicine; HOMOCYSTEINE; EPITHELIOID HEMANGIOMA; Science & Technology; MUTATIONS; ANGIOPOIETIN-2; FOS; Oncology; APOPTOSIS
• Research Categories: Health Sciences, Oncology

Abstract

Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. This has led to the widespread use of propranolol for the treatment of large and life-threatening hemangiomas of infancy. Infants receiving propranolol require monitoring to ensure that they do not suffer from side effects related to beta blockade. The exact mechanism of activity of propranolol in hemangioma of infancy is unknown. In this study, we treated hemangioma stem cells with both beta blockade active S- and inactive R-propranolol and looked for genes that were coordinately regulated by this treatment. Among the genes commonly downregulated, Angiopoietin-like 4 (ANGPTL4) was among the most regulated. We confirmed that propranolol isomers downregulated ANGPTL4 in endothelial cells, with greater downregulation of ANGPTL4 using the beta blockade inactive R-propranolol. ANGPTL4 is present in human hemangiomas of infancy. Finally, R-propranolol inhibited the growth of bEnd.3 hemangioma cells in vivo. The implication of this is that hemangioma growth can be blocked without the side effects of beta blockade. Given that humans have been exposed to racemic propranolol for decades and thus to R-propranolol, clinical development of R-propranolol for hemangiomas of infancy and other angiogenic diseases is warranted.