磷脂酰肌醇3激酶抑制剂逆转胃癌多药耐药的研究 .doc

抑制PI3K/PKB通路逆转胃癌耐药的作用及其机制 谢 霞，高 青(，王艳丽 （重庆医科大学附属第一医院消化内科，重庆 400016） 目的 胃癌作用机制。方法vincristine,VCR）及联合PI3K/PKB抑制剂LY294002对SGC7901/VCR细胞的生长抑制作用；RT-PCR法MDR1、BaxBcl-2基因表达水平；流式细胞仪检测细胞的凋亡结果 LY294002能明显SGC7901/VCR细胞对VCR的敏感性LY294002可降低耐药细胞中磷酸化PKB蛋白表达（P 0.01）和MDR1、Bcl-2的基因表达水平，促进Bax的。结论PI3K/PKB通路降低耐药基因MDR1的表达凋亡相关基因BaxBcl-2的表达。 LY294002；SGC7901/VCR；凋亡Gastric Carcinoma Cell Line by inhibition of PI3K/PKB signal pathway and its mechanism XIE Xia, GAO Qing, WANG Yan-li (Department of Gastroenterology, the first affiliated Hospital, Chongqing Medical University, Chongqing 400016, China) Abstract: Objective To observe whether inhibition of PI3K/AKT signal pathway could reverse drug resistance of gastric carcinoma, and study its potential mechanism. Methods The growth inhibition effects of VCR alone and VCR in combination with PI3K/PKB inhibitor LY294002 on SGC7901/VCR cells were detected by in vivo and in vitro experiments. The protein levels of PKB and phospho-PKB in SGC7901/VCR cells were determined by Western-Blot. And the MDR1, Bax, and Bcl-2 mRNA expression levels were evaluated by semi-quantitative PCR. Besides, the apoptosis was detected by flow cytometry. Results LY294002 enhanced the sensitivities of SGC7901/VCR cells to VCR significantly, and promoted the apoptosis rate induced by VCR prominently, their corresponding IR decreased from 40.45 to 8.5. The protein level of phospho-PKB was reduced(P0.01), MDR1 and Bcl-2 gene expression levels were inhibited, while the expression of Bax was improved significantly(P0.01). Further more, It enhanced the growth inhibition effect of VCR on transplanted gastric carcinoma in nude mice. Conclusion Inhibition of PI3K/PKB signal pathway by LY294002 can reverse the drug resistance of gastric carcinoma cell line. Reduction of MDR1 expression levels, and regulation of apoptosis related genes, such as Bax and Bcl-2 expression levels play key roles in this progress. Key words: PI3K/PKB; LY294002; SGC7901 cells; SGC7901/VCR cells; ap