熊果酸通过靶向多个细胞信号通路抑制裸鼠原位结直肠癌细胞生长和转移：与卡培他滨的协同作用。
Ursolic acid inhibits growth and metastasis of human colorectal cancer in an orthotopic nude mouse model by targeting multiple cell signaling pathways: chemosensitization with capecitabine.
机构信息
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
出版信息
Clin Cancer Res. 2012 Sep 15;18(18):4942-53. doi: 10.1158/1078-0432.CCR-11-2805. Epub 2012 Jul 25.
PURPOSE
Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid, a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated.
EXPERIMENTAL DESIGN
The effect of ursolic acid on proliferation of CRC cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and protein expression by Western blot. The effect of ursolic acid on the growth and chemosensitization was also examined in orthotopically implanted CRC in nude mice.
RESULTS
We found that ursolic acid inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-κB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, and survivin), proliferative (cyclin D1), and metastatic (MMP-9, VEGF, and ICAM-1) proteins. When examined in an orthotopic nude mouse model, ursolic acid significantly inhibited tumor volume, ascites formation, and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that ursolic acid downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-κB, STAT3, and β-catenin. In addition, ursolic acid suppressed EGF receptor (EGFR) and induced p53 and p21 expression. We also observed bioavailability of ursolic acid in the serum and tissue of animals.
CONCLUSION
Overall, our results show that ursolic acid can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through the suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis.
目的
化学耐药性的发展、预后不良和转移常常使目前治疗结直肠癌（CRC）的方法无效。本研究旨在探讨熊果酸（一种多种药用植物的成分）是否能单独或与卡培他滨联合抑制人 CRC 的生长和转移。
实验设计
通过线粒体染料摄取试验、酯酶染色检测细胞凋亡、DNA 结合试验检测 NF-κB 激活以及 Western blot 检测蛋白表达，研究熊果酸对 CRC 细胞系增殖的影响。还在裸鼠原位植入 CRC 模型中研究了熊果酸对肿瘤生长和化疗增敏的影响。
结果
我们发现熊果酸抑制了不同结肠癌细胞系的增殖。这与抑制固有 NF-κB 激活以及下调细胞存活（Bcl-xL、Bcl-2、cFLIP 和 survivin）、增殖（cyclin D1）和转移（MMP-9、VEGF 和 ICAM-1）蛋白有关。在裸鼠原位模型中进行研究时，熊果酸显著抑制了肿瘤体积、腹水形成和远处器官转移，与卡培他滨联合应用时效果增强。肿瘤组织免疫组化分析表明，熊果酸下调了增殖标志物（Ki-67）和微血管密度（CD31）。这种作用伴随着 NF-κB、STAT3 和 β-catenin 的抑制。此外，熊果酸抑制了表皮生长因子受体（EGFR），并诱导了 p53 和 p21 的表达。我们还观察到了动物血清和组织中熊果酸的生物利用度。
结论
总的来说，我们的结果表明，熊果酸可以抑制 CRC 的生长和转移，并通过抑制与炎症、增殖、侵袭、血管生成和转移相关的多个生物标志物，进一步增强卡培他滨的治疗效果。
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