甲氟喹增强紫杉醇诱导胃癌细胞BGC-823细胞凋亡的机制
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摘要
目的 探讨甲氟喹作用于人胃癌细胞BGC-823后对紫杉醇敏感性的影响及作用机制。方法 甲氟喹联合紫杉醇作用于胃癌细胞BGC-823后,流式细胞仪PI单染法检测细胞凋亡率,MTS测定细胞活性,Western blot检测PI3K/Akt/mTOR信号通路蛋白表达水平。结果 与SGC-7901细胞相比,BGC-823细胞对紫杉醇更加不敏感;甲氟喹联合紫杉醇较单药紫杉醇能更明显地诱导BGC-823细胞的凋亡[(33.00±2.83)%vs(15.75±0.64)%],抑制细胞增殖[(44.00±0.07)%vs(72.00±0.09)%],差异均有统计学意义(P<0.05);Western blot法显示在紫杉醇中加入甲氟喹作用后,PI3K/Akt/mTOR信号通路磷酸化蛋白的表达明显降低。结论 甲氟喹能够有效抑制PI3K/Akt/mTOR信号通路磷酸化蛋白的表达水平,从而诱导BGC-823细胞凋亡,明显增加BGC-823细胞对紫杉醇的敏感性。
Objective To investigate the effect of mefloquine on the sensitivity of human gastric cancer cell line BGC-823 to paclitaxel and its mechanism. Methods Apoptotic rate was detected by flow cytometry,MTS assay was used to detect the cell viability of gastric cancer cells BGC-823. The PI3 K/Akt/mT OR signaling pathway protein expression was detected by Western blot. Results Compared with SGC-7901 cells,BGC-823 was not sensitive to paclitaxel. After treatment with 0. 3 μmol/L paclitaxel combined with 0. 5 μmol/L mefloquine for 24 hours,the apoptotic rate was [( 33. 00 ± 2. 83) % vs( 15. 75 ± 0. 64) %]and the proliferation rate was [( 44. 00 ± 0. 07) %vs( 72. 00 ± 0. 09) % ]( P < 0. 05). Western blot analysis showed that the expression of phosphorylated protein of PI3 K/Akt/mT OR pathway was decreased markedly after treatments of paclitaxel combined with mefloquine. Conclusion Mefloquine can inhibit the PI3 K/Akt/mT OR signaling pathway phosphorylated protein expression and induce BGC-823 cells apoptosis,significantly increased the sensitivity of BGC-823 cells to paclitaxel.
Objective To investigate the effect of mefloquine on the sensitivity of human gastric cancer cell line BGC-823 to paclitaxel and its mechanism. Methods Apoptotic rate was detected by flow cytometry,MTS assay was used to detect the cell viability of gastric cancer cells BGC-823. The PI3 K/Akt/mT OR signaling pathway protein expression was detected by Western blot. Results Compared with SGC-7901 cells,BGC-823 was not sensitive to paclitaxel. After treatment with 0. 3 μmol/L paclitaxel combined with 0. 5 μmol/L mefloquine for 24 hours,the apoptotic rate was [( 33. 00 ± 2. 83) % vs( 15. 75 ± 0. 64) %]and the proliferation rate was [( 44. 00 ± 0. 07) %vs( 72. 00 ± 0. 09) % ]( P < 0. 05). Western blot analysis showed that the expression of phosphorylated protein of PI3 K/Akt/mT OR pathway was decreased markedly after treatments of paclitaxel combined with mefloquine. Conclusion Mefloquine can inhibit the PI3 K/Akt/mT OR signaling pathway phosphorylated protein expression and induce BGC-823 cells apoptosis,significantly increased the sensitivity of BGC-823 cells to paclitaxel.
引文
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[12] 潘理会,张平,李春辉.PI3K/AKT/mTOR信号传导通路在胃癌中的研究进展[J].承德医学院学报,2016,33(4):324-7.
[13] Rodrigues F A,Bomfim I S,Cavalcanti B C,et al.Mefloquine-oxazolidine derivatives:a new class of anticancer agents[J].Chem Biol Drug Des,2014,83(1):126-31.
[14] Liu Y,Chen S,Xue R,et al.Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of PI3K/Akt/mTOR signaling pathway[J].Biochem Biophys Res Commun,2016,470(2):350-5.
[2] Noh S H,Park S R,Yang H K,et al.Adjuvantcapecitabineplus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC):5-year follow-up of an open-label,randomised phase 3 trial[J].Lancet Oncol,2014,15(12):1389-96.
[3] Ford H E,Marshall A,Bridgewater J A,et al.Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02):an open-label,phase 3 randomised controlled trial[J].Lancet Oncol,2014,15(1):78-86.
[4] 杜新超,张志勇,李勇.紫杉醇联合顺铂新辅助化疗治疗胃癌的疗效观察[J].中国肿瘤临床与康复,2017,24(4):450-2.
[5] Sukhai M A,Prabha S,Hurren R,et al.Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors[J].J Clin Invest,2013,123(1):315-28.
[6] Li H,Jiao S,Li X,et al.Therapeutic effects of antibiotic drug mefloquine against cervical cancer through impairing mitochondrial function and inhibiting mTOR pathway[J].Can J Physiol Pharmacol,2017,95(1):43-50.
[7] 杨健.COLPH3、PI3K/Akt/mTOR信号通路与胃癌发生、发展关系[J].中国医学创新,2017,14(8):138-40.
[8] Riquelme I,Tapia O,Espinoza J A,et al.The gene expression status of the PI3K/AKT/mTOR pathway in gastric cancer tissues and cell lines[J].Pathol Oncol Res,2016,22(4):797-805.
[9] Wang W,Zheng C,Fang C,et al.Time trends of clinicopathologic features and surgical treatment for gastric cancer:results from 2 high-volume institutions in southern China[J].Surgery,2015,158(6):1590-7.
[10] Samarin J,Laketa V,Malz M,et al.PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells[J].Hepatology,2016,63(3):813-26.
[11] Chen H,Guan R,Lei Y,et al.Lymphangiogenesis in gastric cancer regulated through Akt/mTOR-VEGF-C/VEGF-D axis[J].BMC Cancer,2015,15:103.
[12] 潘理会,张平,李春辉.PI3K/AKT/mTOR信号传导通路在胃癌中的研究进展[J].承德医学院学报,2016,33(4):324-7.
[13] Rodrigues F A,Bomfim I S,Cavalcanti B C,et al.Mefloquine-oxazolidine derivatives:a new class of anticancer agents[J].Chem Biol Drug Des,2014,83(1):126-31.
[14] Liu Y,Chen S,Xue R,et al.Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of PI3K/Akt/mTOR signaling pathway[J].Biochem Biophys Res Commun,2016,470(2):350-5.