LETTER TO THE EDITOR Propranolol: A Novel Antihemangioma Agent With Multiple Potential Mechanisms of Action To the Editor: e read with great interest the article, titled “Propranolol Induces Regression of Hemangioma Cells Through HIF-1αMediated Inhibition of VEGF-A,” by Chim et al.1 The results presented in this study provide the evidence that propranolol can influence several fundamental biological processes underlying the progression of infantile hemangioams (IHs), including the inhibition of hemangioma-derived endothelial cell (HemEC) viability, migration, and tubulogenesis. Moreover, the data revealed that the antiHemEC functions of propranolol are based on the targeting of multiple critical molecular steps. We appreciate the authors’ extraordinary contribution that provides us with a pharmacological basis for the therapeutic use of propranolol in IHs and a basis for further investigation of the cellular and molecular mechanisms of β-adrenergic receptor antagonists in the treatment of IHs. Nonetheless, there are several major points that need further discussion with respect to this article. Propranolol is known to inhibit cell proliferation in endothelial and various cancer cells.2,3 In the study by Chim et al,1 the investigators found that treatment with propranolol at an extremely low concentration (0.3 μM) for 72 hours significantly inhibited cell proliferation compared with the control. Thus, the effective concentration of propranolol was well within the range of propranolol levels that may be achieved in patients. Because the dysregulation of endothelial cell proliferation represents an important pathogenic factor in neovascularization, the antiproliferative activity of propranolol in HemECs may explain the remarkable effect of the propranolol in the treatment of IH. However, in many other experiments, only the most concentrated dam (300 μM) showed significant effects. For instance, inhibition of tubulogenesis by propranolol occurred only at concentrations that were 1000 times of those that cause antiproliferative activity. This high propranolol concentration (300 μM) is not commonly used in patients because the serum propranolol concentration range used in patients is less than 1 μM.4 The discrepancy between these assays
W
Disclosure: The authors declare no conflicts of interest. C 2013 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/13/26102-e0052 DOI: 10.1097/SLA.0000000000000450
e52 | www.annalsofsurgery.com
may be due to the limitation of in vitro models used. Although several types of data support the view that the signaling phenotype of cultured HemECs is similar to that of endothelial cells within the tumors and the dissection of IHs into purified cellular components enabled the exploration of its specific roles, it is possible that HemECs behave differently in a tumor context.5,6 Thus, further in vivo experiments are needed to extend and confirm these findings. Chim et al1 concluded that the VEGFR-2 expression were downregulated by propranolol, consistent with decreased VEGF simulation. This conclusion is not supported by the data because the study did not detect the phosphorylation level of VEGFR2. Based on the results of Jinnin et al,6 VEGF-A exhibits proproliferative function by binding to the tyrosine kinase receptor VEGFR-2 on HemECs. After the binding of VEGF-A, VEGFR-2 dimerizes and autophosphorylates the tyrosine residues in its cytoplasmic domain. Tyr1175 is one of the major autophosphorylation sites in VEGFR-2, and phosphorylation of Tyr1175 mediates the activation of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signalrelated kinase), which is essential in regulating endothelial cell proliferation.7,8 Cultured HemECs share a phenotype of constitutively active VEGFR-2 signaling. The phosphorylation level of VEGFR-2 at residue Tyr1175 was very high in lysates from HemECs. In contrast, the expression level of total VEGFR-2 is stably maintained in cultured HemECs in either the presence or absence of VEGF stimulation and does not differ from that of other endothelial cells.6,9 HIF-1α plays a central role in tumor progression and angiogenesis. During tissue ischemia, the increased expression and stabilization of the transcription factor, HIF-1α, promotes the local production of angiogenic factors (eg, VEGF).10 Previous studies demonstrated that excessive expression of HIF-1α and VEGF in IH tissue parallels the proliferating phase, providing evidence that these lesions may be hypoxic.5,11 Unfortunately, the potential role of the HIF-1α–VEGF pathway in IH pathogenesis (eg, angiogenesis) has not been well investigated.9 In the study by Chim et al,1 the expression of HIF1α and VEGF was inhibited by propranolol in a dose-dependent manner. The study also shows a significant difference in the response of the expression of HIF-1α and VEGF in proliferative and involuting hemangiomas results from treatment with propranolol. The authors concluded that propranolol inhibits VEGF translation through an HIF-1α–dependent mechanism in the HemEC model. But the study did not provide sufficient evidence to support this conclusion. Previous studies have
demonstrated that the expression of VEGF can be modulated by HIF-1α–dependent and HIF-1α–independent mechanisms.12 There is evidence from recent publications that the expression of VEGF can also be controlled by β-adrenergic signaling.2,13,14 Therefore, it is possible that propranolol inhibits the expression of VEGF in HemECs via an HIF-1α– independent signaling. Yi Ji, MD, PhD Department of Pediatric Surgery Children’s Hospital of Fudan University Shanghai, China Division of Oncology Department of Pediatric Surgery West China Hospital of Sichuan University Chengdu, China Siyuan Chen, PhD Research Institute of Pediatrics Children’s Hospital of Fudan University Shanghai, China Kai Li, MD, PhD Xianmin Xiao, MD, PhD Shan Zheng, MD, PhD Department of Pediatric Surgery Children’s Hospital of Fudan University Shanghai, China [email protected]
REFERENCES 1. Chim H, Armijo BS, Miller E, et al. Propranolol induces regression of hemangioma cells through HIF-1α-mediated inhibition of VEGF-A. Ann Surg. 2012;256:146–156. 2. Yang EV, Sood AK, Chen M, et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 2006;66:10357–10364. 3. Lamy S, Lachambre MP, Lord-Dufour S, et al. Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol. 2010;53:200–208. 4. Ponsoda X, Jover R, Nunez C, et al. Evaluation of the cytotoxicity of 10 chemicals in human and rat hepatocytes and in cell lines: correlation between in vitro data and human lethal concentration. Toxicol In Vitro. 1995;9:959–966. 5. Greenberger S, Boscolo E, Adini I, et al. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med. 2010;362:1005–1013. 6. Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14:1236–1246. 7. Cho CH, Lee CS, Chang M, et al. Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK. Am J Physiol Heart Circ Physiol. 2004;286:H1881–H1888. 8. Takahashi T, Yamaguchi S, Chida K, et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 2001;20:2768–2778.
Annals of Surgery r Volume 261, Number 2, February 2015
Copyright © 2013 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 2, February 2015
9. Boye E, Olsen BR. Signaling mechanisms in infantile hemangioma. Curr Opin Hematol. 2009;16:202–208. 10. Hickey MM, Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Curr Top Dev Biol. 2006;76:217–257. 11. Kleinman ME, Greives MR, Churgin SS, et al. Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc Biol. 2007;27:2664–2670. 12. Arany Z, Foo SY, Ma Y, et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008;451:1008–1012. 13. Iaccarino G, Ciccarelli M, Sorriento D, et al. Ischemic neoangiogenesis enhanced by beta2adrenergic receptor overexpression: a novel role for the endothelial adrenergic system. Circ Res. 2005;97:1182–1189. 14. Sloan EK, Priceman SJ, Cox BF, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010;70:7042–7052.
Reply:
W
e thank Ji and colleagues for their comments and contribution to research on the important field of infantile hemangiomas. Certainly, with increasing developments in our understanding of the effects of propranolol on regression of hemangiomas, it has become evident that one of the primary means by which propranolol exerts its effects is through inhibition of the vascular endothelial growth factor (VEGF) pathway. Although we found a small but significant decrease in cell viability at lower concentrations of propranolol,1 this did not become marked until a very high dosage of 300 μM. Like other authors, we found that a significant decrease in other indices of cell activity, such as tubulogenesis and migration, occurred only at higher concentrations of propranolol. Measures of cell viability are highly sensitive indices of the effects of a drug on cells in vitro. Heterogeneity in drug sensitivity among different cell subpopulations in a tumor has been well described,2,3 with certain cells responding to a drug at lower concentrations whereas other cells remain resistant. Hence, a decrease in other indices designed to detect the response of a whole population of Disclosure: The author declares no conflicts of interest. DOI: 10.1097/SLA.0000000000000453
cells to a drug, such as tubulogenesis, mRNA, and protein expression, may not be detectable until higher drug concentrations in an in vitro model due to compensatory upregulation by other cells. Therefore, a decrease in cell viability at lower concentrations of propranolol may not reflect a significant effect on the hemangioma cell population as a whole. The in vivo environment is also very different from an in vitro environment. Apoptosis of individual hemangioma endothelial cells may affect the ability of the entire hemangioma, composed of a heterogeneous mix of cells to survive, and may possibly explain response of infantile hemangiomas in vivo to a lower propranolol dosage. We agree with the importance of VEGF-R2 phosphorylation as a representation of VEGF-R2 activity. Other authors have supported our findings in this study and shown that propranolol inhibits VEGF-induced tyrosine phosphorylation of VEGF-R2 in hemangioma endothelial cells.4,5 It is apparent that propranolol exerts its effects on infantile hemangiomas through a number of mechanisms. Postulated mechanisms besides those proposed by us include inhibition of eNOS (endothelial nitric oxide synthase),6 inhibition of the renin-angiotensin system,7 and inducement of accelerated adipogenesis.8 We showed in our study that propranolol results in HIF-1α–mediated inhibition of VEGF-A expression in hemangioma endothelial cells whereas NF-κβ, another important regulator of VEGF-A secretion implicated in the mechanism of action of corticosteroids through an HIF-1α–independent mechanism, was not involved in the mechanism of action of propranolol. The importance of the HIF-1 pathway in the regulation of hemangioma endothelial cell proliferation has been shown, with HIF-1 proposed to stimulate an autocrine loop of VEGF signaling resulting in hemangioma endothelial cell proliferation.9 A causal link between the β-adrenergic receptor and HIF-1α expression has been shown,10 and it is entirely likely that blockade of β-adrenergic receptors could lead to downregulation of HIF-1α and VEGF signaling, providing a feasible explanation for the action of propranolol, a β-blocker, on inhibition of hemangioma growth. It is impractical to postulate, and prove, that inhibition of the HIF-1α–VEGF axis is the
C 2013 Wolters Kluwer Health, Inc. All rights reserved.
Letter to the Editor
only mechanism of action of propranolol on infantile hemangiomas; however, it is reasonable to conclude that this is one of its primary mechanisms of action. Harvey Chim, MRCS Division of Hand Surgery Department of Orthopedic Surgery Mayo Clinic Rochester, MN [email protected]
REFERENCES 1. Chim H, Armijo BS, Miller E, et al. Propranolol induces regression of hemangioma cells through HIF-1 mediated inhibition of VEGF-A. Ann Surg. 2012;256:146–156. 2. Heppner GH, Dexter DL, DeNucci T, et al. Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Cancer Res. 1978;38:3758–3763. 3. Szulkin A, Nilsonne G, Mundt F, et al. Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezzomib, highlights need for individualized therapy. PloS ONE. 2013; 8:e65903. 4. Stiles J, Amaya C, Pham R, et al. Propranolol treatment of infantile hemangioma endothelial cells: a molecular analysis. Exp Ther Med. 2012;4:594– 604. 5. Lamy S, Lachambre MP, Lord-Dufour S, et al. Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol. 2010;53:200–208. 6. Dai Y, Hou F, Buckmiller L, et al. Decreased eNOS protein expression in involuting and propranolol-treated hemangiomas. Arch Otolaryngol Head Neck Surg. 2012; 138:177–182. 7. Itinteang T, Brasch HD, Tan ST, et al. Expression of components of the renin-angiotensin system in proliferating infantile hemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg. 2011;64:759– 765. 8. Wong A, Hardy KL, Kitajewski AM, et al. Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plast Reconstr Surg. 2012;130:1012–1021. 9. Medici D, Olsen BR. Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1 dependent expression of VEGF. PloS ONE. 2012;7:e42913. 10. Hu HT, Ma QY, Zhang D, et al. HIF-1alpha links beta-adrenoceptor agonists and pancreatic cancer cells under normoxic condition. Acta Pharmacol Sin. 2010;31:102–110.
www.annalsofsurgery.com | e53
Copyright © 2013 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
W
Disclosure: The authors declare no conflicts of interest. C 2013 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/13/26102-e0052 DOI: 10.1097/SLA.0000000000000450
e52 | www.annalsofsurgery.com
may be due to the limitation of in vitro models used. Although several types of data support the view that the signaling phenotype of cultured HemECs is similar to that of endothelial cells within the tumors and the dissection of IHs into purified cellular components enabled the exploration of its specific roles, it is possible that HemECs behave differently in a tumor context.5,6 Thus, further in vivo experiments are needed to extend and confirm these findings. Chim et al1 concluded that the VEGFR-2 expression were downregulated by propranolol, consistent with decreased VEGF simulation. This conclusion is not supported by the data because the study did not detect the phosphorylation level of VEGFR2. Based on the results of Jinnin et al,6 VEGF-A exhibits proproliferative function by binding to the tyrosine kinase receptor VEGFR-2 on HemECs. After the binding of VEGF-A, VEGFR-2 dimerizes and autophosphorylates the tyrosine residues in its cytoplasmic domain. Tyr1175 is one of the major autophosphorylation sites in VEGFR-2, and phosphorylation of Tyr1175 mediates the activation of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signalrelated kinase), which is essential in regulating endothelial cell proliferation.7,8 Cultured HemECs share a phenotype of constitutively active VEGFR-2 signaling. The phosphorylation level of VEGFR-2 at residue Tyr1175 was very high in lysates from HemECs. In contrast, the expression level of total VEGFR-2 is stably maintained in cultured HemECs in either the presence or absence of VEGF stimulation and does not differ from that of other endothelial cells.6,9 HIF-1α plays a central role in tumor progression and angiogenesis. During tissue ischemia, the increased expression and stabilization of the transcription factor, HIF-1α, promotes the local production of angiogenic factors (eg, VEGF).10 Previous studies demonstrated that excessive expression of HIF-1α and VEGF in IH tissue parallels the proliferating phase, providing evidence that these lesions may be hypoxic.5,11 Unfortunately, the potential role of the HIF-1α–VEGF pathway in IH pathogenesis (eg, angiogenesis) has not been well investigated.9 In the study by Chim et al,1 the expression of HIF1α and VEGF was inhibited by propranolol in a dose-dependent manner. The study also shows a significant difference in the response of the expression of HIF-1α and VEGF in proliferative and involuting hemangiomas results from treatment with propranolol. The authors concluded that propranolol inhibits VEGF translation through an HIF-1α–dependent mechanism in the HemEC model. But the study did not provide sufficient evidence to support this conclusion. Previous studies have
demonstrated that the expression of VEGF can be modulated by HIF-1α–dependent and HIF-1α–independent mechanisms.12 There is evidence from recent publications that the expression of VEGF can also be controlled by β-adrenergic signaling.2,13,14 Therefore, it is possible that propranolol inhibits the expression of VEGF in HemECs via an HIF-1α– independent signaling. Yi Ji, MD, PhD Department of Pediatric Surgery Children’s Hospital of Fudan University Shanghai, China Division of Oncology Department of Pediatric Surgery West China Hospital of Sichuan University Chengdu, China Siyuan Chen, PhD Research Institute of Pediatrics Children’s Hospital of Fudan University Shanghai, China Kai Li, MD, PhD Xianmin Xiao, MD, PhD Shan Zheng, MD, PhD Department of Pediatric Surgery Children’s Hospital of Fudan University Shanghai, China [email protected]
REFERENCES 1. Chim H, Armijo BS, Miller E, et al. Propranolol induces regression of hemangioma cells through HIF-1α-mediated inhibition of VEGF-A. Ann Surg. 2012;256:146–156. 2. Yang EV, Sood AK, Chen M, et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 2006;66:10357–10364. 3. Lamy S, Lachambre MP, Lord-Dufour S, et al. Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol. 2010;53:200–208. 4. Ponsoda X, Jover R, Nunez C, et al. Evaluation of the cytotoxicity of 10 chemicals in human and rat hepatocytes and in cell lines: correlation between in vitro data and human lethal concentration. Toxicol In Vitro. 1995;9:959–966. 5. Greenberger S, Boscolo E, Adini I, et al. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med. 2010;362:1005–1013. 6. Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14:1236–1246. 7. Cho CH, Lee CS, Chang M, et al. Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK. Am J Physiol Heart Circ Physiol. 2004;286:H1881–H1888. 8. Takahashi T, Yamaguchi S, Chida K, et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 2001;20:2768–2778.
Annals of Surgery r Volume 261, Number 2, February 2015
Copyright © 2013 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 2, February 2015
9. Boye E, Olsen BR. Signaling mechanisms in infantile hemangioma. Curr Opin Hematol. 2009;16:202–208. 10. Hickey MM, Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Curr Top Dev Biol. 2006;76:217–257. 11. Kleinman ME, Greives MR, Churgin SS, et al. Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc Biol. 2007;27:2664–2670. 12. Arany Z, Foo SY, Ma Y, et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008;451:1008–1012. 13. Iaccarino G, Ciccarelli M, Sorriento D, et al. Ischemic neoangiogenesis enhanced by beta2adrenergic receptor overexpression: a novel role for the endothelial adrenergic system. Circ Res. 2005;97:1182–1189. 14. Sloan EK, Priceman SJ, Cox BF, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010;70:7042–7052.
Reply:
W
e thank Ji and colleagues for their comments and contribution to research on the important field of infantile hemangiomas. Certainly, with increasing developments in our understanding of the effects of propranolol on regression of hemangiomas, it has become evident that one of the primary means by which propranolol exerts its effects is through inhibition of the vascular endothelial growth factor (VEGF) pathway. Although we found a small but significant decrease in cell viability at lower concentrations of propranolol,1 this did not become marked until a very high dosage of 300 μM. Like other authors, we found that a significant decrease in other indices of cell activity, such as tubulogenesis and migration, occurred only at higher concentrations of propranolol. Measures of cell viability are highly sensitive indices of the effects of a drug on cells in vitro. Heterogeneity in drug sensitivity among different cell subpopulations in a tumor has been well described,2,3 with certain cells responding to a drug at lower concentrations whereas other cells remain resistant. Hence, a decrease in other indices designed to detect the response of a whole population of Disclosure: The author declares no conflicts of interest. DOI: 10.1097/SLA.0000000000000453
cells to a drug, such as tubulogenesis, mRNA, and protein expression, may not be detectable until higher drug concentrations in an in vitro model due to compensatory upregulation by other cells. Therefore, a decrease in cell viability at lower concentrations of propranolol may not reflect a significant effect on the hemangioma cell population as a whole. The in vivo environment is also very different from an in vitro environment. Apoptosis of individual hemangioma endothelial cells may affect the ability of the entire hemangioma, composed of a heterogeneous mix of cells to survive, and may possibly explain response of infantile hemangiomas in vivo to a lower propranolol dosage. We agree with the importance of VEGF-R2 phosphorylation as a representation of VEGF-R2 activity. Other authors have supported our findings in this study and shown that propranolol inhibits VEGF-induced tyrosine phosphorylation of VEGF-R2 in hemangioma endothelial cells.4,5 It is apparent that propranolol exerts its effects on infantile hemangiomas through a number of mechanisms. Postulated mechanisms besides those proposed by us include inhibition of eNOS (endothelial nitric oxide synthase),6 inhibition of the renin-angiotensin system,7 and inducement of accelerated adipogenesis.8 We showed in our study that propranolol results in HIF-1α–mediated inhibition of VEGF-A expression in hemangioma endothelial cells whereas NF-κβ, another important regulator of VEGF-A secretion implicated in the mechanism of action of corticosteroids through an HIF-1α–independent mechanism, was not involved in the mechanism of action of propranolol. The importance of the HIF-1 pathway in the regulation of hemangioma endothelial cell proliferation has been shown, with HIF-1 proposed to stimulate an autocrine loop of VEGF signaling resulting in hemangioma endothelial cell proliferation.9 A causal link between the β-adrenergic receptor and HIF-1α expression has been shown,10 and it is entirely likely that blockade of β-adrenergic receptors could lead to downregulation of HIF-1α and VEGF signaling, providing a feasible explanation for the action of propranolol, a β-blocker, on inhibition of hemangioma growth. It is impractical to postulate, and prove, that inhibition of the HIF-1α–VEGF axis is the
C 2013 Wolters Kluwer Health, Inc. All rights reserved.
Letter to the Editor
only mechanism of action of propranolol on infantile hemangiomas; however, it is reasonable to conclude that this is one of its primary mechanisms of action. Harvey Chim, MRCS Division of Hand Surgery Department of Orthopedic Surgery Mayo Clinic Rochester, MN [email protected]
REFERENCES 1. Chim H, Armijo BS, Miller E, et al. Propranolol induces regression of hemangioma cells through HIF-1 mediated inhibition of VEGF-A. Ann Surg. 2012;256:146–156. 2. Heppner GH, Dexter DL, DeNucci T, et al. Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Cancer Res. 1978;38:3758–3763. 3. Szulkin A, Nilsonne G, Mundt F, et al. Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezzomib, highlights need for individualized therapy. PloS ONE. 2013; 8:e65903. 4. Stiles J, Amaya C, Pham R, et al. Propranolol treatment of infantile hemangioma endothelial cells: a molecular analysis. Exp Ther Med. 2012;4:594– 604. 5. Lamy S, Lachambre MP, Lord-Dufour S, et al. Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol. 2010;53:200–208. 6. Dai Y, Hou F, Buckmiller L, et al. Decreased eNOS protein expression in involuting and propranolol-treated hemangiomas. Arch Otolaryngol Head Neck Surg. 2012; 138:177–182. 7. Itinteang T, Brasch HD, Tan ST, et al. Expression of components of the renin-angiotensin system in proliferating infantile hemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg. 2011;64:759– 765. 8. Wong A, Hardy KL, Kitajewski AM, et al. Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plast Reconstr Surg. 2012;130:1012–1021. 9. Medici D, Olsen BR. Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1 dependent expression of VEGF. PloS ONE. 2012;7:e42913. 10. Hu HT, Ma QY, Zhang D, et al. HIF-1alpha links beta-adrenoceptor agonists and pancreatic cancer cells under normoxic condition. Acta Pharmacol Sin. 2010;31:102–110.
www.annalsofsurgery.com | e53
Copyright © 2013 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
