藤黄酸抗淋系肿瘤细胞系的作用及分子机制研究
|
摘要
第一部分藤黄酸对淋系肿瘤细胞系的细胞增殖及细胞周期的调节作用
【目的】研究藤黄酸对人急性T淋巴细胞白血病细胞株Jurkat细胞和人Burkitt淋巴瘤细胞株Raji细胞体外增殖及细胞周期的影响。
【方法】采用MTT法检测藤黄酸处理后的Jurkat细胞和Raji细胞的增殖活性,PI染色流式细胞仪检测细胞周期分布,免疫印迹检测藤黄酸对Jurkat细胞和Raji细胞Cyclin D3及Cyclin E蛋白表达的影响。
【结果】(1)藤黄酸对Jurkat和Raji细胞具有明显的增殖抑制作用,藤黄酸作用Jurkat细胞24 h,48 h,72 h的半数抑制浓度IC50分别为1.69±0.09,0.98±0.13,0.67±0.12μmol/L,P < 0.01;藤黄酸作用Raji细胞24 h,48 h,72 h的半数抑制浓度IC50分别为1.34±0.06,0.39±0.03,0.30±0.02μmol/L,P < 0.01。(2)藤黄酸呈剂量依赖式作用于Jurkat细胞和Raji细胞使细胞周期阻滞在G0/G1期,其比例分别由41.78%提高到62.72%与40.23%提高到67.30%。(3)藤黄酸以剂量依赖式降低细胞周期蛋白Cyclin D3和Cyclin E的表达。
【结论】藤黄酸能抑制Jurkat细胞和Raji细胞增殖,使Jurkat细胞和Raji细胞的细胞周期阻滞于G0/G1期。藤黄酸的细胞周期阻滞作用可能通过Cyclin D3和Cyclin E的下调有关。
第二部分藤黄酸对淋系肿瘤细胞系的细胞凋亡及抗凋亡蛋白的调控作用
【目的】研究藤黄酸对人急性T淋巴细胞白血病细胞株Jurkat细胞和人Burkitt淋巴瘤细胞株Raji细胞的诱导凋亡及抗凋亡蛋白的调控作用。
【方法】采用Annexin-V/PI双标法检测藤黄酸对Jurkat细胞和Raji细胞的诱导凋亡作用,免疫印迹检测藤黄酸对Jurkat细胞和Raji细胞抗凋亡蛋白NF-κB和Bcl-xL蛋白表达的影响。
【结果】0,1,2,3μmol/L藤黄酸处理后的Jurkat细胞的早期凋亡率分别为0.95%、2.09%、34.03%和38.30%。藤黄酸处理后的Raji细胞的早期凋亡率分别为4.21%、10.76%、16.13%和24.38%。以0,0.5,1.0,2.0,4.0μmol/L藤黄酸处理Jurkat细胞24h后,0和0.5μmol/L藤黄酸对NF-κB的表达无明显改变P>0.05,1.0、2.0及4.0μmol/L藤黄酸处理组NF-κB的表达随剂量增加而减低P<0.01;Bcl-xL呈剂量依赖性递减P<0.01。以0,0.5,1.0,2.0,4.0μmol/L藤黄酸处理Raji细胞24h后,,0和0.5μmol/L藤黄酸对Bcl-xL的表达无明显改变P>0.05,1.0、2.0及4.0μmol/L藤黄酸处理组Bcl-xL的表达随剂量增加而减低P<0.01;NF-κB呈剂量依赖性递减P<0.01。
【结论】藤黄酸能够诱导Jurkat细胞和Raji细胞凋亡,其机制可能部分通过下调抗凋亡蛋白Bcl-xL和NF-κB的表达来实现。
第三部分藤黄酸对淋系肿瘤细胞系死亡诱导清理子的调控作用
【目的】探讨藤黄酸对人急性T淋巴细胞白血病细胞株Jurkat细胞和人Burkitt淋巴瘤细胞株Raji细胞的抗癌作用的分子机理。
【方法】免疫印迹检测藤黄酸对Jurkat细胞和Raji细胞DIO-1、Caspase-3及其裂解产物p17和p20表达的影响。Hoechst33258及免疫荧光化学双标法检测藤黄酸作用下DIO-1核转位现象。
【结果】随着藤黄酸浓度的升高,Jurkat细胞和Raji细胞表达DIO-1的量先升高后降低,对应2.0μmol/L藤黄酸的DIO-1的表达量最高,虽然4.0μmol/L藤黄酸作用24h后DIO的表达较2.0μmol/L组明显降低但仍明显高于对照组;随着作用时间的延长,2.0μmol/L藤黄酸处理后,DIO-1表达量递增。pro-Caspase3片段的表达呈上升趋势且出现相应活化的Caspase3片段p17和p20。虽然两个片段在0.5μmol/L藤黄酸处理时即出现,但显著性的增高出现在2μmol/L藤黄酸组,4μmol/L藤黄酸处理组最高。藤黄酸作用Jurkat细胞和Raji细胞后,DIO-1由胞浆转位入胞核。
【结论】藤黄酸能上调DIO-1表达及与DIO-1的核转位有关。藤黄酸诱导Jurkat细胞和Raji细胞凋亡可能通过DIO-1介导,并通过Caspase 3活化来实现。
PART I Regulation of gambogic acid on cell proliferation and cell cycle of lymphoid neoplasm cell lines
【Objective】To explore the Regulation of gambogic acid on cell proliferation and cell cycle of Jurkat cells and Raji cells.
【Methods】Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl) -2,5- diphenyl- tetrazolium bromide assay. Cell cycle was exmined by PI staining thorough flow cytometry. Expressions of Cyclin D3 and Cyclin E were detected by western blotting.
【Results】GA inhibited the proliferation of Jurkat cells and Raji cells with 50% inhibitory concentration values of 1.69±0.09 (24 h), 0.98±0.13 (48 h), and 0.67±0.12 mmol/L (72 h) and 1.34±0.06 (24 h),0.39±0.03 (48 h),0.30±0.02μmol/L (72 h), respecitvely. In a dose-dependent manner, Gambogic acid arrested cell cycle of Jurkat and Raji cells at G0/G1 phase, the percentage of which increased from 41.78% to 62.72% and from 40.23% to 67.30%, respectively. Gambogic acid downregulated the expression of Cyclin D3 and Cyclin E dose and time dependently.
【Conclusion】Gambogic acid suppresses the proliferation of Jurkat cells and Raji cells and arrested cell cycle of them at G0/G1 phase. Cell cycle arrest may be through downregulation of Cyclin D3 and Cyclin E.
Part II Regulation of gambogic acid on anti-apoptotic protein of Jurkat cells and Raji cells
【Objective】To study the Regulation of gambogic acid on anti-apoptotic protein of Jurkat cells and Raji cells.
【Methods】Annexin V-fluorescein-isothiocyanate/propidium iodide were used to detect apoptosis. Expressions of Bcl-xL and NF-κB were detected by western blotting.
【Results】Treated with 0, 1.0, 2.0, and 3.0μmol/L GA for 24 h, percentages of the early apoptotic cells in the whole Jurkat population was from 0.95% and 2.09% to 34.03% and 38.30%, and that of Raja cells from 4.21% and 10.76% to 16.13% and 24.38%. Treated with 0, 0.5, 1.0, 2.0, and 4.0μmol/L GA for 24 h, expression of Bcl-xL and NF-κB was downregulated dose-dependently except Bcl-xL in Jurkat cells by 0.5μmol/L GA and NF-κB in Raji cells by 0.5μmol/L GA. There were no difference in those groups.
【Conclusion】Gambogic acid is able to induce the apoptosis of Jurkat cells and Raji cells, which is partly through the downregulation of the expression of antiapoptotic protein, Bcl-xL and NF-κB.
Part III Gambogic acid induces death inducer-obliterator 1-mediated apoptosis
【Objective】To explore the apoptosis inducing effects of GA on Jurkat cells and Raji cells and its underlying mechanism.
【Methods】Western blotting was used to study the expression of DIO-1 and pro-caspase 3, as well as 2 activated subunits: p17 and p20. The subcellular localization of DIO-1 was examined by immunofluorescence and Hoechst33258 staining.
【Results】Treated with 0, 0.5, 1.0, 2.0, and 4.0μmol/L GA for 24 h, the expression of DIO-1 increased dose-dependently and then declined, and pro-caspase 3 was cleavage into 2 subunits: p17 and p20. Treated with 2.0μmol/L GA for 0, 2, and 24h, the expression of DIO-1 increased time-dependently. GA induced the translocation of DIO-1 from cytoplasm into the nucleus in Jurkat and Raji cells.
【Conclusion】Gambogic acid upregulates the DIO-1 expression and was related to DIO-1 translocation, leading to the apoptosis of Jurkat and Raji cells. The DIO-1 expression is associated with the activation of pro-caspase 3 accompanied with the downregulation of Bcl-xL and NF-kB. DIO-1 triggered early-stage cell death in GA-treated Jurkat cells.
【目的】研究藤黄酸对人急性T淋巴细胞白血病细胞株Jurkat细胞和人Burkitt淋巴瘤细胞株Raji细胞体外增殖及细胞周期的影响。
【方法】采用MTT法检测藤黄酸处理后的Jurkat细胞和Raji细胞的增殖活性,PI染色流式细胞仪检测细胞周期分布,免疫印迹检测藤黄酸对Jurkat细胞和Raji细胞Cyclin D3及Cyclin E蛋白表达的影响。
【结果】(1)藤黄酸对Jurkat和Raji细胞具有明显的增殖抑制作用,藤黄酸作用Jurkat细胞24 h,48 h,72 h的半数抑制浓度IC50分别为1.69±0.09,0.98±0.13,0.67±0.12μmol/L,P < 0.01;藤黄酸作用Raji细胞24 h,48 h,72 h的半数抑制浓度IC50分别为1.34±0.06,0.39±0.03,0.30±0.02μmol/L,P < 0.01。(2)藤黄酸呈剂量依赖式作用于Jurkat细胞和Raji细胞使细胞周期阻滞在G0/G1期,其比例分别由41.78%提高到62.72%与40.23%提高到67.30%。(3)藤黄酸以剂量依赖式降低细胞周期蛋白Cyclin D3和Cyclin E的表达。
【结论】藤黄酸能抑制Jurkat细胞和Raji细胞增殖,使Jurkat细胞和Raji细胞的细胞周期阻滞于G0/G1期。藤黄酸的细胞周期阻滞作用可能通过Cyclin D3和Cyclin E的下调有关。
第二部分藤黄酸对淋系肿瘤细胞系的细胞凋亡及抗凋亡蛋白的调控作用
【目的】研究藤黄酸对人急性T淋巴细胞白血病细胞株Jurkat细胞和人Burkitt淋巴瘤细胞株Raji细胞的诱导凋亡及抗凋亡蛋白的调控作用。
【方法】采用Annexin-V/PI双标法检测藤黄酸对Jurkat细胞和Raji细胞的诱导凋亡作用,免疫印迹检测藤黄酸对Jurkat细胞和Raji细胞抗凋亡蛋白NF-κB和Bcl-xL蛋白表达的影响。
【结果】0,1,2,3μmol/L藤黄酸处理后的Jurkat细胞的早期凋亡率分别为0.95%、2.09%、34.03%和38.30%。藤黄酸处理后的Raji细胞的早期凋亡率分别为4.21%、10.76%、16.13%和24.38%。以0,0.5,1.0,2.0,4.0μmol/L藤黄酸处理Jurkat细胞24h后,0和0.5μmol/L藤黄酸对NF-κB的表达无明显改变P>0.05,1.0、2.0及4.0μmol/L藤黄酸处理组NF-κB的表达随剂量增加而减低P<0.01;Bcl-xL呈剂量依赖性递减P<0.01。以0,0.5,1.0,2.0,4.0μmol/L藤黄酸处理Raji细胞24h后,,0和0.5μmol/L藤黄酸对Bcl-xL的表达无明显改变P>0.05,1.0、2.0及4.0μmol/L藤黄酸处理组Bcl-xL的表达随剂量增加而减低P<0.01;NF-κB呈剂量依赖性递减P<0.01。
【结论】藤黄酸能够诱导Jurkat细胞和Raji细胞凋亡,其机制可能部分通过下调抗凋亡蛋白Bcl-xL和NF-κB的表达来实现。
第三部分藤黄酸对淋系肿瘤细胞系死亡诱导清理子的调控作用
【目的】探讨藤黄酸对人急性T淋巴细胞白血病细胞株Jurkat细胞和人Burkitt淋巴瘤细胞株Raji细胞的抗癌作用的分子机理。
【方法】免疫印迹检测藤黄酸对Jurkat细胞和Raji细胞DIO-1、Caspase-3及其裂解产物p17和p20表达的影响。Hoechst33258及免疫荧光化学双标法检测藤黄酸作用下DIO-1核转位现象。
【结果】随着藤黄酸浓度的升高,Jurkat细胞和Raji细胞表达DIO-1的量先升高后降低,对应2.0μmol/L藤黄酸的DIO-1的表达量最高,虽然4.0μmol/L藤黄酸作用24h后DIO的表达较2.0μmol/L组明显降低但仍明显高于对照组;随着作用时间的延长,2.0μmol/L藤黄酸处理后,DIO-1表达量递增。pro-Caspase3片段的表达呈上升趋势且出现相应活化的Caspase3片段p17和p20。虽然两个片段在0.5μmol/L藤黄酸处理时即出现,但显著性的增高出现在2μmol/L藤黄酸组,4μmol/L藤黄酸处理组最高。藤黄酸作用Jurkat细胞和Raji细胞后,DIO-1由胞浆转位入胞核。
【结论】藤黄酸能上调DIO-1表达及与DIO-1的核转位有关。藤黄酸诱导Jurkat细胞和Raji细胞凋亡可能通过DIO-1介导,并通过Caspase 3活化来实现。
PART I Regulation of gambogic acid on cell proliferation and cell cycle of lymphoid neoplasm cell lines
【Objective】To explore the Regulation of gambogic acid on cell proliferation and cell cycle of Jurkat cells and Raji cells.
【Methods】Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl) -2,5- diphenyl- tetrazolium bromide assay. Cell cycle was exmined by PI staining thorough flow cytometry. Expressions of Cyclin D3 and Cyclin E were detected by western blotting.
【Results】GA inhibited the proliferation of Jurkat cells and Raji cells with 50% inhibitory concentration values of 1.69±0.09 (24 h), 0.98±0.13 (48 h), and 0.67±0.12 mmol/L (72 h) and 1.34±0.06 (24 h),0.39±0.03 (48 h),0.30±0.02μmol/L (72 h), respecitvely. In a dose-dependent manner, Gambogic acid arrested cell cycle of Jurkat and Raji cells at G0/G1 phase, the percentage of which increased from 41.78% to 62.72% and from 40.23% to 67.30%, respectively. Gambogic acid downregulated the expression of Cyclin D3 and Cyclin E dose and time dependently.
【Conclusion】Gambogic acid suppresses the proliferation of Jurkat cells and Raji cells and arrested cell cycle of them at G0/G1 phase. Cell cycle arrest may be through downregulation of Cyclin D3 and Cyclin E.
Part II Regulation of gambogic acid on anti-apoptotic protein of Jurkat cells and Raji cells
【Objective】To study the Regulation of gambogic acid on anti-apoptotic protein of Jurkat cells and Raji cells.
【Methods】Annexin V-fluorescein-isothiocyanate/propidium iodide were used to detect apoptosis. Expressions of Bcl-xL and NF-κB were detected by western blotting.
【Results】Treated with 0, 1.0, 2.0, and 3.0μmol/L GA for 24 h, percentages of the early apoptotic cells in the whole Jurkat population was from 0.95% and 2.09% to 34.03% and 38.30%, and that of Raja cells from 4.21% and 10.76% to 16.13% and 24.38%. Treated with 0, 0.5, 1.0, 2.0, and 4.0μmol/L GA for 24 h, expression of Bcl-xL and NF-κB was downregulated dose-dependently except Bcl-xL in Jurkat cells by 0.5μmol/L GA and NF-κB in Raji cells by 0.5μmol/L GA. There were no difference in those groups.
【Conclusion】Gambogic acid is able to induce the apoptosis of Jurkat cells and Raji cells, which is partly through the downregulation of the expression of antiapoptotic protein, Bcl-xL and NF-κB.
Part III Gambogic acid induces death inducer-obliterator 1-mediated apoptosis
【Objective】To explore the apoptosis inducing effects of GA on Jurkat cells and Raji cells and its underlying mechanism.
【Methods】Western blotting was used to study the expression of DIO-1 and pro-caspase 3, as well as 2 activated subunits: p17 and p20. The subcellular localization of DIO-1 was examined by immunofluorescence and Hoechst33258 staining.
【Results】Treated with 0, 0.5, 1.0, 2.0, and 4.0μmol/L GA for 24 h, the expression of DIO-1 increased dose-dependently and then declined, and pro-caspase 3 was cleavage into 2 subunits: p17 and p20. Treated with 2.0μmol/L GA for 0, 2, and 24h, the expression of DIO-1 increased time-dependently. GA induced the translocation of DIO-1 from cytoplasm into the nucleus in Jurkat and Raji cells.
【Conclusion】Gambogic acid upregulates the DIO-1 expression and was related to DIO-1 translocation, leading to the apoptosis of Jurkat and Raji cells. The DIO-1 expression is associated with the activation of pro-caspase 3 accompanied with the downregulation of Bcl-xL and NF-kB. DIO-1 triggered early-stage cell death in GA-treated Jurkat cells.
引文
1. Chen WH, Chen Y, Cui GH. Effects of TNF-alpha and curcumin on expression of VEGF in Raji and U937 cells and angiogenesis in ECV304 cells. Chin Med J (Engl). 2005;118(24): 2052-2057.
2. Liu HL,Chen Y, Cui GH., et al. Curcumin, a Potent Anti-tumor Reagent, is a Novel Histone Deacetylase Inhibitor Regulating B-NHL Cell Line Raji Proliferation Effect. Acta Pharmacol Sin, 2005; 26 (5): 603-609.
3. Liu HL,Chen Y, Cui GH., et al. Experimental Study on Regulating Expressions of Cyclin D1, pRb and Anticancer Effects of Deguelin on Human Burkitt’s Lymphoma Daudi cells in vitro. Acta Pharmacol Sin, 2005; 26 (7): 873-880.
4. Liu HL,Chen Y, Cui GH., et al. Deguelin regulates nucleocytoplasm shuttling activity of the nuclear pore complex protein Nup98 and Nup88 in U937 cells in vitro. Acta Pharmacol Sin,2005; 26 (10): 1265-1275.
5. Chen WH, Chen Y, Cui GH. Deguelin inhibits the expression of IκBa protein in Raji and U937 cells. Acta Pharmacol Sin, 2005; 27 (4): 485-490.
6. Wang ZH, Yu D, Chen Y. Proteomic analysis of nuclear matrix proteins during arsenic trioxide induced apoptosis in leukemia K562 cells. Chin Med J (Engl). 2005;118(2): 100-104.
7.江苏新医学院编.中药大辞典.下册.上海人民出版社. 1977;2695-2695
8. Gu HY, Guo QL, You QD, et al. Gambogic Acid Induced Apoptosis in Human Hepatoma SMMC27721 Cells with p53 and Bax Up-regulated. Chin J Nat Med, 2005; 13(13):168-172
9. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004; 12(12): 106-110
10. Yu J, Guo QL, You QD, et al. Repression of telomerase reverse transcriptase mRNA and hTERT promoter by gambogic acid in human gastric carcinoma cells. Cancer Chemother Pharmacol, 2006; 58(4): 434-443.
11. Wu ZQ, Guo QL, You QD, et al. Gambogic Acid Inhibits Proliferation of Human Lung Carcinoma SPC-A1 Cells in Vivo and in Vitro and Represses Telomerase Activity and Telomerase Reverse Transcriptase mRNA Expression in the Cells. Biol. Pharm. Bull., 2004; 27(11): 1769-1774.
12. Zhang HZ, Kasibhatla S, Wang Y, et al. Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem, 2004; 12(2): 309-317.
13. Shailaja K, Katayoun AJ, Sergei M, et al. A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. PNAS, 2005, 102(34):12095-12100.
14. David GD, Esther L, Alf G, et al. DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development. Proc Natl Acad Sci. USA 1999; 96:7992-7997.
15. David GD, Dorian R, Gonzalo GB, et al. Death Inducer-Obliterator 1 Triggers Apoptosis after Nuclear Translocation and Caspase Upregulation. Mol Cell Biol. 2003; 23:3216-3225.
16. Perkins ND. Integrating cell-signaling pathways with NF-κB and IKK function. Nature Rev/Mol Cell Biol 2007; 8: 49-62.
17. Agnes F, Miguel RC, Esther L, et al. Dido gene expression alterations are implicated in the induction of hematological myeloid neoplasms. J Clin Invest, 2005; 115: 2351–2362.
1.江苏新医学院编.中药大辞典.下册.上海人民出版社. 1977;2695-2695
2. Gu HY, Guo QL, You QD, et al. Gambogic Acid Induced Apoptosis in Human Hepatoma SMMC27721 Cells with p53 and Bax Up-regulated. Chin J Nat Med, 2005; 13(13):168-172
3. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004; 12(12): 106-110
4. Yu J, Guo QL, You QD, et al. Repression of telomerase reverse transcriptase mRNA and hTERT promoter by gambogic acid in human gastric carcinoma cells. Cancer Chemother Pharmacol, 2006; 58(4): 434-443.
5. Wu ZQ, Guo QL, You QD, et al. Gambogic Acid Inhibits Proliferation of Human Lung Carcinoma SPC-A1 Cells in Vivo and in Vitro and Represses Telomerase Activity and Telomerase Reverse Transcriptase mRNA Expression in the Cells. Biol. Pharm. Bull., 2004; 27(11): 1769-1774
6.刘静冰,秦叔逵,李进.藤黄酸抗胰腺癌作用的实验研究.临床肿瘤学杂志. 2005, 10(3):274-277
7. Shailaja K, Katayoun AJ, Sergei M, et al. A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. PNAS, 2005, 102(34):12095-12100.
8.丘相寰,薛绍白.藤黄酸对Hela细胞及小鼠腹水型肝癌细胞周期的影响.江西医药, 1984, 29 (5):1-4
9. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004, 12(12):106-110
10. Guo QL, Qi Q, You QD, et al. Toxicological Studies of Gambogic Acid and its Potential Targets in Experimental Animals. Basic & Clinical Pharmacology & Toxicology 2006, 99,178-184
11. Obaya AJ , Sedivy JM. Regulation of cyclin-CDK activity in mammalian cells. Cell Mol Life Sci, 2002; 59: 126-142.
12. Moller MB, Nielsen O, Pedersen NT. cyclin D3 expression in non-Hodgkin lymphoma. Correlation with other cell cycle regulators and clinical features. AmJ Clin Pathol , 2001; 115(3): 404.
13. Peterson LF, Boyapati A, Ranganathan V et al. The hematopoietic transcription factor AML1 (RUNX1) is negatively regulated by the cell cycle protein cyclin D3. Mol Cell Biol. 2005; 25 (23): 10205-10219.
14.张乐平,李静.周期蛋白D3在小儿急性白血病中的表达及其作用研究.中华血液学杂志. 1999; 20(7):347-349.
15.刘壮,韦红英,韩蕴丽等.儿童急性白血病细胞周期蛋白D3、E的表达.中国实用儿科杂志. 2005; 20(5): 286-288.
16. Scuderi R, Palucka KA, Pokrovskaja K, et al. Cyclin E overexpression in relapsed adult acute lymphoblastic leukemias of B-cell lineage. Blood, 1996; 87: 3360-3367
1. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16: 225-260.
2. Ghosh S, Karin M. Missing pieces in the NF-kappa B puzzle. Cell. 2002; 109 Suppl: S81-96.
3. Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004; 6: 203-208.
4. Munzert G, KirchnerD, Ottmann O, et al. Constitutive NF-kappaB/Rel activation in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Leuk Lymphoma, 2004; 45(6): 1181-11841
5. Sun SC, Yamaoka S. Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene, 2005; 24(39): 5952-5964.
6. HinzM, Lemke P, Anagnostopoulos I, et al. Nuclear factor kappaB-dependent gene expression profiling of Hodgkin’s disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcrip tion 5a activity. J Exp Med, 2002; 196 (5): 605-617.
7. Stoffel A, Chaurushiya M, Singh B, et al. Activation of NF-kappa B and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis. Proc Natl Acad Sci USA. 2004; 101(24): 9079-9084.
8. Zhou H, Wertz I, Ope K, et al. Bcl-10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature. 2004; 427(6970): 167-171.
9. Barth TF, Martin-Subero JI, Joos S, et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood, 2003; 101 (9): 3681-3686.
10. Scuderi R, Palucka KA, Pokrovskaja K, et al. Cyclin E overexpression in relapsed adult acute lymphoblastic leukemias of B-cell lineage. Blood, 1996; 87: 3360-3367
11.刘元华, Christophe Leboeuf,金晓龙等.非霍奇金淋巴瘤Bcl-xL基因表达及突变的研究.中国实验血液学杂志. 2006; 14 (5): 903–907.
12.施勤,鲁严等. p53基因、Bcl-xL基因表达对淋巴性肿瘤细胞株辐射敏感性的影响. 辐射防护. 2001; 03: 166-170.
1. David GD, Esther L, Alf G, et al. DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development. Proc Natl Acad Sci. USA 1999; 96:7992-7997.
2. David GD, Dorian R, Gonzalo GB, et al. Death Inducer-Obliterator 1 Triggers Apoptosis after Nuclear Translocation and Caspase Upregulation. Mol Cell Biol. 2003; 23:3216-3225.
3. Sánchez-Pulido L, Rojas AM, van Wely KH, et al. SPOC: a widely distributed domain associated with cancer, apoptosis and transcription. BMC Bioinformatics. 2004; 7:91.
1.江苏新医学院编.中药大辞典.下册.上海人民出版社. 1977, 2695-2695
2.喻香.藤黄糊剂与妇炎灵治疗宫颈糜烂的观察.江西医药, 1997, 32(2):87-88
3.朱润衡,凌淑清,张宁.中药藤黄外用治疗带状疱疹及单纯疱疹110例疗效观察及实验研究.中华皮肤科杂志, 1984, 17:18-20
4.张宁,陆洪光,邓艳,等.藤黄外用治疗生殖器疱疹患者的临床疗效和实验室研究.中华皮肤科杂志, 2000, 33(3):167-168
5.孔令东,叶定江,王苏玲,等.藤黄炮制品急性毒性及抗炎作用的研究.中国中药杂志, 1996, 21(4):214-216
6. Han QB, Yang L, Wang YL, et al. A Pair of Novel Cytotoxic Polyprenylated Xanthone Epimers from Gamboges. Chemistry & Biodiversity, 2006, 3:101-105
7. Amorosa M, Lipparini.α-Gambogic Acid: A Constiuent of Gamboge. Annali di Chemica, 1955, 45:977-982
8.黄泉秀,彭国平,何亚维,等.薄层扫描法测定藤黄中藤黄酸的含量.南京中医学院学报, 1991, 7(2):102-103
9.吕归宝,方谨.高效液相色谱法测定藤黄中藤黄酸和新藤黄酸的含量.中草药, 1988, 19(7):10-12
10.杨虹,丛晓东,蒋王林,等.高效液相色谱-蒸发光散射检测法对藤黄中藤黄酸及其衍生物的含量测定.中国药科大学学报, 1999, 30(3):202-205
11.柳文媛,冯锋,尤启冬,等. RP-HPLC法测定总藤黄酸中藤黄酸的含量.中草药, 2003, 34(8):706-707
12.陈优生,冯锋,尤启冬,等. ZrOCl2比色法测定藤黄中总藤黄酸的含量.中国药师, 2002, 5(12):731-732
13. Ollis WD, Ramsay MVJ, Sutherland IO, et al. Constitution of gambogic acid. Tetrahedron, 1965, 21(6):1453-1470.
14.陆跃鸣,叶定江.不同温度、时间的藤黄蒸制品对K562肿瘤细胞生长抑制作用.南京中医药大学学报, 1996, 12(3):26-27
15. Batova A, Lam T, Wascholowski V, et al. Synthesis and evaluation of caged Garcinia xanthones. Org Biomol Chem. 2007, 5(3):494-500
16.曲宝玺,纪远中,章萍,等.藤黄Ⅱ号对白血病L121 0细胞杀伤动力学研究I一显微分光光度计观察.中国肿瘤临床, 1991, 18(1):53-56
17.郭青龙,赵丽,吴照球,等.藤黄酸对实验性动物造血功能及免疫功能的影响.中国天然药物, 2003, 11(1):229-232
18. Shailaja K, Katayoun AJ, Sergei M, et al. A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. PNAS, 2005, 102(34):12095-12100
19. Tao Z, Zhou Y, Lu J, et al. Caspase-8 Preferentially Senses the Apoptosis-Inducing Action of NG-18, A Gambogic Acid Derivative, in Human Leukemia HL-60 Cells. Cancer Biol Ther, 2007, 6(5):691-696
20. Zhang HZ, Kasibhatla S, Wang Y, et al. Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem, 2004, 12(2):309-17.
21.丘相寰,薛绍白.藤黄酸对Hela细胞及小鼠腹水型肝癌细胞周期的影响.江西医药, 1984, 29 (5):1-4
22.董成,吕发度,刘金妹,等.藤黄酸类体外抗癌作用的实验观察药学通报, 1988, 23(2):89-90.
23. Gu HY, Guo QL, You QD, et al. Gambogic Acid Induced Apoptosis in Human Hepatoma SMMC27721 Cells with p53 and Bax Up-regulated. Chin J Nat Med, 2005, 13(13):168-172
24. Guo QL, You QD, Wu ZQ, et al. General gambogic acids inhibited growth of human hepatoma SMMC-7721 cells in vitro and in nude mice. Acta Pharmacol Sin 2004, 25 (6):769-774
25. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004, 12(12):106-110
26. Yu J, Guo QL, You QD, et al. Repression of telomerase reverse transcriptase mRNAand hTERT promoter by gambogic acid in human gastric carcinoma cells. Cancer Chemother Pharmacol, 2006, 58(4):434-443.
27. Liu W, Guo QL, You QD, et al. Anticancer effect and apoptosis induction of gambogic acid in human gastric cancer line BGC-823. World J Gastroenterol 2005,11(24):3655-3659
28.刘静冰,秦叔逵,李进.藤黄酸抗胰腺癌作用的实验研究.临床肿瘤学杂志. 2005, 10(3):274-277
29. Wu ZQ, Guo QL, You QD, et al. Gambogic Acid Inhibits Proliferation of Human Lung Carcinoma SPC-A1 Cells in Vivo and in Vitro and Represses Telomerase Activity and Telomerase Reverse Transcriptase mRNA Expression in the Cells. Biol. Pharm. Bull., 2004, 27(11):1769-1774
30. Guo QL, Qi Q, You QD, et al. Toxicological Studies of Gambogic Acid and its Potential Targets in Experimental Animals. Basic & Clinical Pharmacology & Toxicology 2006, 99,178-184
31.周政涛,王金万.注射用藤黄酸Ⅰ期临床耐受性研究.中国新药杂志, 2007,16(1):79-83
32.郝琨,柳晓泉,王广基.藤黄酸在大鼠体内的药代动力学.中国药科大学学报, 2005, 36(4):338-341
33. Liu YT, Hao K, Liu XQ, et al. Metabolism and metabolic inhibition of gambogic acid in rat liver microsomes. Acta Pharmacol Sin., 2006, 27(9):1253-1258
34.张谨,张洵,王永泉,等.藤黄酸对肿瘤细胞诱导分化作用的探讨.实用癌症杂志. 2003, 18(1):9-10
35.程廷楷,项守仁,黄永昌,等.藤黄酸对小白鼠实验性肿瘤的亚显微结构的影响.江西医学院学报, 1981, 41(2):7-10
36. Guo QL, Lin SS, You QD, et al. Inhibition of human telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma SMMC-7721 cells. Life Sciences, 2006, 78:1238-1245
1. Fr?hling S, Scholl C, Gilliland DG, et al. Genetics of myeloid malignancies- pathogenetic and clinical implications. J Clin Oncol. 2005; 23: 6285-6295.
2. Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004; 18:115-136.
3. Estey E, D?hner H. Acute myeloid leukaemia. Lancet. 2006; 368: 1894-1907.
4. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon,France: IARC Press; 2001.
5. Grisendi S, Mecucci C, Falini B, et al. Nucleophosmin and cancer. Nature Rev Cancer. 2006; 6: 493-505.
6. Falini B, Mecucci C, Tiacci E, et al. Gimema Acute Leukemia Working Party. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005; 352: 254-266.
7. Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biological and clinical features. Blood. 2007; 109: 874-885.
8. D?hner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics-interaction with other gene mutations. Blood. 2005; 106: 3740-3746.
9. Verhaak RGW, Goudswaard CS, van Putten W, et al. Mutations in nucleophosmin NPM1 in acute myeloid leukemia (AML): association with other genetic abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106:3747-3754.
10. Boissel N, Renneville A, Biggio V, et al. Revalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood. 2005; 106: 3618-3620.
11. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006; 107:4011-4020.
12. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favourable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733-3739.
13. Suzuki T, Kiyoi H, Ozeki K, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood. 2005; 106: 2854-2861.
14. Liu H, Tan BC, Tseng KH, et al. Nucleophosmin acts as a novel AP2alpha- binding transcriptional corepressor during cell differentiation. EMBO Rep. 2007; 8: 394-400.
15. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911-1918.
16. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001; 97: 2434-2439.
17. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognosticinformation to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001; 98: 1752-1759.
18. Whitman SP, Archer KJ, Feng L, et al. Absence of the wildtype allele predicts poorprognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61:7233-7239.
19. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372-4380.
20. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenousleukemia: association with FAB subtypes and identification ofsubgroups with poor prognosis. Blood. 2002;99:4326-4335.26.
21. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650-665.
22. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669-3676.
23. Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006; 108: 3262-3270.
24. Levis M, Brown P, Smith BD, et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006; 108: 3477-3483.
25. Whitman SP, Ruppert AS, Marcucci G, et al. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study. Blood. 2007;109:5164-5167.
26. Whitman SP, Liu S, Vukosavljevic T, et al. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood. 2005;106:345-352.
27. End DW. Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway. Invest New Drugs. 1999;17:241-258.
28. Harousseau JL, Reiffers J, Lowenberg B, et al. Zarnestra (R115777) in patients withrelapsed and refractory acute myelogenous leukemia (AML): results of a multicenter phase 2 study. Blood. 2003;102:614.
29. Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood. 2007;109:1387-1394.
30. Summers K, Stevens J, Kakkas I, et al. Wilms’tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia. 2007;21:550-551.
31. Schlenk RF, Corbacioglu A, Krauter J, et al. Gene mutations as predictive markers for postremission therapy in younger adults with normal karyotype AML. Blood. 2006;108:6a
32. Baldus CD, Tanner SM, Ruppert AS, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood. 2003;102:1613-1618.
33. Baldus CD, Liyanarachchi S, Mrozek K, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA. 2004;101:3915-3920.
34. Marcucci G, Maharry K, Whitman SP, et al. High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol. 2007;25:3337-3343.
35. Heuser M, Beutel G, Krauter J, et al. High meningioma (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood. 2006;108:3898-3905.
36. Barjesteh van Waalwijk van Doom-Khosrovani S, Erpelinck C, van Putten WLJ, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia. Blood. 2003;101:837-845
2. Liu HL,Chen Y, Cui GH., et al. Curcumin, a Potent Anti-tumor Reagent, is a Novel Histone Deacetylase Inhibitor Regulating B-NHL Cell Line Raji Proliferation Effect. Acta Pharmacol Sin, 2005; 26 (5): 603-609.
3. Liu HL,Chen Y, Cui GH., et al. Experimental Study on Regulating Expressions of Cyclin D1, pRb and Anticancer Effects of Deguelin on Human Burkitt’s Lymphoma Daudi cells in vitro. Acta Pharmacol Sin, 2005; 26 (7): 873-880.
4. Liu HL,Chen Y, Cui GH., et al. Deguelin regulates nucleocytoplasm shuttling activity of the nuclear pore complex protein Nup98 and Nup88 in U937 cells in vitro. Acta Pharmacol Sin,2005; 26 (10): 1265-1275.
5. Chen WH, Chen Y, Cui GH. Deguelin inhibits the expression of IκBa protein in Raji and U937 cells. Acta Pharmacol Sin, 2005; 27 (4): 485-490.
6. Wang ZH, Yu D, Chen Y. Proteomic analysis of nuclear matrix proteins during arsenic trioxide induced apoptosis in leukemia K562 cells. Chin Med J (Engl). 2005;118(2): 100-104.
7.江苏新医学院编.中药大辞典.下册.上海人民出版社. 1977;2695-2695
8. Gu HY, Guo QL, You QD, et al. Gambogic Acid Induced Apoptosis in Human Hepatoma SMMC27721 Cells with p53 and Bax Up-regulated. Chin J Nat Med, 2005; 13(13):168-172
9. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004; 12(12): 106-110
10. Yu J, Guo QL, You QD, et al. Repression of telomerase reverse transcriptase mRNA and hTERT promoter by gambogic acid in human gastric carcinoma cells. Cancer Chemother Pharmacol, 2006; 58(4): 434-443.
11. Wu ZQ, Guo QL, You QD, et al. Gambogic Acid Inhibits Proliferation of Human Lung Carcinoma SPC-A1 Cells in Vivo and in Vitro and Represses Telomerase Activity and Telomerase Reverse Transcriptase mRNA Expression in the Cells. Biol. Pharm. Bull., 2004; 27(11): 1769-1774.
12. Zhang HZ, Kasibhatla S, Wang Y, et al. Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem, 2004; 12(2): 309-317.
13. Shailaja K, Katayoun AJ, Sergei M, et al. A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. PNAS, 2005, 102(34):12095-12100.
14. David GD, Esther L, Alf G, et al. DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development. Proc Natl Acad Sci. USA 1999; 96:7992-7997.
15. David GD, Dorian R, Gonzalo GB, et al. Death Inducer-Obliterator 1 Triggers Apoptosis after Nuclear Translocation and Caspase Upregulation. Mol Cell Biol. 2003; 23:3216-3225.
16. Perkins ND. Integrating cell-signaling pathways with NF-κB and IKK function. Nature Rev/Mol Cell Biol 2007; 8: 49-62.
17. Agnes F, Miguel RC, Esther L, et al. Dido gene expression alterations are implicated in the induction of hematological myeloid neoplasms. J Clin Invest, 2005; 115: 2351–2362.
1.江苏新医学院编.中药大辞典.下册.上海人民出版社. 1977;2695-2695
2. Gu HY, Guo QL, You QD, et al. Gambogic Acid Induced Apoptosis in Human Hepatoma SMMC27721 Cells with p53 and Bax Up-regulated. Chin J Nat Med, 2005; 13(13):168-172
3. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004; 12(12): 106-110
4. Yu J, Guo QL, You QD, et al. Repression of telomerase reverse transcriptase mRNA and hTERT promoter by gambogic acid in human gastric carcinoma cells. Cancer Chemother Pharmacol, 2006; 58(4): 434-443.
5. Wu ZQ, Guo QL, You QD, et al. Gambogic Acid Inhibits Proliferation of Human Lung Carcinoma SPC-A1 Cells in Vivo and in Vitro and Represses Telomerase Activity and Telomerase Reverse Transcriptase mRNA Expression in the Cells. Biol. Pharm. Bull., 2004; 27(11): 1769-1774
6.刘静冰,秦叔逵,李进.藤黄酸抗胰腺癌作用的实验研究.临床肿瘤学杂志. 2005, 10(3):274-277
7. Shailaja K, Katayoun AJ, Sergei M, et al. A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. PNAS, 2005, 102(34):12095-12100.
8.丘相寰,薛绍白.藤黄酸对Hela细胞及小鼠腹水型肝癌细胞周期的影响.江西医药, 1984, 29 (5):1-4
9. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004, 12(12):106-110
10. Guo QL, Qi Q, You QD, et al. Toxicological Studies of Gambogic Acid and its Potential Targets in Experimental Animals. Basic & Clinical Pharmacology & Toxicology 2006, 99,178-184
11. Obaya AJ , Sedivy JM. Regulation of cyclin-CDK activity in mammalian cells. Cell Mol Life Sci, 2002; 59: 126-142.
12. Moller MB, Nielsen O, Pedersen NT. cyclin D3 expression in non-Hodgkin lymphoma. Correlation with other cell cycle regulators and clinical features. AmJ Clin Pathol , 2001; 115(3): 404.
13. Peterson LF, Boyapati A, Ranganathan V et al. The hematopoietic transcription factor AML1 (RUNX1) is negatively regulated by the cell cycle protein cyclin D3. Mol Cell Biol. 2005; 25 (23): 10205-10219.
14.张乐平,李静.周期蛋白D3在小儿急性白血病中的表达及其作用研究.中华血液学杂志. 1999; 20(7):347-349.
15.刘壮,韦红英,韩蕴丽等.儿童急性白血病细胞周期蛋白D3、E的表达.中国实用儿科杂志. 2005; 20(5): 286-288.
16. Scuderi R, Palucka KA, Pokrovskaja K, et al. Cyclin E overexpression in relapsed adult acute lymphoblastic leukemias of B-cell lineage. Blood, 1996; 87: 3360-3367
1. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16: 225-260.
2. Ghosh S, Karin M. Missing pieces in the NF-kappa B puzzle. Cell. 2002; 109 Suppl: S81-96.
3. Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004; 6: 203-208.
4. Munzert G, KirchnerD, Ottmann O, et al. Constitutive NF-kappaB/Rel activation in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Leuk Lymphoma, 2004; 45(6): 1181-11841
5. Sun SC, Yamaoka S. Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene, 2005; 24(39): 5952-5964.
6. HinzM, Lemke P, Anagnostopoulos I, et al. Nuclear factor kappaB-dependent gene expression profiling of Hodgkin’s disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcrip tion 5a activity. J Exp Med, 2002; 196 (5): 605-617.
7. Stoffel A, Chaurushiya M, Singh B, et al. Activation of NF-kappa B and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis. Proc Natl Acad Sci USA. 2004; 101(24): 9079-9084.
8. Zhou H, Wertz I, Ope K, et al. Bcl-10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature. 2004; 427(6970): 167-171.
9. Barth TF, Martin-Subero JI, Joos S, et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood, 2003; 101 (9): 3681-3686.
10. Scuderi R, Palucka KA, Pokrovskaja K, et al. Cyclin E overexpression in relapsed adult acute lymphoblastic leukemias of B-cell lineage. Blood, 1996; 87: 3360-3367
11.刘元华, Christophe Leboeuf,金晓龙等.非霍奇金淋巴瘤Bcl-xL基因表达及突变的研究.中国实验血液学杂志. 2006; 14 (5): 903–907.
12.施勤,鲁严等. p53基因、Bcl-xL基因表达对淋巴性肿瘤细胞株辐射敏感性的影响. 辐射防护. 2001; 03: 166-170.
1. David GD, Esther L, Alf G, et al. DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development. Proc Natl Acad Sci. USA 1999; 96:7992-7997.
2. David GD, Dorian R, Gonzalo GB, et al. Death Inducer-Obliterator 1 Triggers Apoptosis after Nuclear Translocation and Caspase Upregulation. Mol Cell Biol. 2003; 23:3216-3225.
3. Sánchez-Pulido L, Rojas AM, van Wely KH, et al. SPOC: a widely distributed domain associated with cancer, apoptosis and transcription. BMC Bioinformatics. 2004; 7:91.
1.江苏新医学院编.中药大辞典.下册.上海人民出版社. 1977, 2695-2695
2.喻香.藤黄糊剂与妇炎灵治疗宫颈糜烂的观察.江西医药, 1997, 32(2):87-88
3.朱润衡,凌淑清,张宁.中药藤黄外用治疗带状疱疹及单纯疱疹110例疗效观察及实验研究.中华皮肤科杂志, 1984, 17:18-20
4.张宁,陆洪光,邓艳,等.藤黄外用治疗生殖器疱疹患者的临床疗效和实验室研究.中华皮肤科杂志, 2000, 33(3):167-168
5.孔令东,叶定江,王苏玲,等.藤黄炮制品急性毒性及抗炎作用的研究.中国中药杂志, 1996, 21(4):214-216
6. Han QB, Yang L, Wang YL, et al. A Pair of Novel Cytotoxic Polyprenylated Xanthone Epimers from Gamboges. Chemistry & Biodiversity, 2006, 3:101-105
7. Amorosa M, Lipparini.α-Gambogic Acid: A Constiuent of Gamboge. Annali di Chemica, 1955, 45:977-982
8.黄泉秀,彭国平,何亚维,等.薄层扫描法测定藤黄中藤黄酸的含量.南京中医学院学报, 1991, 7(2):102-103
9.吕归宝,方谨.高效液相色谱法测定藤黄中藤黄酸和新藤黄酸的含量.中草药, 1988, 19(7):10-12
10.杨虹,丛晓东,蒋王林,等.高效液相色谱-蒸发光散射检测法对藤黄中藤黄酸及其衍生物的含量测定.中国药科大学学报, 1999, 30(3):202-205
11.柳文媛,冯锋,尤启冬,等. RP-HPLC法测定总藤黄酸中藤黄酸的含量.中草药, 2003, 34(8):706-707
12.陈优生,冯锋,尤启冬,等. ZrOCl2比色法测定藤黄中总藤黄酸的含量.中国药师, 2002, 5(12):731-732
13. Ollis WD, Ramsay MVJ, Sutherland IO, et al. Constitution of gambogic acid. Tetrahedron, 1965, 21(6):1453-1470.
14.陆跃鸣,叶定江.不同温度、时间的藤黄蒸制品对K562肿瘤细胞生长抑制作用.南京中医药大学学报, 1996, 12(3):26-27
15. Batova A, Lam T, Wascholowski V, et al. Synthesis and evaluation of caged Garcinia xanthones. Org Biomol Chem. 2007, 5(3):494-500
16.曲宝玺,纪远中,章萍,等.藤黄Ⅱ号对白血病L121 0细胞杀伤动力学研究I一显微分光光度计观察.中国肿瘤临床, 1991, 18(1):53-56
17.郭青龙,赵丽,吴照球,等.藤黄酸对实验性动物造血功能及免疫功能的影响.中国天然药物, 2003, 11(1):229-232
18. Shailaja K, Katayoun AJ, Sergei M, et al. A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. PNAS, 2005, 102(34):12095-12100
19. Tao Z, Zhou Y, Lu J, et al. Caspase-8 Preferentially Senses the Apoptosis-Inducing Action of NG-18, A Gambogic Acid Derivative, in Human Leukemia HL-60 Cells. Cancer Biol Ther, 2007, 6(5):691-696
20. Zhang HZ, Kasibhatla S, Wang Y, et al. Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem, 2004, 12(2):309-17.
21.丘相寰,薛绍白.藤黄酸对Hela细胞及小鼠腹水型肝癌细胞周期的影响.江西医药, 1984, 29 (5):1-4
22.董成,吕发度,刘金妹,等.藤黄酸类体外抗癌作用的实验观察药学通报, 1988, 23(2):89-90.
23. Gu HY, Guo QL, You QD, et al. Gambogic Acid Induced Apoptosis in Human Hepatoma SMMC27721 Cells with p53 and Bax Up-regulated. Chin J Nat Med, 2005, 13(13):168-172
24. Guo QL, You QD, Wu ZQ, et al. General gambogic acids inhibited growth of human hepatoma SMMC-7721 cells in vitro and in nude mice. Acta Pharmacol Sin 2004, 25 (6):769-774
25. Guo QL, Zhao Li, You QD, et al. Gambogic Acid Inducing Apoptosis in Human Gastric Adenocarcinoma SGC-7901 Cells. Chin J Nat Med, 2004, 12(12):106-110
26. Yu J, Guo QL, You QD, et al. Repression of telomerase reverse transcriptase mRNAand hTERT promoter by gambogic acid in human gastric carcinoma cells. Cancer Chemother Pharmacol, 2006, 58(4):434-443.
27. Liu W, Guo QL, You QD, et al. Anticancer effect and apoptosis induction of gambogic acid in human gastric cancer line BGC-823. World J Gastroenterol 2005,11(24):3655-3659
28.刘静冰,秦叔逵,李进.藤黄酸抗胰腺癌作用的实验研究.临床肿瘤学杂志. 2005, 10(3):274-277
29. Wu ZQ, Guo QL, You QD, et al. Gambogic Acid Inhibits Proliferation of Human Lung Carcinoma SPC-A1 Cells in Vivo and in Vitro and Represses Telomerase Activity and Telomerase Reverse Transcriptase mRNA Expression in the Cells. Biol. Pharm. Bull., 2004, 27(11):1769-1774
30. Guo QL, Qi Q, You QD, et al. Toxicological Studies of Gambogic Acid and its Potential Targets in Experimental Animals. Basic & Clinical Pharmacology & Toxicology 2006, 99,178-184
31.周政涛,王金万.注射用藤黄酸Ⅰ期临床耐受性研究.中国新药杂志, 2007,16(1):79-83
32.郝琨,柳晓泉,王广基.藤黄酸在大鼠体内的药代动力学.中国药科大学学报, 2005, 36(4):338-341
33. Liu YT, Hao K, Liu XQ, et al. Metabolism and metabolic inhibition of gambogic acid in rat liver microsomes. Acta Pharmacol Sin., 2006, 27(9):1253-1258
34.张谨,张洵,王永泉,等.藤黄酸对肿瘤细胞诱导分化作用的探讨.实用癌症杂志. 2003, 18(1):9-10
35.程廷楷,项守仁,黄永昌,等.藤黄酸对小白鼠实验性肿瘤的亚显微结构的影响.江西医学院学报, 1981, 41(2):7-10
36. Guo QL, Lin SS, You QD, et al. Inhibition of human telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma SMMC-7721 cells. Life Sciences, 2006, 78:1238-1245
1. Fr?hling S, Scholl C, Gilliland DG, et al. Genetics of myeloid malignancies- pathogenetic and clinical implications. J Clin Oncol. 2005; 23: 6285-6295.
2. Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004; 18:115-136.
3. Estey E, D?hner H. Acute myeloid leukaemia. Lancet. 2006; 368: 1894-1907.
4. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon,France: IARC Press; 2001.
5. Grisendi S, Mecucci C, Falini B, et al. Nucleophosmin and cancer. Nature Rev Cancer. 2006; 6: 493-505.
6. Falini B, Mecucci C, Tiacci E, et al. Gimema Acute Leukemia Working Party. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005; 352: 254-266.
7. Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biological and clinical features. Blood. 2007; 109: 874-885.
8. D?hner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics-interaction with other gene mutations. Blood. 2005; 106: 3740-3746.
9. Verhaak RGW, Goudswaard CS, van Putten W, et al. Mutations in nucleophosmin NPM1 in acute myeloid leukemia (AML): association with other genetic abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106:3747-3754.
10. Boissel N, Renneville A, Biggio V, et al. Revalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood. 2005; 106: 3618-3620.
11. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006; 107:4011-4020.
12. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favourable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733-3739.
13. Suzuki T, Kiyoi H, Ozeki K, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood. 2005; 106: 2854-2861.
14. Liu H, Tan BC, Tseng KH, et al. Nucleophosmin acts as a novel AP2alpha- binding transcriptional corepressor during cell differentiation. EMBO Rep. 2007; 8: 394-400.
15. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911-1918.
16. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001; 97: 2434-2439.
17. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognosticinformation to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001; 98: 1752-1759.
18. Whitman SP, Archer KJ, Feng L, et al. Absence of the wildtype allele predicts poorprognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61:7233-7239.
19. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372-4380.
20. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenousleukemia: association with FAB subtypes and identification ofsubgroups with poor prognosis. Blood. 2002;99:4326-4335.26.
21. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650-665.
22. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669-3676.
23. Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006; 108: 3262-3270.
24. Levis M, Brown P, Smith BD, et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006; 108: 3477-3483.
25. Whitman SP, Ruppert AS, Marcucci G, et al. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study. Blood. 2007;109:5164-5167.
26. Whitman SP, Liu S, Vukosavljevic T, et al. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood. 2005;106:345-352.
27. End DW. Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway. Invest New Drugs. 1999;17:241-258.
28. Harousseau JL, Reiffers J, Lowenberg B, et al. Zarnestra (R115777) in patients withrelapsed and refractory acute myelogenous leukemia (AML): results of a multicenter phase 2 study. Blood. 2003;102:614.
29. Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood. 2007;109:1387-1394.
30. Summers K, Stevens J, Kakkas I, et al. Wilms’tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia. 2007;21:550-551.
31. Schlenk RF, Corbacioglu A, Krauter J, et al. Gene mutations as predictive markers for postremission therapy in younger adults with normal karyotype AML. Blood. 2006;108:6a
32. Baldus CD, Tanner SM, Ruppert AS, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood. 2003;102:1613-1618.
33. Baldus CD, Liyanarachchi S, Mrozek K, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA. 2004;101:3915-3920.
34. Marcucci G, Maharry K, Whitman SP, et al. High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol. 2007;25:3337-3343.
35. Heuser M, Beutel G, Krauter J, et al. High meningioma (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood. 2006;108:3898-3905.
36. Barjesteh van Waalwijk van Doom-Khosrovani S, Erpelinck C, van Putten WLJ, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia. Blood. 2003;101:837-845