Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma

• Published in: PloS one 2013-03, Vol.8 (3), p.e60021-e60021
• Main Authors: Stiles, Jessica M, Amaya, Clarissa, Rains, Steven, Diaz, Dolores, Pham, Robert, Battiste, James, Modiano, Jaime F, Kokta, Victor, Boucheron, Laura E, Mitchell, Dianne C, Bryan, Brad A
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacology; Adrenergic beta-Antagonists - therapeutic use; Adrenergic receptors; Animals; Apoptosis; Biocompatibility; Biology; Blotting, Western; Breast cancer; Cancer therapies; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemotherapy; Computer engineering; Cytoskeleton - metabolism; Cytotoxic agents; Cytotoxicity; Effectiveness; Endothelial cells; Female; Fluorescent Antibody Technique; Gene expression; Health sciences; Hemangioendothelioma - drug therapy; Hemangioendothelioma - metabolism; Hemangiosarcoma - drug therapy; Hemangiosarcoma - metabolism; Humans; Immunohistochemistry; Inhibition; Kinases; Laboratory animals; Medical prognosis; Medicine; Melanoma; Metastasis; Mice; Propranolol - pharmacology; Propranolol - therapeutic use; Receptors; Receptors (physiology); Receptors, Adrenergic, beta - metabolism; Regulators; Sarcoma; Signaling; Therapeutic applications; Therapeutic targets; Toxicity; Tumor cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060021

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.