没药甾酮下调PXR/P-gp通路逆转肝癌化疗耐药机制  

Z-guggulsterone reversed multi-drug resistance of hepatocarcinoma chemotherapy through down-regulating a PXR/P-gp pathway

作　　者：夏黄帅 余卓伦 张其海 王娟[2] 许婉婷 徐宏彬 XIA Huang-shuai;YU Zhuo-lun;ZHANG Qi-hai;WANG Juan;XU Wan-ting;XU Hong-bin(Clinical Medical College of Shanghai Tenth People′s Hospital of Nanjing Medical University,Nanjing 211166,China;Dept of Scientific Research,the Second Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210017,China;Dept of Pharmacy,Shanghai Tenth People's Hospital,Tongji University School of Medicine,Shanghai 200072,China)

机构地区：[1]南京医科大学上海十院临床医学院,江苏南京211166 [2]南京中医药大学第二附属医院科教处,江苏南京210017 [3]同济大学医学院上海市第十人民医院药学部,上海200072

出　　处：《中国药理学通报》2022年第5期684-691,共8页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81774040)。

摘　　要：目的研究没药甾酮(guggulsterone,GS)能否通过调控孕烷X受体(pregnane X receptor,PXR)/P-糖蛋白(P-glycoprotein,P-gp)通路增强化疗药物对人肝癌细胞增殖抑制和凋亡诱导作用。方法以人肝癌细胞HepG2为研究对象,检测GS、化疗药物顺铂(cis-platinum,DDP)和5-氟尿嘧啶(5-fluorouracil,5-FU)单独或联合使用对HepG2细胞增殖、凋亡、MDR1 mRNA转录,及PXR/P-gp通路的调控作用。结果与DDP、5-FU单药组相比,联用GS(30μmol·L^(-1))24 h明显增强DDP、5-FU对HepG2细胞的增殖抑制和凋亡诱导作用。与5-FU单药组相比,联用GS(30μmol·L^(-1))24 h明显下调PXR、P-gp表达和MDR1 mRNA转录水平。进一步研究发现,PXR激动剂利福平能够诱导PXR和P-gp表达,与GS联用后,PXR和P-gp明显下调;PXR抑制剂酮康唑能够抑制PXR/P-gp表达,与GS联用后,PXR和P-gp进一步下调。结论GS可通过下调PXR/P-gp通路降低肿瘤细胞对化疗药物耐药性,增强化疗药物对人肝癌细胞的增殖抑制和凋亡诱导作用。Aim To investigate the improved effects of Z-guggulsterone on the chemotherapy agents-induced proliferation and apoptosis through regulating PXR(pregnane X receptor)/P-gp(P-glycoprotein)signaling pathway in human hepatocellular carcinoma cells.Methods HepG2 cells were treated with Z-guggulsterone,DDP(cis-platinum)and 5-FU(5-fluorouracil)alone or in combination.CCK-8(Cell Counting Kit-8),AnnexinⅤ-FITC/PI(Annexin V-fluorescein isothiocyanate isomer/propidium iodide)flow cytometry,RT-qPCR(Real-time quantitively Polymerase Chain Reaction)and Western blot were used to determine cell proliferation,apoptosis,the expression of MDR1 mRNA,PXR and P-gp respectively.Results Compared to DDP or 5-FU treatment alone,Z-guggulsterone(30μmol·L^(-1)) enhanced the inhibitory effects of DDP or 5-FU on the proliferation and apoptosis of HepG2 cells.Z-guggulsterone(30μmol·L^(-1)) also significantly reduced the expression levels of PXR,P-gp and MDR1 mRNA in HepG2 cells.Further research demonstrated that rifampicin,one agonist of PXR,increased the expression of PXR and P-gp,while Z-guggulsterone reversed its effects.Meanwhile,the expressions of PXR and P-gp were reduced by ketoconazole,one antagonist of PXR,and further decreased by co-administration with Z-guggulsterone.Conclusion Z-guggulsterone can improve the effects of chemotherapy on the proliferation and apoptosis of hepatocellular carcinoma cell lines by down-regulating the PXR/P-gp signaling pathway.

关 键 词：没药甾酮 孕烷X受体 P-糖蛋白 顺铂 5-氟尿嘧啶 多药耐药 

分 类 号：R282.71[医药卫生—中药学] R329.25[医药卫生—中医学]