Propranolol Induces Regression of Hemangioma Cells Through HIF-1α–Mediated Inhibition of VEGF-A

Chim, Harvey; Armijo, Bryan S.; Miller, Erin; Gliniak, Christy; Serret, Marc A.; Gosain, Arun K.

doi:10.1097/sla.0b013e318254ce7a

Cited by 124 publications

(123 citation statements)

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“…Another study has identified that rapamycin acts by inhibiting the mTOR pathway, thus suppressing HIF-1α and VEGF and subsequently inhibiting vascular endothelial cell proliferation (43). A study also identified that propranolol decreases HIF-1α, reduces downstream VEGF, VEGFR-1 and VEGFR-2 and the expression of monocyte chemoattractant protein-1, thus inhibiting angiomatous proliferation; however, there were no significant differences in the expression of matrix metalloproteinases (44). Artesunate, a compound isolated from a traditional Chinese medicine plant, is currently being evaluated for anti-tumor activity (45,46).…”

Section: Discussionmentioning

confidence: 99%

Artesunate inhibits proliferation and invasion of mouse hemangioendothelioma cells in?vitro and of tumor growth in?vivo

et al. 2017

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Abstract. Artesunate has been demonstrated to be a novel potential antitumor agent in numerous studies. However, its efficacy in infantile hemangioma is unknown. The aim of the present study was to investigate the role of artesunate in the control of vascular tumor biological behavior and molecular mechanism using mouse hemangioendothelioma endothelial (EOMA) cells and a nude mouse model. Cell viability, apoptosis and invasion were determined by an MTT assay, flow cytometric analysis and Transwell invasion assay, respectively. Reverse transcription-quantitative polymerase chain reaction and western blotting were utilized to examine the expression of genes and proteins. Inoculated EOMA cells were injected into the subcutaneous tissues of nude mice to observe the effect of artesunate therapy on the vascular tumor, an effect that was similar to that of pingyangmycin (PYM). It was identified that artesunate treatment (0-600 µg/ml) inhibited cell growth in a time-and dose-dependent manner. Artesunate at 300 µg/ml significantly reduced the proliferation and invasion of EOMA cells, and significantly decreased the expression of vascular endothelial growth factor (VEGF)-A, VEGFR-1, VEGFR-2 and hypoxia inducible factor-1α over time; caspase-3 was simultaneously upregulated in vitro. Artesunate significantly inhibited tumor growth, and the curative effect was similar to that observed with PYM in vivo. It was concluded that artesunate could effectively inhibit the growth of vascular tumors, and thus could be a novel drug candidate for the treatment of infantile hemangioma.

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Section: Discussionmentioning

confidence: 99%

Artesunate inhibits proliferation and invasion of mouse hemangioendothelioma cells in?vitro and of tumor growth in?vivo

et al. 2017

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“…Regarding apoptosis, adrenergic stimulation inhibits apoptosis through the intervention of several enzymes (src, mitogen-activated protein kinases, caspase cascade), thus the adrenergic block induced by propranolol can increase the cellular apoptosis rate. 18,19 Since the initial report of propranolol use for the treatment of IH, some published case series [8][9][10][11][12][13][14] and many case reports have confirmed its effectiveness in reducing the sizes of IH in 82 to 100% of treated patients and have proved the safety of the treatment. The report of a consensus conference on the initiation and the use of propranolol for IH was published in 2013.…”

Section: Discussionmentioning

confidence: 99%

“…The vasoconstriction occurs because propranolol inhibits the vasodilator effect of adrenaline via beta-receptors, but does not affect the activity of adrenalin on alfa1-receptors. 18,19 The inhibition of angiogenesis occurs because of the effects of adrenaline and noradrenaline, which consist in the stimulation of the synthesis of the pro-angiogenic factors VEGF and bFGF, which in turn are inhibited by the propranolol-induced beta-block. 19 Another mechanism to explain the effect of propranolol in accelerating the regression of proliferating infantile emangioma is linked to its action on the renin-angiotensin system, as proposed by Itinteang and co-authors.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 The inhibition of angiogenesis occurs because of the effects of adrenaline and noradrenaline, which consist in the stimulation of the synthesis of the pro-angiogenic factors VEGF and bFGF, which in turn are inhibited by the propranolol-induced beta-block. 19 Another mechanism to explain the effect of propranolol in accelerating the regression of proliferating infantile emangioma is linked to its action on the renin-angiotensin system, as proposed by Itinteang and co-authors. 20 They demonstrated that CD34+/CD33+/VEGFR+ cells present within the immature capillaries of proliferating IH are responsive to angiotensin II and suggested that beta-blockers, acting on the kidney, reduce renin activity and consequently the agiotensin II, a factor that stimulates mesenchimal stem cells of IH to secrete the VEGF.…”

Section: Discussionmentioning

confidence: 99%

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Propranolol treatment for infantile hemangioma: a case series of sixty-two patients

Stringari¹,

Barbato²,

Zanzucchi³

et al. 2016

Pediatr Med Chir

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Infantile hemangiomas (IH) complicated by ulceration, disfigurement, functional impairment or life-threatening conditions need early, safe and effective treatment. This study explores the impact of propranolol on complicated IH. We report our experience of 62 patients treated with oral propranolol for complicated IH. The effect of propranolol was assessed using a score on a visual analogue scale integrated with echo, magnetic resonance or endoscopic findings. The average age at the beginning of the treatment was seven months [standard deviation (SD)±8.9], with a median of four months (range 1-53 months). The average age at the end of the treatment was 15 months (SD±8.4), with a median of 13 months (range 7-59 months). The mean treatment length was eight months (SD±3.2). Oral propranolol was successful in 95.2% of the patients in reducing the volume, the intensity of color and the elevation of IH. Statistically significant improvement of IH volume was observed in the first two months of therapy (P≤0.001), and between the second month and the end of the treatment (P<0.05). No significant bradycardia or hypotension occurred. Severe hypoglycemia occurred in one patient. Mild adverse effects were observed in seven patients. Our study demonstrates that propranolol administered orally at 2 to 3 mg/kg/day has a rapid therapeutic effect leading to remarkable shortening of the natural course of IH and it is safe in the majority of patients.

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“…Beta blockers are proposed to downregulate angiogenic growth factors, such as VEGFA, matrix metalloproteinases (MMP-2 and MMP-9), and IL-6. [9] Chim et al treated proliferating and regressing IH endothelial cells with propranolol and found that propranolol induces a cytotoxic effect on IH endothelial cells through HIF 1alpha mediated inhibition of VEGF-A [10].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Propranolol for Infantile Hemangiomas: A Review

Hogeling

2012

Curr Derm Rep

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Infantile hemangiomas (IHs) are the most common vascular tumors of infancy. Since it was discovered several years ago, propranolol hydrochloride has become a very popular and successful treatment for complicated and aesthetically disfiguring IHs. The recent literature on propranolol is reviewed, including a summary of larger studies, discussion of adverse effects, and the use of propranolol in complicated IHs, such as ulcerated IHs, airway, and hepatic IHs.

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Propranolol Induces Regression of Hemangioma Cells Through HIF-1α–Mediated Inhibition of VEGF-A

Cited by 124 publications

References 38 publications

Artesunate inhibits proliferation and invasion of mouse hemangioendothelioma cells in?vitro and of tumor growth in?vivo

Artesunate inhibits proliferation and invasion of mouse hemangioendothelioma cells in?vitro and of tumor growth in?vivo

Propranolol treatment for infantile hemangioma: a case series of sixty-two patients

Propranolol for Infantile Hemangiomas: A Review

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