AKT抑制剂NTQ1062与Olaparib在卵巢癌细胞中的联用研究  

Effects of Combined AKT Inhibitor NTQ1062 and PARP Inhibitor Olaparib in Ovarian Cancer Cells

作　　者：李月楚 周秋华 苗雷 季晓君 马昌友 吴舰 李念光[1] 徐丹 LI Yuechu;ZHOU Qiuhua;MIAO lei;JI Xiaojun;MA Changyou;WU Jian;LI Nianguang;XU Dan(Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization,Nanjing University of Chinese Medicine,Nanjing 210023,China;Nanjing Chia-Tai Tianqing Pharmaceutical Co.,Ltd.,Nanjing 210046,China)

机构地区：[1]江苏省中药资源产业化过程协同创新中心南京中医药大学,南京210023 [2]南京正大天晴制药有限公司,南京210046

出　　处：《药学与临床研究》2024年第2期97-102,共6页Pharmaceutical and Clinical Research

基　　金：江苏省自然科学基金(BK20210055)。

摘　　要：目的:探讨AKT抑制剂NTQ1062和PARP抑制剂Olaparib的对卵巢癌细胞的联用增效可行性及作用机制。方法:研究NTQ1062和Olaparib联用对三种人卵巢癌细胞系(OVCAR-3、TOV-21G、A2780)增殖的影响,并通过Western blot技术检测PI3K/AKT信号通路及同源重组修复、DNA损伤修复相关蛋白的表达,最后使用Annexin V-FITC双染法检测细胞凋亡。结果:实验结果显示,NTQ1062对TOV-21G、A2780细胞株具有较强的增殖抑制作用,对OVCAR-3细胞增殖的抑制作用较弱,并且联合处理会增加三株卵巢癌细胞的增殖抑制作用;Western blot实验中NTQ1062增加卵巢癌细胞中AKT的磷酸化、抑制S6RP的磷酸化、增加γH2AX蛋白表达、降低RAD51蛋白表达,并发现联合处理具有协同作用;进一步研究发现,联合用药会降低TOV-21G细胞中BRCA1蛋白的表达,但对A2780细胞影响不显著;细胞凋亡实验中,NTQ1062增加细胞凋亡群,并且联合处理显著增加了细胞凋亡效果。结论:NTQ1062可抑制OVCAR-3、TOV-21G、A2780细胞增殖,与Olaparib联用具有协同作用,通过抑制PI3K/AKT通路、DNA损伤、减少同源重组修复、降低BRCA1蛋白表达、增加凋亡来发挥作用。本研究可为临床制订AKT抑制剂NTQ1062与PARP抑制剂联合应用于卵巢癌治疗策略提供理论和技术依据。Objective:To investigate the synergism and mechanism of AKT inhibitor NTQ1062 and PARP inhibitor Olaparib in ovarian cancer cells.Methods:The effects of NTQ1062 and Olaparib on the proliferation of three ovarian cancer cell lines(OVCAR-3,TOV-21G,A2780)were studied.The expression of proteins related to PI3K/AKT signaling pathway,homologous recombination repair and DNA damage repair were detected by Western blot.Apoptosis were detected by Annexin V-FITC double staining.Results:The results showed that NTQ1062 had strong inhibitory effects on proliferation of TOV-21G and A2780 cell lines,but had a weak inhibitory effect on proliferation of OVCAR-3 cells,and the combined treatment could increase the proliferation inhibition of the three ovarian cancer cell lines.In Western blot experiments,NTQ1062 increased the phosphorylation of AKT,inhibited the phosphorylation of S6RP,increased the expression ofγH2AX protein and decreased the expression of RAD51 protein in the ovarian cancer cells,and the combination treatment had synergistic effects;Further studies found that the combination treatment decreased the expression of BRCA1 protein in TOV-21G cells,but had no significant effect on A2780 cells.In apoptosis experiments,NTQ1062 increased apoptosis and the combination treatment significantly increased the effects of apoptosis.Conclusion:NTQ1062 can inhibit OVCAR-3,TOV-21G and A2780 cell proliferation,and has synergistic effects when combined with olaparib,which may be effective in inhibiting PI3K/AKT pathway,reducing DNA damage and homologous recombination repair,decreasing BRCA1 protein expression and increasing apoptosis.This study can provide theoretical and technical basis for the clinical formulation of AKT inhibitor NTQ1062 combining with PARP inhibitor olaparib in the treatment of ovarian cancers.

关 键 词：卵巢癌 AKT抑制剂 PARP抑制剂 联用 DNA损伤 同源重组修复 

分 类 号：R966[医药卫生—药理学]