Abstract
Doxazosin is an α1 adrenergic receptor blocker that also exerts antitumor effects. However, the underlying mechanisms by which it modulates PI3K/Akt intracellular signaling are poorly understood. In this study, we reveal that doxazosin functions as a novel antiangiogenic agent by inhibiting vascular endothelial growth factor (VEGF)-induced cell migration and proliferation. It also inhibited VEGF-induced capillary-like structure tube formation in vitro. Doxazosin inhibited the phosphorylation of VEGF receptor-2 (VEGFR-2) and downstream signaling, including PI3K, Akt, 3-phosphoinositide-dependent protein kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor 1 (HIF-1α). However, it had no effect on VEGF-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Furthermore, doxazosin reduced tumor growth and suppressed tumor vascularization in a xenograft human ovarian cancer model. These results provide evidence that doxazosin functions in the endothelial cell system to modulate angiogenesis by inhibiting Akt and mTOR phosphorylation and interacting with VEGFR-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-1 Receptor Antagonists / pharmacology
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Animals
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Antihypertensive Agents / pharmacology
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Doxazosin / pharmacology*
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Female
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Human Umbilical Vein Endothelial Cells / physiology
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunohistochemistry
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Mice, Nude
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / prevention & control
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Neovascularization, Physiologic / drug effects
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Ovarian Neoplasms / blood supply
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / metabolism*
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism*
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Tumor Burden / drug effects
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Adrenergic alpha-1 Receptor Antagonists
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Antihypertensive Agents
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Hypoxia-Inducible Factor 1, alpha Subunit
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Doxazosin