Targeting of Beta Adrenergic Receptors Results in Therapeutic Efficacy against Models of Hemangioendothelioma and Angiosarcoma

Abstract

Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans.

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

“…Our rationale for comparing the efficacy of six therapeutic strategies for reversing established lymphangiectasia was based on published reports of their use in prevention or treatment of lymphatic malformations, hemangiomas, and related conditions (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Inhibition of VEGFR-2 and VEGFR-3 signaling by function-blocking antibodies prevents lymphatic growth in inflammation and in CCSP/VEGF-C mice (6,13).…”

“…Inhibition of VEGFR-2 and VEGFR-3 by function-blocking antibodies (6,13) was compared with inhibition of Notch signaling by the γ-secretase inhibitor DAPT (14), suppression of β-adrenergic receptor signaling by propranolol (15,16), inhibition of autophagy by chloroquine (17,18), suppression of inflammation by dexamethasone (13,19), or inhibition of mTOR by rapamycin (18,20). Surprisingly, only rapamycin led to significant reversal of lymphangiectasia in this model, and the efficacy of rapamycin was not improved by coadministration of anti-VEGFR-2/VEGFR-3 antibodies, propranolol, or chloroquine.…”

Adrenoceptor modulators and cancer progression

“…Stiles and colleagues [7] reported that β-blockers could induce apoptosis in angiosarcoma cells in vitro and also inhibit proliferation of angiosarcoma. However, the data of clinical studies are controversial.…”

Influência de agentes antiangiogênicos (propranolol) em endometriose experimentalmente induzida em ratas

“…O uso de inibidores de neoangiogênese têm sido amplamente estudados no tratamento de endometriose [24][25][26][27] . β-bloqueadores como o propranolol, devido à sua ação em inibição de neoangiogênese, possuem efeitos antitumorais em diferentes tipos de tumores, e principalmente tumores vasculares 10,11,13,28 .…”

“…A ação anticancerígena do propranolol em diferentes tipos de tumores [9][10][11][12] , além de efeito antitumoral dos β-bloqueadores em sarcomas in vivo e in vitro 11,13 , e por fim, pelo sinergismo entre quimioterapia e β-bloqueadores em câncer de mama e neuroblastoma, por mecanismos ainda não totalmente elucidados 14,15 é sugerido que o propranolol possa contribuir clinicamente exercendo papel sobre a inibição de neoangiogênese, e tal efeito resultar em um impacto sobre as lesões de endometriose.…”