黄芪-莪术药对增强卡培他滨对胃癌细胞杀伤作用的生物学机制  

Biological mechanism of Astragalus membranaeus-Rhizoma curcuma on enhancing the killing effect of capecitabine on gastric cancer cells

作　　者：谭喜莹 陶靖 张宇[3] 孙程 TAN Xiying;TAO Jing;ZHANG Yu;SUN Cheng(Department of Pharmacy,Affiliated Hospital of Nanjing University of Chinese Medicine,Jiangsu Nanjing 210029,China;School of Basic Medicine and Clinical Pharmacy,China Pharmaceutical University,Jiangsu Nanjing 210009,China;School of Pharmacy,Nanjing Medical University,Jiangsu Nan-jing 211166,China)

机构地区：[1]南京中医药大学附属医院药学部,江苏南京210029 [2]中国药科大学基础医学与临床药学学院,江苏南京210009 [3]南京医科大学药学院,江苏南京211166

出　　处：《中国医院药学杂志》2025年第3期256-261,共6页Chinese Journal of Hospital Pharmacy

基　　金：国家自然科学基金项目(编号:82003961);江苏省中医药科技发展计划项目(编号:YB201921);北京医卫健康公益基金会项目(编号:YWKYQ4007)。

摘　　要：目的:探究黄芪-莪术药对对胃癌细胞中卡培他滨代谢、转化和靶点的影响,并解析黄芪-莪术协同增强卡培他滨化疗作用的潜在生物学机制。方法:采用CCK-8法评价黄芪-莪术药对与卡培他滨联用对胃癌细胞增殖的影响。采用HPLC-MS/MS检测联用后胃癌细胞中卡培他滨向5-氟尿嘧啶(5-FU)的转化效率。通过实时荧光定量PCR(RT-qPCR)和Western blot技术测定与卡培他滨-5-FU转化相关酶胞苷脱氨酶(cytidine deaminase,CDD)和胸腺嘧啶磷酸化酶(thymidine phosphorylase,TP)的mRNA与蛋白表达水平。此外,通过Western blot检测药物外排相关蛋白P-糖蛋白(P-gp)及5-FU靶酶胸苷酸合成酶(thymidylate synthetase,TS)的表达水平。结果:黄芪-莪术药对显著增强了卡培他滨对SGC7901细胞的增殖抑制作用,这一效果与黄芪-莪术药对促进细胞内卡培他滨转化为活性代谢物5-FU相关。在mRNA和蛋白质水平,黄芪-莪术药对剂量依赖性地上调了SGC7901细胞中代谢转化相关酶CDD和TP的表达。同时,黄芪-莪术药对剂量依赖性地降低了药物外排相关靶点P-gp的蛋白表达,并剂量依赖性地降低了5-FU关键作用靶点TS的蛋白表达。结论:黄芪-莪术药对能通过促进卡培他滨在胃癌细胞SGC7901中向5-FU的转化、抑制药物外排和降低TS表达,从而增强卡培他滨的抗肿瘤作用。OBJECTIVE To investigate the impact of Astragalus membranaeus-Rhizoma curcuma(HQEZ)drug pair on the metabolism,transformation,and targets of capecitabine in gastric cancer cells,and to elucidate the underlying biological mechanisms by which this drug pair synergistically enhances the chemotherapeutic effect of capecitabine.METHODS The influence of HQEZ combined with capecitabine on gastric cell proliferation was evaluated using the CCK-8 assay.High-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)was employed to assess the conversion of capecitabine to 5-fluorouracil(5-FU)in gastric cancer cells after co-administration with HQEZ.Real-time fluorescence quantitative PCR(RT-qPCR)and Western blot analyses were conducted to determine the mRNA and protein levels of 5-FU-related enzymes,cytidine deaminase(CDD)and thymidine phosphorylase(TP),respectively.Protein expressions of membrane drug efflux protein Pglycoprotein(P-gp)and 5-FU target enzyme thymidylate synthase(TS)were also examined by Western blot.RESULTS HQEZ combined with capecitabine significantly enhanced the inhibitory effect of capecitabine alone on the proliferation of SGC7901 cells,which was associated with an increase in the intracellular content of the active metabolite 5-FU derived from capecitabine.At the mRNA and protein levels,HQEZ dose-dependently upregulated metabolic transformation-related enzymes CDD and TP in SGC7901 cells.Furthermore,HQEZ dose-dependently downregulated the protein expressions of drug effluxrelated target P-gp,and the key target TS of 5-FU.CONCLUSION HQEZ can enhance the antitumor effect of capecitabine by facilitating its transformation to 5-FU in gastric cancer cells SGC7901 by reducing drug efflux to increase the concentration of 5-FU,and inhibiting the expression of TS.

关 键 词：胃癌 黄芪 莪术 药对 卡培他滨 5-氟尿嘧啶 

分 类 号：R285[医药卫生—中药学] R966[医药卫生—中医学]