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目的研究糖原合酶激酶-3β抑制剂4,6-二取代吡咯并嘧啶(TWS119)体外抗肿瘤活性和对人γδT细胞活性的影响。方法用不同浓度的4,6-二取代吡咯并嘧啶分别作用于人胃癌SGC-7901细胞和γδT细胞24、48和72 h后,用CCK-8法测定4,6-二取代吡咯并嘧啶对人胃癌SGC-7901细胞和γδT细胞增殖的影响及γδT细胞对SGC-7901细胞杀伤能力;流式细胞术分析4,6-二取代吡咯并嘧啶对SGC-7901细胞凋亡的影响,Western blot检测4,6-二取代吡咯并嘧啶对Bcl-2、p-STAT3和p-ERK1/2表达的影响。结果 0~8.0μmol·L~(-1)4,6-二取代吡咯并嘧啶能抑制人胃癌SGC-7901细胞的生长并诱导其凋亡,抑制Bcl-2的表达,促进p-ERK1/2和p-STAT3的表达。而在γδT细胞中,4,6-二取代吡咯并嘧啶在0~4.0μmol·L~(-1)时能促进其增殖和对SGC-7901细胞的体外杀伤活性,促进Bcl-2的表达,抑制pERK1/2和p-STAT3的表达。结论一定浓度的4,6-二取代吡咯并嘧啶能抑制人胃癌SGC-7901细胞的增殖并诱导其凋亡,同时能促进γδT细胞增殖和对SGC-7901细胞的杀伤活性,其机制可能与4,6-二取代吡咯并嘧啶激活Wnt信号传导通路及其对p-ERK1/2、Bcl-2和p-STAT3表达的影响有关。
Objective To study the antitumor activity and the effect on the activity of human γδT cells of glycogen synthase kinase-3β inhibitor 4,6-disubstituted pyrrolopyrimidine (TWS119) in vitro. Methods After treated with different concentrations of 4,6-disubstituted pyrrolopyrimidine for 24, 48 and 72 h in human gastric cancer cell line SGC-7901 and γδT cells, the 4,6-disubstituted pyrrolopyrimidines were determined by CCK-8 The effect of 4,6-disubstituted pyrrolopyrimidine on the apoptosis of human gastric cancer SGC-7901 cells and γδT cells and the effect of γδT cells on SGC-7901 cells were analyzed by flow cytometry. Effect of 4,6-disubstituted pyrrolopyrimidine on the expression of Bcl-2, p-STAT3 and p-ERK1 / 2. Results 0 ~ 8.0μmol·L -1 4,6-disubstituted pyrrolopyrimidine could inhibit the growth of human gastric cancer cell SGC-7901, induce its apoptosis, inhibit the expression of Bcl-2 and promote the expression of p-ERK1 / 2 And p-STAT3 expression. In γδT cells, 4,6-disubstituted pyrrolopyrimidine could promote the proliferation and SGC-7901 cells cytotoxicity in vitro and Bcl-2 expression at 0 ~ 4.0μmol·L -1, Inhibit the expression of pERK1 / 2 and p-STAT3. Conclusions A certain concentration of 4,6-disubstituted pyrrolopyrimidine can inhibit the proliferation and induce the apoptosis of human gastric cancer SGC-7901 cells as well as promote the proliferation of γδT cells and the cytotoxicity to SGC-7901 cells. The mechanism may be related to 4 , 6-disubstituted pyrrolopyrimidine activated Wnt signaling pathway and its effect on the expression of p-ERK1 / 2, Bcl-2 and p-STAT3.