Qin Tian, Wang Chenlong, Chen Xuewei, Duan Chenfan, Zhang Xiaoyan, Zhang Jing, Chai Hongyan, Tang Tian, Chen Honglei, Yue Jiang, Li Ying, Yang Jing
Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Animal Experimental Center of Wuhan University, Wuhan 430071, China.
Toxicol Appl Pharmacol. 2015 Jul 15;286(2):112-23. doi: 10.1016/j.taap.2015.03.021. Epub 2015 Mar 25.
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.
多巴胺（DA）是一种具有抗血管生成活性的单胺类儿茶酚胺神经递质，可稳定结肠癌、前列腺癌和卵巢癌中的肿瘤血管，从而提高化疗疗效。在此，我们在大鼠C6胶质瘤模型中研究了DA的血管正常化作用及其作用机制。DA（25、50mg/kg）抑制肿瘤生长，而DA的前体左旋多巴延长了原位C6胶质瘤大鼠的生存时间。DA改善了肿瘤灌注，从第3天起有显著效果，在第5至7天达到更高水平。此外，DA降低了肿瘤组织中的微血管密度和缺氧诱导因子-1α表达，同时增加了周细胞的覆盖率。相反，多巴胺受体2（DR2）拮抗剂（埃替氯必利）而非DR1拮抗剂（布他拉莫）消除了DA诱导的肿瘤消退和血管正常化。此外，DA提高了替莫唑胺治疗的递送和疗效。重要的是，DA增加了代表性的M1标志物（诱导型一氧化氮合酶、CXC趋化因子配体9等），同时降低了M2标志物（CD206、精氨酸酶-1等）。用氯膦酸盐或唑来膦酸清除巨噬细胞减弱了DA的作用。值得注意的是，DA处理诱导RAW264.7细胞和小鼠腹腔巨噬细胞从M2向M1极化，并增强了类周细胞（10T1/2）的迁移，这被埃替氯必利或DR2小干扰RNA逆转。这些变化伴随着血管内皮生长因子/血管内皮生长因子受体2信号的下调。总之，DA通过重新编程M2极化巨噬细胞诱导生长抑制和血管正常化。因此，通过DA靶向肿瘤微血管代表了一种有前景的人类胶质瘤治疗策略。
