Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
Cancer Chemother Pharmacol. 2014 Apr;73(4):807-18. doi: 10.1007/s00280-014-2408-x. Epub 2014 Mar 18.
Paris Saponin II (PSII) is an active component of Rhizoma Paridis-an essential ingredient in traditional Chinese herbal medicines. PSII can induce cytotoxic effects in cancer cells and inhibit ovarian cancer growth. Since pathological angiogenesis (henceforth, angiogenesis) is often associated with gynecological cancers, here, we investigated whether PSII renders effects on angiogenesis and examined possible molecular mechanisms underlying the effects of PSII.
The effects of PSII on the biofunctions of endothelial cells (EC), the crucial components of blood vessels, were examined by standardized angiogenesis in vitro and ex vivo assays, Western blot analysis, ELISA, and kinase assay. Angiogenesis in a xenograft mouse model of ovarian cancer was evaluated by color Doppler ultrasound and immunohistochemistry.
PSII exerted marked inhibitory effect on the growth of VEGF-stimulated human umbilical vein endothelial cells in a dose-time-dependent manner, inhibited cell's motility, and interfered with tubulogenesis. PSII also blocked microvessel outgrowth in a rat aortic ring assay and compromised angiogenesis in a mouse model of ovarian carcinoma using either SKOV3 or HOC-7 cell lines. VEGF levels in PSII-treated EC and tumor cells were reduced. In EC, PSII blocked the activation of VEGFR2 in dose-dependent manner leading to the reduction of VEGF-induced phosphorylation on several intracellular pro-angiogenic kinase, including the extracellular signal-related kinase, Src family kinase, focal adhesion kinase, and AKT kinase.
The results provided the first insight into the anti-angiogenesis properties of Saponin family in solid tumors and suggested a promising therapeutic potential of PSII in the ovarian cancer treatment.
巴黎七叶皂甙 II（PSII）是重楼根茎的一种活性成分，为重楼根茎在传统中药中的主要成分。PSII 可以诱导癌细胞的细胞毒性作用并抑制卵巢癌的生长。由于病理性血管生成（以下简称血管生成）通常与妇科癌症相关，因此，我们在此研究 PSII 是否对血管生成产生影响，并探讨 PSII 作用的可能分子机制。
通过标准化的体外和离体血管生成实验、Western blot 分析、ELISA 和激酶测定，研究 PSII 对血管内皮细胞（EC）这一血管关键组成部分的生物功能的影响。通过彩色多普勒超声和免疫组织化学评估 PSII 在卵巢癌异种移植小鼠模型中的血管生成作用。
PSII 以剂量和时间依赖的方式对 VEGF 刺激的人脐静脉内皮细胞的生长表现出显著的抑制作用，抑制细胞的迁移，并干扰管形成。PSII 还阻断了大鼠主动脉环实验中的微血管生长，并使用 SKOV3 或 HOC-7 细胞系损害了卵巢癌小鼠模型中的血管生成。PSII 处理的 EC 和肿瘤细胞中的 VEGF 水平降低。在 EC 中，PSII 以剂量依赖性方式阻断 VEGFR2 的激活，从而减少 VEGF 诱导的几种细胞内促血管生成激酶（包括细胞外信号调节激酶、Src 家族激酶、黏着斑激酶和 AKT 激酶）的磷酸化。
这些结果首次深入了解了皂甙家族在实体肿瘤中的抗血管生成特性，并表明 PSII 在卵巢癌治疗中有很大的治疗潜力。
