Department of Pharmacology, Yong Loo Lin School of Medicine, Cancer Science Institute of Singapore, National University of Singapore.
Clin Cancer Res. 2012 Apr 15;18(8):2220-9. doi: 10.1158/1078-0432.CCR-11-2470. Epub 2012 Feb 20.
Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether γ-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.
The effect of γ-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and gene expression by Western blotting. The effect of γ-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.
γ-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-κB, and suppressed the NF-κB-regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of γ-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and γ-tocotrienol. As compared with vehicle control, γ-tocotrienol also suppressed the NF-κB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.
Overall our results show that γ-tocotrienol can potentiate the effects of capecitabine through suppression of NF-κB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.
由于预后不良和对化疗药物的耐药性发展，目前治疗胃癌的方法效果不佳。因此，急需安全有效的新型药物。本研究旨在探讨γ-生育三烯酚是否能在体外和异种移植小鼠模型中增强胃癌对卡培他滨的敏感性。
通过线粒体染料摄取试验、酯酶染色法检测细胞凋亡、DNA 结合试验检测 NF-κB 激活、Western 印迹法检测基因表达，研究γ-生育三烯酚对胃癌细胞系增殖的影响。还在裸鼠皮下植入的肿瘤中研究了 γ-生育三烯酚对生长和化疗增敏的影响。
γ-生育三烯酚抑制了各种胃癌细胞系的增殖，增强了卡培他滨的促凋亡作用，抑制了 NF-κB 的组成性激活，并抑制了 NF-κB 调节的 COX-2、细胞周期蛋白 D1、Bcl-2、CXCR4、VEGF 和基质金属蛋白酶-9（MMP-9）的表达。在裸鼠人胃癌异种移植模型中，我们发现单独给予γ-生育三烯酚（1mg/kg 体重，每周腹腔内 3 次）可显著抑制肿瘤生长，而卡培他滨可进一步增强该作用。肿瘤组织中增殖指数 Ki-67 和微血管密度 CD31 的标志物均下调。与载体对照组相比，γ-生育三烯酚还抑制了 NF-κB 激活以及细胞周期蛋白 D1、COX-2、细胞间黏附分子-1（ICAM-1）、MMP-9、存活素、Bcl-xL 和 XIAP 的表达。
综上所述，我们的研究结果表明，γ-生育三烯酚通过抑制 NF-κB 调节的增殖、侵袭、血管生成和转移标志物，增强卡培他滨的作用。
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