Once-a-Day Administration of R(+) Propranolol Is Sufficient to Block Vasculogenesis in a Xenograft Model of Infantile Hemangioma

Abstract

Objective: Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of infants, predominantly in female and preterm neonates. Propranolol is the mainstay of treatment for IH. Given the short half-life of propranolol regarding β-adrenergic receptor inhibition as well as its side effects, propranolol is administered to infants 2–3 times daily with 1 mg/kg/dose. We previously demonstrated propranolol inhibits IH vessel formation via an effect of its R(+) enantiomer on the endothelial-specific transcription factor SRY box 18 (SOX18). In light of this, we hypothesized that R(+) propranolol inhibition of SOX18 is long-lived compared to the beta-blocker effects, and therefore administration of R(+) propranolol once a day would be sufficient to block IH vessel formation. Methods: We tested the effect of 1 dose versus 2 doses of R(+) propranolol in a xenograft model of IH wherein patient-derived hemangioma stem cells were implanted subcutaneously into nude mice. Mice were treated for 7 days with 2 × 12.5 mg/kg/d (n = 12) versus 1 × 25 mg/kg/d (n = 14) as well as phosphate-buffered saline (vehicle control) (n = 16) via intraperitoneal injections. The doses were estimated to correlate with those given to infants with IH. Results: Treatment with R(+) propranolol significantly inhibited vasculogenesis in our IH xenograft model at both 2 × 12.5 mg/kg/d and 1 × 25 mg/kg/d, compared to vehicle controls. No significant difference was observed between the 2 treatment regimens. Conclusion: Our results suggest implications for the clinical management of infants with IH: Administration of R(+) propranolol can possibly minimize or omit concerning β-adrenergic side effects while only requiring 1 dose per day.