抗肝癌及逆转MDR中药成分多靶点筛选方法建立的实验研究
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摘要
目的在转录水平上建立抗肝癌及逆转MDR中药的多靶点高通量筛选方法。
方法采用体外培养人肝癌细胞BEL-7402及其耐5-氟尿嘧啶细胞Bel-FU,MTT法检测Bel-FU的多药耐药性、5种中药成分的(槲皮素、EGCG、老鼠簕生物碱A、乙酰老鼠簕生物碱A、龙血素B)细胞敏感性以及药物浓度依赖的逆转耐药性;选择与肝癌发生发展相关途径的42个功能基因,采用实时定量PCR微阵列技术检测各中药成分作用于耐药细胞前后的差异表达基因,实时定量PCR检测槲皮素、EGCG、乙酰老鼠簕生物碱A分别作用于Bel-FU后H-ras、MDR1基因表达,以验证微阵列结果。
结果Bel-FU对5-氟尿嘧啶、阿糖胞苷、长春新碱、阿霉素、柔红霉素的耐药指数分别为:89.6、3.4、37.2、16.5、3.7倍。槲皮素、EGCG、老鼠簕生物碱A、乙酰老鼠簕生物碱A、龙血素B对Bel-FU的IC50值分别为193.9μM、1230.8μM、507.8μM、244.9μM、163.7μM,对Bel-FU的IC10值分别为58.2μM、159.5μM、75.3μM、64.7μM、25.8μM。43.6、87.2、130.8μM的EGCG对Bel-FU的耐药逆转倍数分别为1.04、1.36、2.10倍;16.5、33、49.5μM的槲皮素对Bel-FU的耐药逆转倍数分别为1.14、1.68、2.38倍;13.2、33、66μM的老鼠簕生物碱A对Bel-FU的耐药逆转倍数分别为1.13、1.54、1.33倍;21、42、63μM的乙酰老鼠簕生物碱A对Bel-FU的耐药逆转倍数分别为1.26、1.78、1.42倍;6、12、24μM的龙血素B对细胞Bel-FU耐药逆转倍数分别为2.25、3.80、5.76倍;阳性对照剂VRP(5μg·mL-1)则为1.11倍。与Bel-7402比较,Bel-FU中的基因H-ras、Bcl-2、PDGFA、MDR1、BCRP表达上调(P<0.05),cyclinB1下调(P<0.05);槲皮素下调Bel-FU中基因H-ras、EGFR、FGF、VEGFA、PDGFA、MDR1、Erk1的表达(P<0.05);EGCG下调Bel-FU中基因H-ras、EGFR、PDGFA、MDR1、VEGFA的表达(P<0.05);乙酰老鼠簕生物碱A下调基因H-ras、VEGFA、PDGFA、C-myc、NF-κB的表达(P<0.05),老鼠簕生物碱A与龙血素B均下调Wnt1、VEGFA的表达(P<0.05)。实时定量PCR结果:槲皮素、EGCG均下调Bel-FU中基因H-ras、MDR1表达(P<0.05),乙酰老鼠簕生物碱A下调Bel-FU中基因H-ras的表达(P<0.05)。
结论定量PCR微阵列可作为在转录水平上进行抗肝癌及逆转MDR中药多靶点高通量筛选的方法。
目的通过筛选三种中药成分作用于人肝细胞癌MDR细胞前后表达差异的蛋白质点,在检测靶蛋白水平上建立抗肝癌及逆转MDR中药筛选方法。
方法采用2-DE及MALDI-TOF-MS技术,检测肝癌敏感细胞Bel-7402与耐药细胞Bel-FU之间的差异蛋白以及三种中药成分作用于Bel-FU前后的差异蛋白,差异倍数为2.5倍以上者定义为差异蛋白。Western blot法检测三种中药成分作用于Bel-FU后蛋白P-gp、FAK、CRT表达。
结果与Bel-7402比较, Bel-FU中有24个蛋白表达上调,其中包括FAK、TM3、ORP150、CRT、NSE、80K-H protein、EF-1-D、phosphoprotein等,12个蛋白表达下调;EGCG作用Bel-FU后,下调蛋白FAK、CRT、TM3、80K-H protein、EF-1-D的表达;槲皮素作用Bel-FU后,下调蛋白phosphoprotein、CRT、TM3、EF-1-D的表达;乙酰老鼠簕生物碱A作用Bel-FU后下调蛋白FAK、80K-H protein、CRT、TM3的表达。Western blot检测结果:EGCG、槲皮素均下调P-gp在Bel-FU中的表达(P < 0.05)。EGCG、乙酰老鼠簕生物碱A下调Bel-FU中的FAK的表达(P < 0.05)。经三种中药成分作用后,Bel-FU中的CRT表达均下调。
结论EGCG、槲皮素、乙酰老鼠簕生物碱A均具有逆转Bel-FU MDR的作用。运用蛋白质组学技术检测与逆转MDR相关的蛋白质差异表达为MDR逆转剂筛选提供了一个高通量的平台。
Objective To establish a high throughput and multi-target method for screening traditional Chinese medicine as to anti-hepatocellular carcinoma and reversing MDR in the course of genetic transcription .
Methods Human hepatocellular carcinoma cell line Bel-7402 and 5-FU resistant cell line Bel-FU were cultured in vitro. The multidrug resistance(MDR) of Bel-FU ,drug sensitivity of 5 kinds of traditional Chinese medicine(quercetin,EGCG,IA , ACO-IA,loureirin B)to Bel-FU and their dose-dependen reversal effects were determined by Methyl thiazolyl tetrazolium (MTT) assay.To confine the scope of the hepatocarcinogenesis, 42 gene expression profiles in Bel-FU were detected by q-PCR microarray before and after treatment of traditional Chinese medicine. Then the gene expression of H-ras,MDR1 in Bel-FU treated with quercetin,EGCG, ACO-IA respectively were detected by real-time quantitative PCR to confirm the results of q-PCR microarray.
Results In Bel-FU the resistance index (IR)of 5-fluorouracil ,cytarabine, vincristin, doxorubicin, daunorubicin were 89.6,3.4,37.1, 15.0, 3.7respectively. The 50% inhibitory concentration(IC50) of quercetin ,EGCG ,IA ,ACO-IA and loureirin B were 193.9μM,1230.8μM,507.8μM,244.9μΜ,163.7μΜrespectively. The 10% inhibitory concentration(IC10) were 58.2μM,159.5μM,75.3μM, 64.7μM, 25.8μM respectively. 43.6,87.2,130.8μM EGCG reversed the MDR by 1.04,1.36,2.10 folds respectively .16.5,33,49.5μM quercetin reversed the MDR by 1.14,1.68,2.38 folds respectively . 13.2,33,66μM IA reversed the MDR by 1.13,1.54,1.33 folds respectively . 21,42,63μM ACO-IA reversed the MDR by 1.44, 2.87, 1.76 folds respectively . 6, 12, 24μM loureirin B reversed the MDR by 2.25,3.80,5.76 folds respectively . Positive control VRP(5μg·mL-1)was 1.11 folds .Compared with those in Bel-7402, the gene expression of H-ras,Bcl-2,PDGFA,MDR1,BCRP were up-regulated (P<0.05)and cyclinB1 was down-regulated in Bel-FU(P<0.05). H-ras,EGFR,FGF,VEGFA,PDGFA,MDR1,Erk1 were down-regulated in Bel-FU treated with quercetin(P<0.05). The gene expression of H-ras,EGFR,PDGFA,MDR1,VEGFA were down-regulated in Bel-FU treated with EGCG(P<0.05). The gene expression of H-ras, VEGFA,PDGFA,C-myc,NF-κB were down-regulated in Bel-FU treated with ACO-IA ( P < 0.05 ) . The gene expression of Wnt1,VEGFA were down-regulated in Bel-FU treated with both IA and loureirin B(P<0.05). Real-time quantitative PCR showed that quercetin and EGCG could down-regulate the gene expression of H-ras,MDR1 in Bel-FU(P<0.05),then ACO-IA just could down-regulate the gene expression of H-ras in Bel-FU(P<0.05).
Conclusion qPCR microarray is a high throughput and multi-target method for screening traditional Chinese medicine as to anti-hepatocellular carcinoma and reversing MDR in the course of genetic transcription .
Objective To screen differentially expressed proteins in the human HCC MDR cell line before and after treatment of 3 kinds of traditional Chinese medicine respectively,to found a method for screening traditional Chinese medicine as to anti-hepatocellular carcinoma and reversing MDR by detecting target protein.
Methods Detected the differentially expressed proteins between human hepatocellular carcinoma sensitive cell line Bel-7402 and drug -resistant cell line Bel-FU,and that in Bel-FU treated by 3 kinds of traditional Chinese medicine respectively.Differentially expressed proteins were defined as whose absolute ratio values were greater than 2.5. Western blot was used to detect the expression of P-gp ,FAK and CRT in Bel-FU treated with 3 kinds of traditional Chinese medicine.
Results Compared with that in Bel-7402,24 proteins expression were up-regulated , including FAK,TM3,ORP150,CRT,NSE ,80K-H protein,EF-1-D,phosphoprotein and so on ,then 12 were down-regulated in Bel-FU.EGCG could down-regulate the proteins expression of FAK,CRT,TM3,80K-H protein,EF-1-D. quercetin could down-regulate the proteins expression of phosphoprotein,CRT,TM3,EF-1-D. COA-IA could down-regulate the proteins expression of FAK,80K-H protein,CRT,TM3 in Bel-FU. The results of Western blot showed that both EGCG and quercetin could down-regulate the proteins expression of P-gp(P < 0.05), EGCG and COA-IA could down-regulate the proteins expression of FAK(P < 0.05), 3 kinds of traditional Chinese medicine could down-regulate the proteins expression of CRT(P < 0.05).
Conclusion EGCG , quercetin and COA-IA can reverse the MDR of HCC .Detecting protein differential expression as to anti-HCC and reversing MDR by proteomics technique provides a platform for high throughput drug screen.
方法采用体外培养人肝癌细胞BEL-7402及其耐5-氟尿嘧啶细胞Bel-FU,MTT法检测Bel-FU的多药耐药性、5种中药成分的(槲皮素、EGCG、老鼠簕生物碱A、乙酰老鼠簕生物碱A、龙血素B)细胞敏感性以及药物浓度依赖的逆转耐药性;选择与肝癌发生发展相关途径的42个功能基因,采用实时定量PCR微阵列技术检测各中药成分作用于耐药细胞前后的差异表达基因,实时定量PCR检测槲皮素、EGCG、乙酰老鼠簕生物碱A分别作用于Bel-FU后H-ras、MDR1基因表达,以验证微阵列结果。
结果Bel-FU对5-氟尿嘧啶、阿糖胞苷、长春新碱、阿霉素、柔红霉素的耐药指数分别为:89.6、3.4、37.2、16.5、3.7倍。槲皮素、EGCG、老鼠簕生物碱A、乙酰老鼠簕生物碱A、龙血素B对Bel-FU的IC50值分别为193.9μM、1230.8μM、507.8μM、244.9μM、163.7μM,对Bel-FU的IC10值分别为58.2μM、159.5μM、75.3μM、64.7μM、25.8μM。43.6、87.2、130.8μM的EGCG对Bel-FU的耐药逆转倍数分别为1.04、1.36、2.10倍;16.5、33、49.5μM的槲皮素对Bel-FU的耐药逆转倍数分别为1.14、1.68、2.38倍;13.2、33、66μM的老鼠簕生物碱A对Bel-FU的耐药逆转倍数分别为1.13、1.54、1.33倍;21、42、63μM的乙酰老鼠簕生物碱A对Bel-FU的耐药逆转倍数分别为1.26、1.78、1.42倍;6、12、24μM的龙血素B对细胞Bel-FU耐药逆转倍数分别为2.25、3.80、5.76倍;阳性对照剂VRP(5μg·mL-1)则为1.11倍。与Bel-7402比较,Bel-FU中的基因H-ras、Bcl-2、PDGFA、MDR1、BCRP表达上调(P<0.05),cyclinB1下调(P<0.05);槲皮素下调Bel-FU中基因H-ras、EGFR、FGF、VEGFA、PDGFA、MDR1、Erk1的表达(P<0.05);EGCG下调Bel-FU中基因H-ras、EGFR、PDGFA、MDR1、VEGFA的表达(P<0.05);乙酰老鼠簕生物碱A下调基因H-ras、VEGFA、PDGFA、C-myc、NF-κB的表达(P<0.05),老鼠簕生物碱A与龙血素B均下调Wnt1、VEGFA的表达(P<0.05)。实时定量PCR结果:槲皮素、EGCG均下调Bel-FU中基因H-ras、MDR1表达(P<0.05),乙酰老鼠簕生物碱A下调Bel-FU中基因H-ras的表达(P<0.05)。
结论定量PCR微阵列可作为在转录水平上进行抗肝癌及逆转MDR中药多靶点高通量筛选的方法。
目的通过筛选三种中药成分作用于人肝细胞癌MDR细胞前后表达差异的蛋白质点,在检测靶蛋白水平上建立抗肝癌及逆转MDR中药筛选方法。
方法采用2-DE及MALDI-TOF-MS技术,检测肝癌敏感细胞Bel-7402与耐药细胞Bel-FU之间的差异蛋白以及三种中药成分作用于Bel-FU前后的差异蛋白,差异倍数为2.5倍以上者定义为差异蛋白。Western blot法检测三种中药成分作用于Bel-FU后蛋白P-gp、FAK、CRT表达。
结果与Bel-7402比较, Bel-FU中有24个蛋白表达上调,其中包括FAK、TM3、ORP150、CRT、NSE、80K-H protein、EF-1-D、phosphoprotein等,12个蛋白表达下调;EGCG作用Bel-FU后,下调蛋白FAK、CRT、TM3、80K-H protein、EF-1-D的表达;槲皮素作用Bel-FU后,下调蛋白phosphoprotein、CRT、TM3、EF-1-D的表达;乙酰老鼠簕生物碱A作用Bel-FU后下调蛋白FAK、80K-H protein、CRT、TM3的表达。Western blot检测结果:EGCG、槲皮素均下调P-gp在Bel-FU中的表达(P < 0.05)。EGCG、乙酰老鼠簕生物碱A下调Bel-FU中的FAK的表达(P < 0.05)。经三种中药成分作用后,Bel-FU中的CRT表达均下调。
结论EGCG、槲皮素、乙酰老鼠簕生物碱A均具有逆转Bel-FU MDR的作用。运用蛋白质组学技术检测与逆转MDR相关的蛋白质差异表达为MDR逆转剂筛选提供了一个高通量的平台。
Objective To establish a high throughput and multi-target method for screening traditional Chinese medicine as to anti-hepatocellular carcinoma and reversing MDR in the course of genetic transcription .
Methods Human hepatocellular carcinoma cell line Bel-7402 and 5-FU resistant cell line Bel-FU were cultured in vitro. The multidrug resistance(MDR) of Bel-FU ,drug sensitivity of 5 kinds of traditional Chinese medicine(quercetin,EGCG,IA , ACO-IA,loureirin B)to Bel-FU and their dose-dependen reversal effects were determined by Methyl thiazolyl tetrazolium (MTT) assay.To confine the scope of the hepatocarcinogenesis, 42 gene expression profiles in Bel-FU were detected by q-PCR microarray before and after treatment of traditional Chinese medicine. Then the gene expression of H-ras,MDR1 in Bel-FU treated with quercetin,EGCG, ACO-IA respectively were detected by real-time quantitative PCR to confirm the results of q-PCR microarray.
Results In Bel-FU the resistance index (IR)of 5-fluorouracil ,cytarabine, vincristin, doxorubicin, daunorubicin were 89.6,3.4,37.1, 15.0, 3.7respectively. The 50% inhibitory concentration(IC50) of quercetin ,EGCG ,IA ,ACO-IA and loureirin B were 193.9μM,1230.8μM,507.8μM,244.9μΜ,163.7μΜrespectively. The 10% inhibitory concentration(IC10) were 58.2μM,159.5μM,75.3μM, 64.7μM, 25.8μM respectively. 43.6,87.2,130.8μM EGCG reversed the MDR by 1.04,1.36,2.10 folds respectively .16.5,33,49.5μM quercetin reversed the MDR by 1.14,1.68,2.38 folds respectively . 13.2,33,66μM IA reversed the MDR by 1.13,1.54,1.33 folds respectively . 21,42,63μM ACO-IA reversed the MDR by 1.44, 2.87, 1.76 folds respectively . 6, 12, 24μM loureirin B reversed the MDR by 2.25,3.80,5.76 folds respectively . Positive control VRP(5μg·mL-1)was 1.11 folds .Compared with those in Bel-7402, the gene expression of H-ras,Bcl-2,PDGFA,MDR1,BCRP were up-regulated (P<0.05)and cyclinB1 was down-regulated in Bel-FU(P<0.05). H-ras,EGFR,FGF,VEGFA,PDGFA,MDR1,Erk1 were down-regulated in Bel-FU treated with quercetin(P<0.05). The gene expression of H-ras,EGFR,PDGFA,MDR1,VEGFA were down-regulated in Bel-FU treated with EGCG(P<0.05). The gene expression of H-ras, VEGFA,PDGFA,C-myc,NF-κB were down-regulated in Bel-FU treated with ACO-IA ( P < 0.05 ) . The gene expression of Wnt1,VEGFA were down-regulated in Bel-FU treated with both IA and loureirin B(P<0.05). Real-time quantitative PCR showed that quercetin and EGCG could down-regulate the gene expression of H-ras,MDR1 in Bel-FU(P<0.05),then ACO-IA just could down-regulate the gene expression of H-ras in Bel-FU(P<0.05).
Conclusion qPCR microarray is a high throughput and multi-target method for screening traditional Chinese medicine as to anti-hepatocellular carcinoma and reversing MDR in the course of genetic transcription .
Objective To screen differentially expressed proteins in the human HCC MDR cell line before and after treatment of 3 kinds of traditional Chinese medicine respectively,to found a method for screening traditional Chinese medicine as to anti-hepatocellular carcinoma and reversing MDR by detecting target protein.
Methods Detected the differentially expressed proteins between human hepatocellular carcinoma sensitive cell line Bel-7402 and drug -resistant cell line Bel-FU,and that in Bel-FU treated by 3 kinds of traditional Chinese medicine respectively.Differentially expressed proteins were defined as whose absolute ratio values were greater than 2.5. Western blot was used to detect the expression of P-gp ,FAK and CRT in Bel-FU treated with 3 kinds of traditional Chinese medicine.
Results Compared with that in Bel-7402,24 proteins expression were up-regulated , including FAK,TM3,ORP150,CRT,NSE ,80K-H protein,EF-1-D,phosphoprotein and so on ,then 12 were down-regulated in Bel-FU.EGCG could down-regulate the proteins expression of FAK,CRT,TM3,80K-H protein,EF-1-D. quercetin could down-regulate the proteins expression of phosphoprotein,CRT,TM3,EF-1-D. COA-IA could down-regulate the proteins expression of FAK,80K-H protein,CRT,TM3 in Bel-FU. The results of Western blot showed that both EGCG and quercetin could down-regulate the proteins expression of P-gp(P < 0.05), EGCG and COA-IA could down-regulate the proteins expression of FAK(P < 0.05), 3 kinds of traditional Chinese medicine could down-regulate the proteins expression of CRT(P < 0.05).
Conclusion EGCG , quercetin and COA-IA can reverse the MDR of HCC .Detecting protein differential expression as to anti-HCC and reversing MDR by proteomics technique provides a platform for high throughput drug screen.
引文
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[27]赵杨,郭科军,张颐,等.细胞外信号调节激酶在卵巢癌中的表达及临床意义[J].中国肿瘤临床,2006,33(17):978-981.
[28]姚凡,金锋,樊华,等.ERK信号传导抑制逆转大肠癌多药耐药的研究[J].中国肿瘤临床,2005,32(5):290-291.
[29]荆薇,张晔,刘云鹏.ERK通路对胃癌细胞顺铂敏感性的调节作用[J].世界华人消化杂志,2009,17(28):2931-2935.
[30] G Galizia, E Lieto, F Ferraraccio, et al. Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery[J]. Ann Surg Oncol, 2006. 13(6): 823-835.
[31]杨冬艳,张宏宇,孔晓霞白血病耐药细胞中多药耐药基因MDR1与核转录因子κB的关系[J].吉林大学学报(医学版),2009,35(4):650-655.
[32] Azab SS,Salama SA,Abdel-Naim AB,et al.2-Methoxye-stradiol and multidrug resistance:can2-methoxyestradiol chemosensitize resistant breast cancer cells? [J].Breast Cancer ResTreat.2008,113(1):9-19.
[33] Cengiz E, Karaca B, Kucukzeybek Y, et al. Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination[J]. Mol Biol Rep ,2010, 37:1269- 1277.
[1] Van Nimwegen MJ, Huigsloot M, Camier A, et al. Focal adhesion kinase and protein kinase B cooperate to suppress doxorubicin induced apoptosis of breast tumor cells [J]. Mol Pharmacol, 2006 , 70( 4) : 1330 .
[2] SchmitzKJ, GrabellusF, CalliesR, et al .High expression of focal adhesion kinase (p125FAK) in node-negative breast cancer is related to over expression of HER-2 /neu and activatedAktkinase butdoes not predict outcome[ J]. Breast Cancer Res, 2005, 7 (2): 194-203.
[3] Michael JBouchard, LihuaWang, Robert JSchneider, et al .Activation of focal adhesion kinase by hepatitisB virus HBx protein: multiple functions in viral replication[J]. J Viro,l 2006, 80(9): 4406-4414. [ 4] Wu ZM, Yuan XH, Jiang PC, et al .Antisense oligonucleodes targeting the focal adhesion kinase inhibit prolif eration, induce apoptosis and cooperat e with cyt ot oxic drugs in human glioma cells [J].Neurooncol, 2006, 77(2) : 117.
[5] ZHOU Hai-Jun, HEI Zhen-Yu,SHI Jiong, ,Over expression and Effect on Apoptosis of the 150-ku Oxygen-regulated Protein(ORP150) in Human Hepatocellular Carcinoma [J].Progress in Biochemistry and Biophysics 2009,36(10):1275-1282.
[6] N Chignard, S Shang, H Wang, et al. Cleavage of Endoplasmic ReticulumProteins in Hepatocellular Carcinoma: Detection of Generated Fragments in Patient Sera.Gastroenterology, 2006, 130: 2010- 2022.
[7]孙明莉,李薇,张一琼.原肌球蛋白、丙酮酸激酶在急性早幼粒细胞白血病耐药细胞中表达上调.中国实验诊断学,2007,11(3):388-390.
[8]叶丽虹,秦宵然,张晓东.原肌球蛋白、波形纤维蛋白和热休克蛋白70在肝癌转移亚细胞中表达上调.中国生物化学与分子生物学报,2005,21(2):244-249.
[9] Mandal M, Vadlamudi R, Nguyen D, et al. Growth factors regulate heterogeneous nuclear ribonucleoprotein K expression and function [J] . J Biol Chem, 2001, 276( 13) : 9699- 9704.
[10] Bomsztyk I,Denisenko O,Ostrowski J.hnRNP K:one protein multiple processes [J].Bioessays,2000,26(6):629-638.
[11] Brendel C, Rehbein M, Kreienkamp HJ, et al. Characterization of Staufen 1 ribonucleoprotein complexes [J].Biochem J,2004, 384 (2): 239-246 .
[12] Laury-Kleintop LD, Tresini M, Ostrowski J. Compartmentalization of hnRNP-K during cell cycle progression and its interaction with calponin in the cytoplasm [J]. Cell Biochem, 2005, 95(5) : 1042-1056.
[13] Moumen A,Masterson P,O'Connor M J,et a1.hnRNPK:all HDM2 target and transcriptional coactivator of p53 in response to DNA damage [J].Cell,2005,123(6):1065-1078.
[14] Tsui KH, Cheng AJ, Chang PL, et al. Association of nucleo- phosmin /B23 mRNA expression with clinical outcome in patients with bladdercarcinoma [J]. Urology, 2004, 64 (4) : 839 - 844.
[15] Hsu CY, Yung BY. Over-expression of nucleophosmin /B23 decreases the suscep tibility of human leukemia HL260 cells to retinoic acid-induced differentiation and apop tosis [J]. Int J Cancer, 2000, 88 (3) : 392 - 400.
[16] Meera P.Shuji N,Matthias S,et a1.LXNp63 induces-catenin nuclearaccunlulation and signaling [J].Cancer Cel1,2002,1(4):369-379.
[17] Madeleine G. Crista H,Collins M .et aZ.Role for PP2A in signaling to p53[J].PNAS.2004 ,101(39):14063-14066.
[1] Snowden M, Green DV. The impact of diversity-based, high-throughput screening on drug discovery:“chance favours the prepared mind”[J]. Curr Opin Drug Discov Devel. 2008, 11(4): 553-558.
[2]杜冠华.高通量药物筛选模型和常用技术方法.高通量药物筛选,化学工业出版社[J].2002, 66-87.
[3] Carnero A. High throughput screening in drug discovery[J]. Clin Transl Oncol, 2006, 8(7): 482-490.
[4] Macarron R. Critical review of the role of HTS in drug discovery[J]. Drug Discov Today, 2006, 11(7-8): 277-279.
[5]杜冠华.高通量药物筛选在新药研究中的应用[J].基础医学与临床.2001,21(4):289-293.
[6] Mishra KP, Ganju L, Sairam M, et al. A review of high throughput technology for the screening of natural products[J]. Biomed Pharmacother, 2008, 62(2):94-97
[7]郭涛.药物研究与开发[M].人民卫生出版社,2007,1.
[8] Tian H, Luo H, Chang DC, Luo KQ. A high throughput drug screen based on fluorescence resonance energy transfer (FRET) for anticancer activity of compounds from herbal medicine[J]. Br J Pharmacol, 2007, 150(3): 321-334.
[9] Abdulhalim I, Zourob M, Lakhtakia A. Surface plasmon resonance for biosensing: a mini-review[J]. Electromagnetics, 2008, 28(3): 214-242
[10] Schou C,Heegaard NH.Recent applications of affinity interactions in capillary electrophoresis. Electrophoresis, 2006, 27(1): 44-59.
[11] Dunlop J, Bowlby M, Peri R, Vasilyev D, Arias R. High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology[J]. Nat Rev Drug Discov, 2008, 7(4): 358-368.
[12] BAINS W,SMITH GC.A novel method for nucleic acid sequencedetermination[J].J Theor Biol,1988,135:303-307.
[13] FODOR SPA,READ JL,PIRRUNG MC,et al. Light-di-rected,spatially addressable parallel chemical synthesis[J]. Science,1991,251(4995):767-773.。
[14] Wang JJ, Li BW, Cheng J, et al .Up-regulat ing effects of glycyrrhizin on interleukin- 18 gene expression by cDNA microarray [J] World Chin J Digestol (Chin) , 2004 , 12(4) : 855- 858.
[15] Iizuka N , Oka M, Yamamoto K, et al. Ident ification of common or distinct genes related t o antitumor activities of a medicinal herb and its major component by ol igonucleot ide microarray[J] Int J Cancer, 2003, 107( 4) : 666- 672.
[16] Kiviharju TM, Lecane PS, Sellers RG, et al.Antiproliferative and proapopt otic activit ies of triptolide ( PG490) , a natural product entering clinical trials, on primary cultures of human prost atic epithelial cells[J] Clin Cancer Res, 2002, 8( 8) , 2666- 2674.
[17]邹明瑾,杨美香,郭文静,等.基因芯片技术在研究中药分子作用机制中的应用[J].山东大学学报, 2005,43(7) :653 -565.
[18]强兆艳,汤华,李欣.cDNA基因芯片对人胶质瘤组织原发性耐药相关基因的筛查[J].中国肿瘤生物治疗杂志.2008,15(4):369-373.
[19]周向东,钱桂生,刘凌志.采用基因芯片技术筛选人小细胞肺癌SH77/CDDP多药耐药相关基因表达谱的研究[J].第三军医大学学报. 2007 ,29(4):279-283.
[20]黄美兰,冉志华,邹健.羟基喜树碱耐药结肠癌细胞株SW1116/HCPT肿瘤耐药相关基因的表达[J].肿瘤,2007,27(2) :96-100.
[21]唐海桦,周铭,梁钢.表没食子儿茶素没食子酸酯对两株不同肝癌耐药细胞株基因表达谱的影响[J].癌症,2008,27(10):1056-1064.
[22]徐珊,罗莉,朱利群.4′-甲醚-黄芩素对绒癌耐药细胞株多药耐药性的逆转作用研究[J].生物化学与生物物理进展,2006,33(11): 1061-1073.
[23]侯丽,刘雪强,陈信义等.利用基因芯片技术研究乌头碱抗KBv200细胞耐药机制[J].中国中医药信息杂志,2005, 2(12):34-36.
[24] Labbozzetta M,Notarbartolo M,Pomoa Poma P,et al.Curcuminas a possible lead compound against hormone-indendent, Multidrug Resistance breast cancer[J].Ann N Y Acad Sci,2009,1155:278-283.
[25]陈晓松,包明红,梅晓冬.粉防己碱对人口腔上皮癌多药耐药KB-MRP1细胞株多药耐药性的逆转作用[J].癌症,2007,26(8):846-850
[26]何璐璐,符仁义等.槲皮素逆转K562、K562/ADM细胞耐药性研究[J].实用儿科临床杂志,2006,21(21):1491-1494.
[27]陈春美,杨卫忠,王春华.榄香烯对人脑胶质瘤U25 1/ADM耐药细胞株多药耐药性的逆转作用[ J ] .中华实验外科杂志,2006.23(4):601-603.
[28]胥雄阳,何松.苦参碱逆转人肝癌细胞株QGY/CDDP多药耐药性的实验研究.重庆医科大学学报.2008,33(4):411-413.
[29]陈英玉,郑合勇,胡建达.大黄素抑制HL60/ADR耐药细胞增殖和诱导凋亡的作用[J].中国实验血液学杂志.2007,15(5):955-960.
[30]杨春旭,韦晓谋,朱灵.蝎毒对耐药肝癌细胞株Bel-7404/ADM逆转作用研究[J].广西医科大学学报.2007,24(2),243-244.
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[32] Cengiz E, Karaca B, Kucukzeybek Y, et al. Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination[J]. Mol Biol Rep ,2010,37:1269- 1277.
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[16] Evans JD, Cornford PA, Dodson A, et al. Expression patterns of protein kinase C isoenzymes are characteristically modulated in chronic pancreatitis and pancreatic cancer [ J ]. Am J Clin Pathol,2003, 119 (3) : 392–402.
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[23]周源,凌贤龙.人肝癌顺铂耐药细胞系SK-Hep1/CDDP的建立[J].《癌症》,2010,29(2):176-181.
[24]王晓庆,梁中琴,顾振纶,等.槲皮素抑制血管生成作用的实验研究[J].中国药理学通报,2004,20(10):1161-1164.
[25] RANELLETTI FO,MAGGIANO N,SERRA FG,et al.Quercetin inhibits p21 RAS expression in human colon cancer cell lines and in primary colorectal tumors[J].Int J cancer,2000,85(3):438-445.
[26]陈华,郑军.槲皮素对HepG2细胞的抑制作用及对耐药基因和P-糖蛋白的影响[J].检验医学与临床,2010,7(9):791-794.
[27]赵杨,郭科军,张颐,等.细胞外信号调节激酶在卵巢癌中的表达及临床意义[J].中国肿瘤临床,2006,33(17):978-981.
[28]姚凡,金锋,樊华,等.ERK信号传导抑制逆转大肠癌多药耐药的研究[J].中国肿瘤临床,2005,32(5):290-291.
[29]荆薇,张晔,刘云鹏.ERK通路对胃癌细胞顺铂敏感性的调节作用[J].世界华人消化杂志,2009,17(28):2931-2935.
[30] G Galizia, E Lieto, F Ferraraccio, et al. Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery[J]. Ann Surg Oncol, 2006. 13(6): 823-835.
[31]杨冬艳,张宏宇,孔晓霞白血病耐药细胞中多药耐药基因MDR1与核转录因子κB的关系[J].吉林大学学报(医学版),2009,35(4):650-655.
[32] Azab SS,Salama SA,Abdel-Naim AB,et al.2-Methoxye-stradiol and multidrug resistance:can2-methoxyestradiol chemosensitize resistant breast cancer cells? [J].Breast Cancer ResTreat.2008,113(1):9-19.
[33] Cengiz E, Karaca B, Kucukzeybek Y, et al. Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination[J]. Mol Biol Rep ,2010, 37:1269- 1277.
[1] Van Nimwegen MJ, Huigsloot M, Camier A, et al. Focal adhesion kinase and protein kinase B cooperate to suppress doxorubicin induced apoptosis of breast tumor cells [J]. Mol Pharmacol, 2006 , 70( 4) : 1330 .
[2] SchmitzKJ, GrabellusF, CalliesR, et al .High expression of focal adhesion kinase (p125FAK) in node-negative breast cancer is related to over expression of HER-2 /neu and activatedAktkinase butdoes not predict outcome[ J]. Breast Cancer Res, 2005, 7 (2): 194-203.
[3] Michael JBouchard, LihuaWang, Robert JSchneider, et al .Activation of focal adhesion kinase by hepatitisB virus HBx protein: multiple functions in viral replication[J]. J Viro,l 2006, 80(9): 4406-4414. [ 4] Wu ZM, Yuan XH, Jiang PC, et al .Antisense oligonucleodes targeting the focal adhesion kinase inhibit prolif eration, induce apoptosis and cooperat e with cyt ot oxic drugs in human glioma cells [J].Neurooncol, 2006, 77(2) : 117.
[5] ZHOU Hai-Jun, HEI Zhen-Yu,SHI Jiong, ,Over expression and Effect on Apoptosis of the 150-ku Oxygen-regulated Protein(ORP150) in Human Hepatocellular Carcinoma [J].Progress in Biochemistry and Biophysics 2009,36(10):1275-1282.
[6] N Chignard, S Shang, H Wang, et al. Cleavage of Endoplasmic ReticulumProteins in Hepatocellular Carcinoma: Detection of Generated Fragments in Patient Sera.Gastroenterology, 2006, 130: 2010- 2022.
[7]孙明莉,李薇,张一琼.原肌球蛋白、丙酮酸激酶在急性早幼粒细胞白血病耐药细胞中表达上调.中国实验诊断学,2007,11(3):388-390.
[8]叶丽虹,秦宵然,张晓东.原肌球蛋白、波形纤维蛋白和热休克蛋白70在肝癌转移亚细胞中表达上调.中国生物化学与分子生物学报,2005,21(2):244-249.
[9] Mandal M, Vadlamudi R, Nguyen D, et al. Growth factors regulate heterogeneous nuclear ribonucleoprotein K expression and function [J] . J Biol Chem, 2001, 276( 13) : 9699- 9704.
[10] Bomsztyk I,Denisenko O,Ostrowski J.hnRNP K:one protein multiple processes [J].Bioessays,2000,26(6):629-638.
[11] Brendel C, Rehbein M, Kreienkamp HJ, et al. Characterization of Staufen 1 ribonucleoprotein complexes [J].Biochem J,2004, 384 (2): 239-246 .
[12] Laury-Kleintop LD, Tresini M, Ostrowski J. Compartmentalization of hnRNP-K during cell cycle progression and its interaction with calponin in the cytoplasm [J]. Cell Biochem, 2005, 95(5) : 1042-1056.
[13] Moumen A,Masterson P,O'Connor M J,et a1.hnRNPK:all HDM2 target and transcriptional coactivator of p53 in response to DNA damage [J].Cell,2005,123(6):1065-1078.
[14] Tsui KH, Cheng AJ, Chang PL, et al. Association of nucleo- phosmin /B23 mRNA expression with clinical outcome in patients with bladdercarcinoma [J]. Urology, 2004, 64 (4) : 839 - 844.
[15] Hsu CY, Yung BY. Over-expression of nucleophosmin /B23 decreases the suscep tibility of human leukemia HL260 cells to retinoic acid-induced differentiation and apop tosis [J]. Int J Cancer, 2000, 88 (3) : 392 - 400.
[16] Meera P.Shuji N,Matthias S,et a1.LXNp63 induces-catenin nuclearaccunlulation and signaling [J].Cancer Cel1,2002,1(4):369-379.
[17] Madeleine G. Crista H,Collins M .et aZ.Role for PP2A in signaling to p53[J].PNAS.2004 ,101(39):14063-14066.
[1] Snowden M, Green DV. The impact of diversity-based, high-throughput screening on drug discovery:“chance favours the prepared mind”[J]. Curr Opin Drug Discov Devel. 2008, 11(4): 553-558.
[2]杜冠华.高通量药物筛选模型和常用技术方法.高通量药物筛选,化学工业出版社[J].2002, 66-87.
[3] Carnero A. High throughput screening in drug discovery[J]. Clin Transl Oncol, 2006, 8(7): 482-490.
[4] Macarron R. Critical review of the role of HTS in drug discovery[J]. Drug Discov Today, 2006, 11(7-8): 277-279.
[5]杜冠华.高通量药物筛选在新药研究中的应用[J].基础医学与临床.2001,21(4):289-293.
[6] Mishra KP, Ganju L, Sairam M, et al. A review of high throughput technology for the screening of natural products[J]. Biomed Pharmacother, 2008, 62(2):94-97
[7]郭涛.药物研究与开发[M].人民卫生出版社,2007,1.
[8] Tian H, Luo H, Chang DC, Luo KQ. A high throughput drug screen based on fluorescence resonance energy transfer (FRET) for anticancer activity of compounds from herbal medicine[J]. Br J Pharmacol, 2007, 150(3): 321-334.
[9] Abdulhalim I, Zourob M, Lakhtakia A. Surface plasmon resonance for biosensing: a mini-review[J]. Electromagnetics, 2008, 28(3): 214-242
[10] Schou C,Heegaard NH.Recent applications of affinity interactions in capillary electrophoresis. Electrophoresis, 2006, 27(1): 44-59.
[11] Dunlop J, Bowlby M, Peri R, Vasilyev D, Arias R. High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology[J]. Nat Rev Drug Discov, 2008, 7(4): 358-368.
[12] BAINS W,SMITH GC.A novel method for nucleic acid sequencedetermination[J].J Theor Biol,1988,135:303-307.
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