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PROPRANOLOL ACTION IS MEDIATED VIA THE BETA-2 ADRENERGIC RECEPTOR IN HEMANGIOMA STEM CELLS
Presenter: Ryan W England, Student
Co-Authors: Banerjee D; Shawber CJ; Kitajewski A; Kitajewski J; Wu JK
Columbia University

Purpose: Infantile hemangiomas (IH) are benign vascular tumors that originate from hemangioma stem cells (HemSC). Propranolol, a nonspecific beta-adrenergic antagonist, has proven efficacy in the treatment of problematic IHs, although the molecular mechanism of action is not well understood. We hypothesize that propranolol s effects are mediated preferentially via the beta-1 and/or beta-2 adrenergic receptors.

Methods: HemSCs were isolated from resected IH specimens using CD133 magnetic bead selection. Cells were treated in triplicate with vehicle, 100uM propranolol, 50uM or 100uM atenolol (selective beta-1 antagonist), or 50uM or 100uM ICI 118,551(selective beta-2 antagonist). Cellular proliferation was quantified by WST-8 assay after three days in growth media. Student s t-test was used for statistical analysis.

Results: HemSCs showed a significant decrease in proliferation with propranolol treatment (p <0.0002). Treatment with atenolol, a selective beta-1 adrenergic antagonist, resulted in no change in HemSC proliferation, when compared to vehicle (Figure 1). In contrast, treatment with ICI 118,551, a selective beta-2 adrenergic antagonist, resulted in a dose-dependent decrease in HemSC proliferation, comparable to propranolol (p <0.005) (Figure 2).

Conclusion: The beta-2 selective antagonist ICI 118,551 caused decreased proliferation of HemSCs in a dose dependent manner, while the beta-1 selective antagonist atenolol had no effect. This preliminary study indicates that the effectiveness of propranolol in IH may be mediated selectively via the beta-2 receptor and implicates the beta-2 adrenergic receptor-signaling pathway in IH pathobiology. These results suggest that non-selective beta-blockers are more efficacious in treating IHs than selective beta-1 blockers. Furthermore, therapeutics with beta-2 selective antagonist can be designed to minimize potential adverse effects from non-selective beta-adrenergic antagonists.


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