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Pediatr Blood Cancer. 2015 Aug;62(8):1414-20. doi: 10.1002/pbc.25453. Epub 2015 Mar 1.

Propranolol induces regression of hemangioma cells via the down-regulation of the PI3K/Akt/eNOS/VEGF pathway.

Author information

1
Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China.

Abstract

BACKGROUND:

Infantile hemangioma (IH) is a benign vascular neoplasm resulting from the abnormal proliferation of endothelial cells and pericytes in infants. Propranolol, a non-selective β-adrenergic blocker, has recently emerged as an effective therapy for IH, causing regression. However, its potential therapeutic mechanism remains largely unknown.

PROCEDURE:

An XPTS-1 cell line was established by isolating hemangioma-derived endothelial cells (HemECs) from a specimen of human proliferating IH. Flow cytometer assay was performed to assess the effect of propranolol on cell cycle distribution. Western blot was employed to determine changes of protein expression. Matrigel invasion and tube formation assays were used to measure invasion ability and tube formation ability, respectively. Commercial kits were employed to quantify NO and VEGF levels.

RESULTS:

Propranolol blocked norepinephrine-induced HemECs cell cycle progression as well as the expression of cyclin A2 and cyclin D2; whereas p21 and p27 proteins were altered conversely. Propranolol inhibited norepinephrine-induced cell invasion by reducing the expression of MMP-9, VEGF, and p-cofilin. NO and VEGF release induced by norepinephrine was decreased by propranolol pretreatment, coincident with alterations in the phosphorylation of Akt, eNOS, and VEGFR-2. Tube formation ability and subsequent levels of NO and VEGF elevated by norepinephrine were distinctively counteracted in HemECs.

CONCLUSIONS:

The current study demonstrated the antiangiogenic properties of propranolol in vitro and that the drug was able to induce the regression of hemangioma cells via the inhibition of cell cycle progression, invasion, and tube formation, concomitantly with decreased NO and VEGF levels through the down-regulation of the PI3K/Akt/eNOS/VEGF pathway.

KEYWORDS:

VEGF; eNOS; infantile hemangioma; propranolol

PMID:
25728347
DOI:
10.1002/pbc.25453
[Indexed for MEDLINE]

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