<strong>Combinative effects of β-elemene and propranolol on the proliferation, migration,</strong> <strong>and angiogenesis of hemangioma</strong>

Hemangioma (HA) is one of the most common benign vascular tumors among children. Propranolol is used as the first-line treatment for hemangioma and is a non-selective blocker of the β-adrenergic receptor. β-elemene is a compound extracted from Rhizoma zedoariae and has been approved for the treatment of tumors in clinical practice. However, the combinatorial effects of β-elemene and propranolol in the treatment of HA remains unclear. This study explored, the combinative effects and mechanisms of β-elemene and propranolol using hemangioma-derived endothelial cells (HemEC). Cytotoxic assays showed that the combinatorial treatment of β-elemene and propranolol did not increase the cytotoxic effects of HemEC cells. Furthermore, functional analysis showed that the combinatorial treatment with β-elemene and propranolol significantly inhibited proliferation, migration, and tube formation of the HemEC cells compared to the single treatment regimens. Mechanistic analysis showed that combinative treatment with β-elemene and propranolol synergistically down-regulated the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor-A (HIF-1-α/VEGFA) signaling pathway. Additionally, in a xenograft tumor model, angiogenesis in the combinatorial treatment group was significantly lower than in the control, propranolol, and β-elemene treatment alone groups. Our results suggest that β-elemene combined with propranolol can significantly inhibit the proliferation, migration, and tube formation of HemEC cells via synergistically down-regulating the HIF-1-α/VEGFA signaling pathway without increasing any cytotoxic side effects.