Anti-angiogenic activity of cranberry proanthocyanidins and cytotoxic properties in ovarian cancer cells
Anti-angiogenic activity of cranberry proanthocyanidins and cytotoxic properties in ovarian cancer cells
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DOI：
10.3892/ijo.2011.1198
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发表时间：
2012-01-01
影响因子：
5.2
通讯作者：
Moore, Richard G.
中科院分区：
文献类型：
--
作者：
Kim, Kyu Kwang;Singh, Ajay P.;Moore, Richard G.
蔓越莓提取物可能在治疗包括癌症在内的各种疾病中提供有益的健康效果。然而，抗肿瘤特性的潜在分子机制尚不清楚。我们报道了蔓越莓中富含原花青素（PAC）的分离物（PAC-1）作为一种具有双重活性的治疗剂，在体外靶向卵巢癌生存能力和血管生成。PAC-1治疗化疗耐药SKOV-3细胞阻断G(2)/M期细胞周期进程，增加活性氧（ROS）的产生，并通过激活内源性和外源性途径组分诱导细胞凋亡。PAC-1的细胞毒性部分基于ROS的产生，可以通过与抗氧化剂谷胱甘肽共处理来阻断。PAC-1以剂量依赖的方式降低SKOV-3卵巢癌细胞和HUVEC内皮细胞的细胞活力，并阻断促生存因子AKT的激活。此外，PAC-1阻断内皮细胞中血管内皮生长因子（VEGF）刺激的受体磷酸化，这与体外抑制内皮管形成有关。我们的研究结果表明PAC-1具有有效的抗癌和抗血管生成特性，从蔓越莓中提取的高纯度PAC可以进一步开发用于联合或单药治疗卵巢癌。
Cranberry extracts may provide beneficial health effects in the treatment of various diseases, including cancer. However, the underlying molecular mechanisms of antineoplastic properties are not understood. We report the effect of a proanthocyanidin (PAC)-rich isolate from cranberry (PAC-1) as a therapeutic agent with dual activity to target both ovarian cancer viability and angiogenesis in vitro. PAC-1 treatment of chemotherapy-resistant SKOV-3 cells blocked cell cycle progression through the G(2)/M phase, increased the generation of reactive oxygen species (ROS), and induced apoptosis through activation of intrinsic and extrinsic pathway components. Cytotoxicity of PAC-1 was partially based on ROS generation and could be blocked by co-treatment with antioxidant glutathione. PAC-1 reduced the cell viability of both SKOV-3 ovarian cancer cells and HUVEC endothelial cells in a dose-dependent manner and blocked the activation of the pro-survival factor AKT. Furthermore, PAC-1 blocked vascular endothelial growth factor (VEGF)-stimulated receptor phosphorylation in endothelial cells, which correlated with the inhibition of endothelial tube formation in vitro. Our findings suggest that PAC-1 exerts potent anticancer and anti-angiogenic properties and that highly purified PAC from cranberry can be further developed to treat ovarian cancer in combinational or single-agent therapy.