丹参酮ⅡA调控孕烷X受体的转录因子活性诱导肝细胞癌细胞对分子靶向药物索拉非尼耐受  

Tanshinone ⅡA Regulates the Transcription Factor Activity of Pregnane X Receptor and Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agent Sorafenib

作　　者：唐滋贵 赵松峰[2] 王艳丽 TANG Zi-gui;ZHAO Song-feng;WANG Yan-li(Henan Medical College,Zhengzhou 451191,China;Department of Pharmacy,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China)

机构地区：[1]河南医学高等专科学校,郑州451191 [2]郑州大学第一附属医院药学部,郑州450052

出　　处：《科学技术与工程》2020年第8期3003-3010,共8页Science Technology and Engineering

摘　　要：旨在探索丹参酮ⅡA对孕烷X受体(pregnane X receptor,PXR),PXR转录因子活性的影响,确定丹参酮ⅡA诱导肝细胞癌(hepatocellular carcinoma,HCC)细胞对分子靶向药物索拉非尼等耐受的分子机制。使用系列浓度梯度的丹参酮ⅡA处理HCC细胞系MHCC97-H细胞,检测丹参酮ⅡA对PXR转录因子活性以及PXR下游耐药基因表达的影响。同时在裸鼠中利用MHCC97-H细胞建立HCC肿瘤模型,对动物给予丹参酮ⅡA后,再使用分子靶向药物索拉非尼对动物进行抗肿瘤治疗,确定丹参酮ⅡA对索拉非尼抗肿瘤作用的影响。利用液相色谱-质谱联用技术(LC-MS/MS)检测丹参酮ⅡA对MHCC97-H细胞及肿瘤组织中索拉非尼代谢与清除速率(半衰期)的影响。结果显示,丹参酮ⅡA能够在HCC细胞中诱导PXR的转录因子活性、上调PXR下游耐药相关基因CYP3A4以及MDR-1的表达、加速分子靶向药物索拉非尼在HCC细胞中的代谢与清除作用,最终诱导HCC细胞对分子靶向药物索拉非尼的耐受。这表明,丹参酮ⅡA调控孕烷X受体的转录因子活性诱导肝细胞癌细胞对索拉非尼耐受。This study aims to explore the effect of tanshinone IIA on the transcription factor activity of pregnane X receptor,and to determine the molecular mechanisms of tanshinone IIA-induced hepatocellular carcinoma(HCC)cells’resistance to the molecularly targeting agent,sorafenib.A highly aggressive HCC cell line,MHCC97-H,was treated with indicated concentrations of tanshinone IIA to detect the effect of tanshinone IIA on PXR’s transcription factor activity and PXR’s downstream/drug-resistance genes’expression.At the same time,subcutaneous HCC tumor models were established in nude mice by using MHCC97-H cells.After the administration of tanshinone IIA,animals were administered with the sorafenib to determine the effects of tanshinone IIA on sorafenib’antitumor effect.The effects of tanshinone IIA on the metabolism and clearance rate(half-life values)of sorafenib in MHCC97-H cells or HCC tumor tissues were detected by the liquid chromatography-mass spectrometry/mass spectrometry(LC-MS/MS)methods.Results show that tanshinone IIA induces the transcription factor activity of PXR in HCC cells and expression of drug-resistant related the genes,CYP3A4 and MDR-1.Treatment of tanshinone IIA accelerates the clearance of sorafenib in HCC cells and induces the resistance of HCC cells to sorafenib.Treatment of tanshinone IIA also induces the resistance of HCC cells to some other molecular targeting agents,Regorafenib,Lenvatinib,Apatinib or Anlotinib.Therefore,Tanshinone IIA regulates transcription factor activity of PXR and induces the resistance of molecular targeting agents in hepatocellular carcinoma cells.

关 键 词：肝细胞癌 丹参酮IIA 分子靶向治疗 药物耐受 

分 类 号：R966[医药卫生—药理学] R735.7[医药卫生—药学]