Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-κB
Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-κB
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DOI：
10.1002/ijc.22570
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发表时间：
2007-06-15
影响因子：
6.4
通讯作者：
Nonomura, Norio
中科院分区：
文献类型：
--
作者：
Oka, Daizo;Nishimura, Kazuo;Nonomura, Norio
转录因子核因子-κ B（NF-κ B）已被证明在各种人类恶性肿瘤中被组成性激活，包括白血病、淋巴瘤和许多实体瘤。NF-κ B B调节肿瘤侵袭、转移和化疗耐药的重要基因的转录。倍半萜内酯小白菊是NF-κ B的抑制剂，已常规用于治疗偏头痛和炎症。在这项研究中，肾癌细胞系OUR-10和ACHN用于体外实验以评估孤雌菊的生长抑制作用。还使用裸鼠中的OUR-10异种移植模型来研究孤雌菊的体内生长抑制作用。证实了响应于孤雌菊处理的OUR-10细胞的凋亡。通过用针对NF-κ B p65的抗体对OUR-10细胞进行免疫荧光染色，并通过对OUR-10细胞和肿瘤细胞核和细胞质部分进行Western印迹分析，来检测响应于孤雌生殖器处理的NF-κ B的定位。孤雌菊在体外能有效抑制OUR-10细胞的增殖并诱导其凋亡。皮下注射或口服小白菊通过减少白细胞介素-8（IL-8）或血管内皮生长因子（VEGF）的产生，在异种移植模型中显示出显著的肿瘤生长抑制作用。免疫组化和Western blot分析显示孤雌激素治疗后NF-κ B和磷酸化NF-κ B蛋白的核定位减少，随后MMP-9、Bcl-xL和考克斯-2的表达减少。这些结果表明，孤雌菊是一个有用的治疗肾细胞癌，并通过抑制NF-κ B。(c)2007年威利-利斯。Inc.
The transcription factor nuclear factor-kappa B (NF-kappa B) has been shown to be constitutively activated in various human malignancies, including leukemia, lymphoma and a number of solid tumors. NF-kappa B regulates the transcriptional of genes important for tumor invasion, metastasis and chemoresistance. The sesquiterpene lactone parthenolide, an inhibition of NF-kappa B, has been used conventionally to treat migraines and inflammation. In this study, renal cancer cell lines OUR-10 and ACHN were used for in vitro experiments to evaluate growth- inhibitory effects of parthenolide. An OUR-10 xenograft model in nude mice was also used to investigate the in vivo growth-inhibitory effects of parthenolide. Apoptosis in response to treatment of OUR-10 cells with parthenolide was confirmed. Localization of NF-kappa B in response to parthenolide treatment was examined of by immunofluorostaining of OUR-10 cells with antibody against NF-kappa B p65 and by Western blot analysis of OUR-10 cell and tumor nuclear and cytosol fraction. Parthenolide effectively inhibited proliferation of cultured OUR-10 cells and triggered apoptosis in vitro. Subcutaneous injection or oral administration of parthenolide showed significant tumor growth inhibition in the xenograft model via decreased production of interleukin-8 (IL-8) or vascular endothelial growth factor (VEGF). Immunohistochemistry and Western blot analysis showed decreased nuclear localization of NF-kappa B and phosphorylated NF-kappa B protein and subsequently expression of MMP-9, Bcl-xL and Cox-2 in response to parthenolide treatment. These results indicate that parthenolide is a useful in the treatment of renal cell carcinoma and acts via inhibition of NF-kappa B. (c) 2007 Wiley-Liss. Inc.