黄酮类化合物 CH625 通过 CB2 和 EGFR-STAT3 轴重编程 TAMs 抑制 CYP4X1 使胶质瘤血管正常化。
CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis.
机构信息
Department of Pharmacology and Hubei Province Key Laboratory of Allergy and Immune-related Diseases (C.W., Y.L., K.H., X.L., M.Q., Y.L., J.Y.), Experimental Teaching Center (J.Y.), and Department of Pathology and Pathophysiology (H.C.), School of Basic Medical Sciences, Wuhan University, Wuhan, China; Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis & Treatment, South-central University for Nationalities, Wuhan, China (C.W.); and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey (Y.Y.).
Department of Pharmacology and Hubei Province Key Laboratory of Allergy and Immune-related Diseases (C.W., Y.L., K.H., X.L., M.Q., Y.L., J.Y.), Experimental Teaching Center (J.Y.), and Department of Pathology and Pathophysiology (H.C.), School of Basic Medical Sciences, Wuhan University, Wuhan, China; Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis & Treatment, South-central University for Nationalities, Wuhan, China (C.W.); and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey (Y.Y.)
出版信息
J Pharmacol Exp Ther. 2018 Apr;365(1):72-83. doi: 10.1124/jpet.117.247130. Epub 2018 Feb 1.
Tumor-associated macrophages (TAMs) are pivotal effector cells in angiogenesis. Here, we tested whether CYP4X1 inhibition in TAMs by flavonoid CH625 prolongs survival and normalizes glioma vasculature. CH625 was selected against the CYP4X1 3D model by virtual screening and showed inhibitory activity on the CYP4X1 catalytic production of 14,15-EET-EA in the M2-polarized human peripheral blood mononuclear cells (IC = 16.5 M). CH625 improved survival and reduced tumor burden in the C6 and GL261 glioma intracranial and subcutaneous model. In addition, CH625 normalized vasculature (evidenced by a decrease in microvessel density and HIF-1 expression and an increase in tumor perfusion, pericyte coverage, and efficacy of temozolomide therapy) accompanied with the decreased secretion of 14,15-EET-EA, VEGF, and TGF- in the TAMs. Furthermore, CH625 attenuated vascular abnormalization and immunosuppression induced by coimplantation of GL261 cells with CYP4X1 macrophages. In vitro TAM polarization away from the M2 phenotype by CH625 inhibited proliferation and migration of endothelial cells, enhanced pericyte migration and T cell proliferation, and decreased VEGF and TGF- production accompanied with the downregulation of CB2 and EGFR-dependent downstream STAT3 expression. These effects were reversed by overexpression of CYP4X1 and STAT3 or exogenous addition of 14,15-EET-EA, VEGF, TGF-, EGF, and CB2 inhibitor AM630. These results suggest that CYP4X1 inhibition in TAMs by CH625 prolongs survival and normalizes tumor vasculature in glioma via CB2 and EGFR-STAT3 axis and may serve as a novel therapeutic strategy for human glioma.
肿瘤相关巨噬细胞（TAMs）是血管生成的关键效应细胞。在这里，我们测试了黄酮类化合物 CH625 对 TAMs 中 CYP4X1 的抑制作用是否能延长生存期并使胶质瘤血管正常化。CH625 通过虚拟筛选针对 CYP4X1 3D 模型进行了选择，并显示出对 M2 极化人外周血单核细胞中 CYP4X1 催化产生的 14,15-EET-EA 的抑制活性（IC = 16.5 M）。CH625 改善了 C6 和 GL261 脑内和皮下胶质瘤模型的存活率并降低了肿瘤负担。此外，CH625 使血管正常化（通过降低微血管密度和 HIF-1 表达以及增加肿瘤灌注、周细胞覆盖和替莫唑胺治疗的疗效来证明），同时减少 TAMs 中 14,15-EET-EA、VEGF 和 TGF- 的分泌。此外，CH625 减轻了 GL261 细胞与 CYP4X1 巨噬细胞共植入诱导的血管异常化和免疫抑制。CH625 使 TAM 从 M2 表型极化远离，抑制内皮细胞的增殖和迁移，增强周细胞的迁移和 T 细胞的增殖，并减少 VEGF 和 TGF- 的产生，同时下调 CB2 和 EGFR 依赖性下游 STAT3 表达。这些作用被 CYP4X1 和 STAT3 的过表达或 14,15-EET-EA、VEGF、TGF-、EGF 和 CB2 抑制剂 AM630 的外源添加所逆转。这些结果表明，CH625 对 TAMs 中 CYP4X1 的抑制作用通过 CB2 和 EGFR-STAT3 轴延长了生存期并使胶质瘤血管正常化，可能成为人类胶质瘤的一种新的治疗策略。
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