711 Propranolol exhibits activity against hemangiomas independent of beta blockade

Abstract

Propranolol is a widely used beta-blocker that consists of a racemic mixture of R and S stereoisomers, but only the S-stereoisomer has significant activity against the beta-adrenergic receptor. Infants receiving propranolol for the treatment of hemangiomas require frequent monitoring to ensure that they do not suffer from side effects related to beta-blockade. The exact mechanism of activity of propranolol in hemangiomas of infancy is unknown. In this study, we treated hemangioma stem cells with both beta-blockade active (S) and inactive (R) propranolol and searched for genes that were coordinately regulated by this treatment. Angiopoietin-like 4 (Angptl4) was among the most downregulated. We confirmed that propranolol isomers downregulated Angptl4 in endothelial cells, with greater downregulation of Angptl4 using the beta-blockade inactive R-propranolol. Notably, Angptl4 is present in human hemangiomas of infancy. R-propranolol inhibited the growth of b.End3 hemangioma cells in vivo. Both isomers of propranolol converted the glycolytic phenotype of bend3 cells to a more respiratory phenotype. Finally, we established that EGR1 and APOA1, genes responsible for tumor suppression and lipid metabolism, were the most upregulated genes in cells treated with R-propranolol when compared with untreated cells. The implication of these findings 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, we propose the clinical development of R-propranolol for hemangiomas of infancy and other angiogenic diseases.