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目的 探讨丙戊酸钠联合紫杉醇对荷瘤裸鼠的抗肿瘤作用及其机制.方法 构建裸鼠移植瘤模型(将MKN45细胞移植于裸鼠右上腋,使成为荷瘤裸鼠)共48只,并随机分为4组(每组12只):对照组(给予生理氯化钠溶液)、丙戊酸钠组(丙戊酸钠治疗),紫杉醇组(紫杉醇治疗),联合治疗组(给予丙戊酸钠+紫杉醇).用药21d后将裸鼠处死,取瘤体组织进行HE、TUNEL染色,并用Western blotting检测MKN45肿瘤细胞中线粒体信号通路及P13K/AKT/mTOR信号通路相关凋亡因子的变化情况.结果 与对照组比较,丙戊酸钠组、紫杉醇组均表现出较多死亡细胞及凋亡细胞数,联合治疗组死亡细胞及凋亡细胞数均多于单独用药组;单独用药组与对照组比较,促凋亡蛋白t-Bid(丙戊酸钠组除外)、Bax、Puma、Cleaved-caspase3、Cleaved-caspase9表达水平明显上调,Bcl-2、Mcl-1、Bcl-xL抗凋亡蛋白表达水平有明显下调(P＜0.05);联合治疗组与对照组比较,促凋亡蛋白t-Bid、Bax、Puma、Cleaved-easpase3、Cleaved-caspase9表达水平下调更明显(P＜0.01);与对照组比较,联合治疗组p-p70S6K、Raptor、P13Kp110α、p-AKT-Ser473蛋白水平下调明显,有显著性差异(P＜0.01),下调幅度优于单独用药组(P＜0.05).结论 丙戊酸钠联合紫杉醇用于荷瘤裸鼠抗肿瘤的治疗,能促进MKN45肿瘤细胞的凋亡,其机制主要是通过调节线粒体信号通路和P13K/AKT/mTOR信号通路的相关凋亡蛋白共同作用的结果.“,”Objective To investigate the antitumor effect of sodium valproate(VPA) combined with paclitaxel(PTX) on tumor-bearing nude mice and its mechanism.Methods A total of 48 nude mouse xenograft models were constructed by transplanting MKN45 cells to nude mice on the right axilla to make them tumor-bearing nude mice.They were randomly divided into 4 groups (12 rats in each):NS group (saline was used as a control),VPA group,PTX group,and combination group (given VPA and PTX).After administration of 21d,the mice were sacrificed,and the tumor tissues were stained with HE and TUNEL.Western blotting was used to detect the changes of apoptosis-related factors in mitochondrial signaling pathway and p13k/ATK/mtor signaling pathway in tumor cells MKN45.Results There were more dead cells and apoptotic cells in VPA group and PTX group than in NS group.The number of dead cells and apoptotic cells in combination group was larger than that in VPA group and in PTX group.The apoptosis promoting protein t-Bid (except VPA group),Bax,puma,cleaved-caspase3,and cleaved-caspase9 were all upregulated more significantly in single-drug groups than in NS group,while the expressions of Bcl-2,Mcl-1 and Bcl-xL were down regulated,and the difference was statistically significant (P ＜0.05).The expression levels of pro apoptotic protein t-Bid,Bax,puma,cleaved-caspase3,and cleaved-caspase9 increased more significantly in combination group than in NS group,while the expression levels of Bcl-2,Mcl-1,Bcl-xL and anti apoptotic protein decreased more obviously(P ＜0.01).Conclusion VPA combined with PTX is effective in the treatment of tumor bearing nude mice.MKN45 can promote apoptosis of tumor cells.The mechanism is mainly mediated by regulating the mitochondrial signaling pathway and the associated apoptotic proteins of the P13k/AKT/mtor signaling pathway.