Angiopreventive efficacy of pure flavonolignans from milk thistle extract against prostate cancer: targeting VEGF-VEGFR signaling.
Angiopreventive efficacy of pure flavonolignans from milk thistle extract against prostate cancer: targeting VEGF-VEGFR signaling.
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DOI：
10.1371/journal.pone.0034630
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Agarwal R
中科院分区：
文献类型：
--
作者：
Deep G;Gangar SC;Rajamanickam S;Raina K;Gu M;Agarwal C;Oberlies NH;Agarwal R
新血管生成在前列腺癌（PCA）生长和转移中的作用已得到充分证实，但开发有效且无毒的血管生成药理学抑制剂仍然是一个未实现的目标。在这方面，通过无毒植物化学物质靶向异常血管生成可能是针对 PCA 的一种有吸引力的血管预防策略。本研究的基本原理是比较四种纯非对映异构黄酮木脂素（即水飞蓟宾 A、水飞蓟宾 B、异水飞蓟宾 A 和异水飞蓟宾 B）的抗血管生成潜力，我们之前将其确定为水飞蓟提取物中的生物活性成分。结果表明，口服这些黄酮木脂素（50 和 100 毫克/千克体重）可有效抑制晚期人类 PCA DU145 异种移植物的生长。免疫组织化学分析表明，这些黄酮木脂素可抑制肿瘤血管生成生物标志物（CD31 和巢蛋白）和调节血管生成的信号分子（VEGF、VEGFR1、VEGFR2、磷酸化 Akt 和 HIF-1α），而不会对荷瘤小鼠正常组织（肝、肺和肾）的血管计数产生不利影响。这些黄酮木脂素还抑制离体小鼠背主动脉的微血管萌发，以及体外抑制 VEGF 诱导的细胞增殖、毛细血管样管形成和人脐静脉内皮细胞 (HUVEC) 的侵袭性。 HUVEC 的进一步研究表明，这些非对映异构体靶向细胞周期、细胞凋亡和 VEGF 诱导的信号级联。三维生长测定以及共培养侵袭和体外血管生成研究（使用 HUVEC 和 DU145 细胞）表明非对映异构体对 PCA 和内皮细胞的不同功效。总体而言，这些研究阐明了水飞蓟纯黄酮木脂素的抗血管生成功效，并表明它们在 PCA 血管预防中的有用性。
The role of neo-angiogenesis in prostate cancer (PCA) growth and metastasis is well established, but the development of effective and non-toxic pharmacological inhibitors of angiogenesis remains an unaccomplished goal. In this regard, targeting aberrant angiogenesis through non-toxic phytochemicals could be an attractive angiopreventive strategy against PCA. The rationale of the present study was to compare the anti-angiogenic potential of four pure diastereoisomeric flavonolignans, namely silybin A, silybin B, isosilybin A and isosilybin B, which we established previously as biologically active constituents in Milk Thistle extract. Results showed that oral feeding of these flavonolignans (50 and 100 mg/kg body weight) effectively inhibit the growth of advanced human PCA DU145 xenografts. Immunohistochemical analyses revealed that these flavonolignans inhibit tumor angiogenesis biomarkers (CD31 and nestin) and signaling molecules regulating angiogenesis (VEGF, VEGFR1, VEGFR2, phospho-Akt and HIF-1α) without adversely affecting the vessel-count in normal tissues (liver, lung, and kidney) of tumor bearing mice. These flavonolignans also inhibited the microvessel sprouting from mouse dorsal aortas ex vivo, and the VEGF-induced cell proliferation, capillary-like tube formation and invasiveness of human umbilical vein endothelial cells (HUVEC) in vitro. Further studies in HUVEC showed that these diastereoisomers target cell cycle, apoptosis and VEGF-induced signaling cascade. Three dimensional growth assay as well as co-culture invasion and in vitro angiogenesis studies (with HUVEC and DU145 cells) suggested the differential effectiveness of the diastereoisomers toward PCA and endothelial cells. Overall, these studies elucidated the comparative anti-angiogenic efficacy of pure flavonolignans from Milk Thistle and suggest their usefulness in PCA angioprevention.
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DOI：
10.3322/caac.20075
发表时间：
2010-07
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Cook KM;Figg WD
通讯作者：
Figg WD
影响因子：
2.9
作者：
Kroll, David J.;Shaw, Heather S.;Oberlies, Nicholas H.
通讯作者：
Oberlies, Nicholas H.
影响因子：
11.2
作者：
Gu, Mallikarjuna;Singh, Rana P.;Agarwal, Rajesh
通讯作者：
Agarwal, Rajesh
影响因子：
5.7
作者：
Kaur M;Velmurugan B;Tyagi A;Deep G;Katiyar S;Agarwal C;Agarwal R
通讯作者：
Agarwal R
影响因子：
6.4
作者：
Deep, Gagan;Oberlies, Nicholas H.;Agarwal, Rajesh
通讯作者：
Agarwal, Rajesh