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Title: Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling.more » In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor microenvironment.« less
Authors:
; ; ; ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [1] ;  [1] ;  [1]
  1. Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China)
  2. Animal Experimental Center of Wuhan University, Wuhan 430071 (China)
  3. Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China)
  4. Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China)
  5. Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China)
Publication Date:
OSTI Identifier:
22465786
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 286; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; ANOXIA; ARGINASE; CATECHOLAMINES; DOPAMINE; GLIOMAS; GROWTH FACTORS; INDIUM OXIDES; INHIBITION; LARGE INTESTINE; MACROPHAGES; MICE; OVARIES; PHENOTYPE; PROSTATE; RADIOPROTECTIVE SUBSTANCES; RATS; RECEPTORS; SURVIVAL TIME