大黄素增强吉西他滨对裸鼠SW1990细胞移植瘤的抑瘤作用

Emodin enhances antitumor effect of gemcitabine in model of SW1990 cell xenograft on athymic mouse

目的:探讨大黄素增强吉西他滨对裸鼠SW1990细胞移植瘤的抑瘤作用及其机制。方法:在裸鼠SW1990细胞移植瘤的动物模型上,分为生理盐水组(N组),大黄素组(E组,40 mg.kg-1),吉西他滨组(G组,125 mg.kg-1),联合用药组(E+G组,大黄素40 mg.kg-1+吉西他滨80 mg.kg-1)。各组均采取腹腔注射药物,3 d 1次,前后共11次。观察各组用药过程中肿瘤体积、瘤重、体重的变化。末次用药后1周处死裸鼠取肿瘤组织。采用Tunel法检测各组肿瘤组织凋亡情况。采用免疫组织化学染色法和Western blot法检测肿瘤组织凋亡相关蛋白Bax,Bcl-2和Cytochrome C的表达变化。结果:末次用药后1周E+G组肿瘤体积和瘤重明显小于其他各组;Tunel法显示E+G组肿瘤细胞凋亡比其余各组显著增多;免疫组织化学染色和Western blot法显示E+G组的Bax,Cytochrome C的表达比其他各组显著增多,而Bcl-2的表达比其余各组明显降低,经计算Bcl-2/Bax显著下降。结论:大黄素能显著增强吉西他滨对裸鼠体内人胰腺癌SW1990细胞移植瘤的抑瘤效果,其机制可能是大黄素通过促进胰腺癌SW1990细胞中Bax的表达和抑制Bcl-2的表达,降低Bcl-2/Bax,继而促进线粒体Cytochrome C释放,从而增强吉西他滨对胰腺癌SW1990细胞移植瘤的促凋亡作用,达到增强吉西他滨在体内的抑瘤效果。

Objective： To evaluate the enhanced effect of gemcitabine by emodin and the possible mechanisms of the enhancement. Method： Based on the model of SW1990 cell xenograft on athymic mouse, the mice were randomized to four groups with intraperitoneal（IP） injections of different drugs： group N （injecting 0. 9% sodium chloride）, group E （emodin, 40 mg·kg^-1 ）, group G （gemcitabine, 125 mg·kg^-1）, and group E ＋ G （emodin 40 mg·kg^-1 and gemcitabine 80 mg·kg^-1in combination）. The tumor volume, tumor weight and body weight of mice were measured during the drug therapy. The mice were sacrificed one week after last injection of drug. Tune1 assay were used used to detect the apoptosis of tumor cells. And immunohistochemistry （IHC） and Western blot （WB） were used to detect the variance of the apoptotsis relative protein expression of Bax, Bct-2, and Cytochrome C . Result： One week after the last administration, the mean tumor volume and tumor weight in group E ＋ G were significantly decreased compared to the other groups. Tunel assay showed group E ＋ G presented apparently more apoptosis than the other groups. Immunohistochemistry （IHC） and Western blot（WB） analysis showed the expression of Cytochrome C in cytoplasmin and Bax in group E ＋ G was apparently upregulated while the expression of Bcl-2 was apparendy downregulated compared to the other groups. As a result, Bcl-2/Bax ratio was significantly decreased in group E ＋ G. Conclusion： Emodin can significantly improve the antitumor effect of gemcitabine on transplan- ted tumor of SW1990 cell line through apparently enhancing the tumor cell apoptosis by gemcitabine. Downregnlation of Bcl-2/Bax ratio and promoting release of Cytochrome C from mitochondria is possibly one of the mechanisms of the augmented apoptosis.