Amala Cancer Research Center, Amala Nagar, Thrissur, India.
Drug Chem Toxicol. 2012 Jan;35(1):57-70. doi: 10.3109/01480545.2011.589437.
Berberine, a naturally occurring isoquinoline alkaloid, is present in a number of important medicinal plants. Berberine has a wide range of biochemical and pharmacological effects, including anticancer effects. In this study, we elucidated the mechanism of antiangiogenic activity of berberine using in vivo and in vitro models. In vivo antiangiogenic activity was studied using B16F-10 melanoma cells and induced capillary formation in C57BL/6 mice. Berberine, at 10 mg/kg body weight, showed significant inhibition in tumor-directed capillary formation and in various proangiogenic factors, such as vascular endothelial growth factor (VEGF), and proinflammatory mediators, such as interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF), which are involved in tumor angiogenesis. At the same time, it could also increase antitumor factors, such as IL-2 and tissue-inhibitor metalloproteinase (TIMP) levels in the serum. Berberine could also inhibit endothelial motility, migration, tube formation, and vessel sprouting from rat aortic ring in vitro. Further, berberine inhibited various transcription factors involved in tumor development and angiogenesis, such as NF-ĸB, c-Fos, CREB, and ATF-2. mRNA expression levels of proangiogenic factors, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and hypoxia-inducible factor (HIF), were also downregulated in tumor cells after treatment with berberine. Drastically elevated expressions of HIF and VEGF mRNA by tumor cells under hypoxic conditions were also decreased after treatment with berberine. This result clearly demonstrates that the antiangiogenic activity of berberine is mainly mediated through the inhibition of various proinflammatory and pro-angiogenic factors and the major ones are HIF, VEGF, COX-2, NO, NF-ĸB, and proinflammatory cytokines.
小檗碱是一种天然存在的异喹啉生物碱，存在于许多重要的药用植物中。小檗碱具有广泛的生化和药理作用，包括抗癌作用。在这项研究中，我们使用体内和体外模型阐明了小檗碱的抗血管生成活性机制。在体内抗血管生成活性研究中，使用 B16F-10 黑色素瘤细胞和 C57BL/6 小鼠诱导的毛细血管形成。小檗碱在 10mg/kg 体重时，显著抑制肿瘤定向毛细血管形成和各种促血管生成因子，如血管内皮生长因子（VEGF）和促炎介质，如白细胞介素（IL）-1β、IL-6、肿瘤坏死因子α（TNF-α）和粒细胞巨噬细胞集落刺激因子（GM-CSF），这些因子参与肿瘤血管生成。同时，它还可以增加血清中的抗肿瘤因子，如 IL-2 和组织抑制剂金属蛋白酶（TIMP）水平。小檗碱还可以抑制内皮细胞的迁移、迁移、管形成和大鼠主动脉环的血管发芽。此外，小檗碱还抑制了参与肿瘤发生和血管生成的各种转录因子，如 NF-κB、c-Fos、CREB 和 ATF-2。用小檗碱处理后，肿瘤细胞中促血管生成因子，如环氧化酶-2（COX-2）、诱导型一氧化氮合酶（iNOS）和缺氧诱导因子（HIF）的 mRNA 表达水平也下调。肿瘤细胞在缺氧条件下 HIF 和 VEGF mRNA 的表达水平也明显升高，用小檗碱处理后也降低。这一结果清楚地表明，小檗碱的抗血管生成活性主要是通过抑制各种促炎和促血管生成因子来介导的，其中主要的是 HIF、VEGF、COX-2、NO、NF-κB 和促炎细胞因子。
