title: Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma.
abstract: 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, 50mg/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. 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.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Chenlong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Chenfan
authors.initials: C
authors.lastname: Duan
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Animal Experimental Center of Wuhan University, Wuhan 430071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chai
authors.affiliation: Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Tang
authors.affiliation: Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Honglei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: lyying0@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: yangjingliu2013@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D000077204:Temozolomide; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D017448:Receptors, Dopamine D2; D042461:Vascular Endothelial Growth Factor A; D003606:Dacarbazine; D040301:Vascular Endothelial Growth Factor Receptor-2; D004298:Dopamine; D000077204:Temozolomide
keywords: Dopamine; Glioma; Growth; Macrophage polarization; VEGF/VEGFR2 signaling; Vascular normalization