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: Tian Qin, Chenlong Wang, Xuewei Chen, Chenfan Duan, Xiaoyan Zhang, Jing Zhang, Hongyan Chai, Tian Tang, Honglei Chen, Jiang Yue, Ying Li, Jing Yang
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 286 Issue 2 Pg. 112-23 (Jul 15 2015) ISSN: 1096-0333 [Electronic] United States
• PMID: 25818600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents, Alkylating
• Receptors, Dopamine D2
• Vascular Endothelial Growth Factor A
• Dacarbazine
• Vascular Endothelial Growth Factor Receptor-2
• Dopamine
• Temozolomide

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Cell Movement (drug effects)
• Dacarbazine (analogs & derivatives, pharmacology)
• Dopamine (pharmacology)
• Gene Expression (drug effects)
• Glioma (pathology)
• Macrophages (drug effects)
• Male
• Rats
• Rats, Wistar
• Receptors, Dopamine D2 (drug effects)
• Temozolomide
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)