Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice
Silibinin inhibits inflammatory and angiogenic attributes in photocarcinogenesis in SKH-1 hairless mice
复制标题
DOI：
10.1158/0008-5472.can-06-3955
复制
发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
--
作者：
Gu, Mallikarjuna;Singh, Rana P.;Agarwal, Rajesh
防晒霜部分过滤中波紫外线，因此可以部分预防皮肤癌；然而，需要有效的方法来有效地预防光致癌。据推测，无毒药理活性天然化合物可增强光保护作用。我们已完成的研究表明，水飞蓟宾是一种具有生物活性的植物化学物质，对光致癌有很强的预防作用；然而，其机制尚不完全清楚。本研究首次采用临床相关的UVB剂量（30 mJ/cm(2)/day）研究水飞蓟宾对SKH1无毛小鼠的光保护作用及其相关机制。局部或膳食水飞蓟宾治疗在延缓肿瘤出现、多样性和体积方面对光致癌有很强的保护作用。水飞蓟宾对正常皮肤、荷瘤小鼠未受损伤皮肤和皮肤肿瘤的分析显示，水飞蓟宾对诱导型一氧化氮合酶（iNOS）和环氧合酶2 （COX-2）水平的降低具有统计学意义（P < 0.05-0.001）。与此同时，磷酸化信号转导和转录激活因子3 （Tyr(705)）和磷酸化p65（Ser(536)）也被水飞蓟宾减少，它们是iNOS和COX-2的潜在上游调节剂。同时水飞蓟宾还能抑制uvb引起的细胞增殖和微血管密度的增加。在肿瘤中，水飞蓟宾可降低低氧诱导因子（HIF-1 α）和血管内皮生长因子蛋白水平。进一步分析表明，水飞蓟宾素抑制uvb引起的STAT3和p65的磷酸化和核转位，以及核因子κ B (nf - κ B) MA的结合活性。综上所述，这些结果表明水飞蓟宾通过下调炎症和血管生成反应，包括HIF-1 α、STAT3和NF-kappa B转录因子，以及COX2和iNOS，对光致癌有很强的保护作用。
Sunscreens partially filter UVB and, therefore, could partially prevent skin cancer; however, efficient approaches are desired to effectively prevent photocarcinogenesis. It is hypothesized that nontoxic pharmacologically active natural compounds can increase photoprotective effects. Our completed studies suggest that silibinin, a bioactive phytochemical, strongly prevents photocarcinogenesis; however, its mechanism is not fully understood. Herein, for the first time, we used a clinically relevant UVB dose (30 mJ/cm(2)/day) to examine the photoprotective effect and associated mechanisms of silibinin in SKH1 hairless mice. Topical or dietary silibinin treatment caused a strong protection against photocarcinogenesis in terms of delay in tumor appearance, multiplicity, and volume. Analyses of normal skin, uninvolved skin from tumor-bearing mice, and skin tumors showed a statistically significant decrease (P < 0.05-0.001) in inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) levels by silibinin. Concomitantly, phospho-signal transducers and activators of transcription 3 (Tyr(705)) and phospho-p65(Ser(536)) were also decreased by silibinin, which are potential up-stream regulators of iNOS and COX-2. Simultaneously, silibinin also decreased UVB-caused increase in cell proliferation and microvessel density. In tumors, hypoxia-inducible factor lot (HIF-1 alpha) and vascular endothelial growth factor protein levels were decreased by silibinin. Further analysis showed that silibinin inhibited UVB-caused phosphorylation and nuclear translocation of STAT3 and p65, as well as nuclear factor kappa B (NF-kappa B) MA binding activiity. Together, these results suggest that silibinin causes a strong protective effect against photocarcinogenesis via down-regulation of inflammatory and angiogenic responses, involving HIF-1 alpha, STAT3, and NF-kappa B transcription factors, as well as COX2 and iNOS.