大黄素对白血病细胞K562、U937的增殖抑制及机制初探
摘要
目的:白血病(Leukemia)是一类造血干细胞的克隆性疾病,这些白血病细胞失去正常的成熟分化能力而停滞在细胞发育的某一阶段,在骨髓和其他造血组织中白血病细胞大量增殖聚集,并浸润其他组织器官,使正常造血功能受到抑制。我国白血病的发病率约为2.76/10万。在恶性肿瘤所致的死亡率中,白血病居第6位(男性)和第8位(女性),但在儿童则居第一位。尽管不断有新的化疗药物问世、并用于白血病的治疗,造血干细胞移植技术也在不断提高,但目前仍有许多白血病患者不能取得完全缓解或在完全缓解后复发。原发或继发耐药及多药耐药的出现更增加了白血病治疗的难度。因此,对于血液工作者而言,寻找新的有效治疗白血病的药物和有效的治疗方案已经成为一项长期艰巨的任务。
大黄素(Emodin,EM)是一种羟基蒽醌类化合物。它具有抗炎抑菌、免疫调节、抗胰酶、保护肝肾功能、抗肿瘤等生物活性,特别是大黄素的抗肿瘤作用,成为近年研究热点。它通过抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、影响细胞信号转导途径和影响细胞周期、逆转多药耐药等机制发挥其抗肿瘤作用。
本文主要观察不同浓度的大黄素对白血病细胞株K562、U937的增殖抑制作用,在细胞水平通过荧光显微镜和流式细胞仪检测不同浓度大黄素对两种细胞的形态学、细胞周期及凋亡率的影响,在分子水平上通过RT-PCR技术检测不同浓度大黄素对两种细胞内bcl-2及NF-κB基因表达的影响,从而探讨大黄素抑制白血病细胞株K562、U937增殖的有关机制。
方法:
1细胞培养:将K562、U937细胞按常规用RPMI 1640培养液培养,培养液内含10%新生牛血清(FBS)、100μg/mL青霉素、100U/mL链霉素和2mmol/L谷氨酰胺。置37℃,饱和度5%CO2环境下培养、传代,每2-3天传代一次。待细胞进入对数生长期后进行实验。
2细胞增殖抑制实验:分别测定不同浓度大黄素对K562、U937细胞作用48小时的增殖抑制率。取对数生长期的细胞加入不同浓度的大黄素,培养48小时后,加入CCK-8试剂。在相同条件下继续培养4小时后,在450nm波长下检测吸光度。根据吸光度(A值)计算细胞增殖抑制率。抑制率(%)=(A对照组-A实验组)/A对照组×100%。
3荧光染色观察细胞形态改变:分别收集IC50浓度的大黄素作用48h的K562、U937细胞,同时设立不加大黄素的空白对照组。将细胞用PBS洗后重悬,加入Hochest 33342荧光试剂染色。置荧光显微镜下计数400个细胞,观察细胞的形态学变化。
4流式细胞术检测细胞周期分布及凋亡率:取对数生长期的K562、U937细胞,加入不同浓度的大黄素作用于K562、U937细胞,48h后收集细胞,PBS洗后用70%乙醇4℃固定细胞,PBS再洗后加入RNA酶,10分钟后用终浓度为50μg/ml的PI染色30 min。流式细胞仪测定细胞周期,计算细胞周期变化及凋亡率。
5酶标仪检测caspase3/7活性:将K562、U937细胞接种于96孔板上。处理组的培养液中加入大黄素,使大黄素终浓度为IC50浓度。在37℃、5%CO_2体积分数的条件下培养48h后,加入100μl caspase3/7试剂,4h后酶标仪检测各组细胞在405nm处的吸光度(A值)。
6 RT-PCR检测bcl-2、NF-κB的表达:Trizol法提取细胞总RNA,采用随机引物法以M-MLV合成cDNA,以特异的引物扩增目的基因,琼脂糖凝胶电泳后Goldview染色,以β-action为内参,分析mRNA相对表达水平。
结果:
1大黄素能抑制K562、U937细胞生长并具有浓度依赖性,对K562细胞的IC50为51.58μmol/L,对U937细胞的IC50为48.00μmol/L。
2大黄素处理后,荧光显微镜下出现荧光标记的细胞增多,呈现亮蓝色。
3流式细胞仪检测结果:大黄素处理后,K562细胞主要表现为S期细胞增多、G0/G1期及G2/M期细胞减少(P<0.05);U937细胞主要表现为G0/G1期细胞增多、G2/M期及S期细胞减少(P<0.05)。两种细胞的凋亡率也随浓度的增加而增加(P<0.05)。
4酶标仪检测caspase3/7活性:大黄素处理后K562、U937细胞内的caspase3/7酶活性增加,与对照组相比有显著性差异(P<0.05)。
5 RT-PCR检测bcl-2、NF-κB的表达:大黄素处理后,K562、U937细胞内的bcl-2、NF-κB的表达均较对照组下调。
结论:大黄素对K562细胞、U937细胞生长抑制作用明显,可能通过下调bcl-2、NF-κB的表达,使细胞周期进程被阻滞,同时还促进肿瘤细胞发生凋亡。
Objective: Leukemia is a group of malignant clonal diseases derived from the hematopoietic stem cells (HSC), or from leukemic stem cells (LSC). These cells lose their normal ability of differentiation and maturation and accumulated in bone marrow and other hematopoietic tissues, such as liver and spleen. Leukemia cells can also infiltrate in other organs such as central nervous system (CNS) and testis. Growing of normal hematopoietic cells is suppressed by leukemia cells. The incidence of leukemia in our country is 2.76 per 100 thousands people. The mortality of leukemia occupies the top 6th for male and 8~(th) for female among the overall mortalities of adult malignant tumors. However, it rises to highest among children malignant tumors. Although several new effective drugs have been developed and the skills for hematopoietic stem cell transplantation improved during last decade, there are still many leukemia patients who can not achieve complete remission or relapse sooner or later after the complete remission. The treatment of leukemia becomes more difficult with the appearance of the primary or secondary drug resistance, especially multidrug resistance (MDR). Therefore, it is a long-term and pressing task to find new effective drugs without or with slight side-effect for the treatment of leukemia.
Emodin is a kind of hydroxyanthraquinone chemical compound. It has many functions, such as anti-inflammation, bacteriostasis, immune regulation, inhibiting the secretion of trypsin, protecting the hepatic function and renal function, as well as anti-tumor effect. The anti-tumor effect of Emodin, including anti-proliferation and inducing apoptosis of tumor cells, reversing multidrug resistance, becomes the focus of medical research recent years.
The present study is thus designed to explore the effects of Emodin, at different concentrations, on the proliferation inhibition of leukemia cell lines K562 and U937, by observing the morphological changes, apoptosis bodies, measuring the change of cell cycle distributions and the apoptosis rates, and detecting the expression levels of bcl-2 and NF-κB mRNA by reverse transcriptase polymerase chain reaction (RT-PCR).
Methods:
1 Cell culture: K562 cells and U937 cells were cultured in RPMI-1640 medium which supplemented with 10% newborn bovine serum, at 37℃, 5% CO_2, and fully humidified atmosphere. Cells at logarithmic growth phase were treated with Emodin (at different final concentrations for 48 hours) as different treatment groups or without Emodin treatment as control group for 48 hours, then, they used for the following experiments.
2 Cells proliferation assay: A cell counting kit-8 (CCK-8) was used to measure the growing inhibition effect of Emodin on K562 cells or U937 cells. After the cells were treated with or without Emodin for 48 hours, 10μl of CCK8 solution were added to each group of cells, incubated at 37℃for another 2 hours. The absorbance of each sample was measured at 450 nm by using an enzyme-labeling measuring instrument. The inhibition rates were calculated based on the following formula: the inhibition rate (%) = (the absorbance value of control group - the absorbance value of experiment group)/the absorbance value of control group×100 % . The 50% inhibiting concentration (IC50) were also calculated from the result of this experiment.
3 Hoechst 33342 staining was performed to measure the index of cell apoptosis: K562 cells and U937 cells which had been treated with Emodin at IC50 concentration for 48h were collected, washed with PBS, then stained with Hoechst 33342. At least 400 cells were examined under a fluorescence microscope to observe morphological changes of apoptosis.
4 Flow cytometry (FCM) was used to measure the changes of cell cycle distribution and apoptosis rate: For FCM analysis, K562 cells and U937 cells were treated with Emodin at different concentrations for 48h. The cells were collected, washed with PBS and fixed with 70% ethanol. After the cells were washed with PBS again, RNAase were added to destroy RNA, then stained with propidium iodide (PI) for 30 minutes. 1×10~6 fixed cells were examined by FCM to measure the change of cell cycle distribution and apoptosis rate.
5 Measurement of enzyme activity of caspase3/7: K562 cells and U937 cells were treated with Emodin at different concentrations for 48h. Then 100μl of caspase3/7 enzyme activity measurement reagent were added to each cell culture and the cells were cultured for another 2 hours. The absorbance value was measured at 405 nm by using enzyme-labeling measuring instrument.
6 RT-PCR was performed to measure the mRNA expression levels of Bcl-2 and NF-κB: Total RNA was extracted from each group of cells by Trizol. The reverse transcription reaction was performed to synthesize cDNA by using M-MLV enzyme and random primer. The cDNA and the special primers were then used to amplify the target genes by PCR. PCR products were examined by agarose gel electrophoresis with Goldview staining, and the relative expression levels of Bcl-2 and NF-κB mRNA were calculated according to the expression level ofβ-action.
Results:
1 Emodin inhibited the growth of K562cells and U937 cells in a dose dependent manner and the IC50 of Emodin for K562 cells was 51.58μmol/L and 48.00μmol/L for U937 cells.
2 After cells had been treated with Emodin for 48 hours, morphological changes of cell apoptosis were observed clearly. The percentage of cells with bright blue fluorescence increased in the Emodin treated groups compared with that of control group, observed under a fluorescence microscope.
3 FCM examination results showed that the percentage of cells in S phase increased and the percentage of cells in G0/G1 phase and G2/M phase decreased in Emodin treated K562 cells compared with that of control cells (all P values are <0.05) in a dose-dependence manner. In U937 cell line cells, the percentage of cells in G0/G1 phase increased and the percentages of cells of S phase and G2/M phase decreased in Emodin treated cells compared with that of control cells (all P values are <0.05). Moreover, Emodin increased significantly the apoptosis rate of both cell lines in a dose-dependent manner (P values are <0.05).
4 The enzyme activity of caspase3/7 increased significance in both cell lines, after the treatment of Emodin (P values are <0.05).
5 RT-PCR results showed that the mRNA expression levels of bcl-2 and NF-κB decreased significantly in both K562 and U937 cells with the treatment of Emodin compared with that of control cells.
Conclusion: Emodin inhibited in vitro the growth of K562 cells and U937 cells efficiently. It probably played its role through down-regulating the expression of bcl-2 and NF-κB mRNA, blocking cells cycle progression and inducing the apoptosis of cells.
大黄素(Emodin,EM)是一种羟基蒽醌类化合物。它具有抗炎抑菌、免疫调节、抗胰酶、保护肝肾功能、抗肿瘤等生物活性,特别是大黄素的抗肿瘤作用,成为近年研究热点。它通过抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、影响细胞信号转导途径和影响细胞周期、逆转多药耐药等机制发挥其抗肿瘤作用。
本文主要观察不同浓度的大黄素对白血病细胞株K562、U937的增殖抑制作用,在细胞水平通过荧光显微镜和流式细胞仪检测不同浓度大黄素对两种细胞的形态学、细胞周期及凋亡率的影响,在分子水平上通过RT-PCR技术检测不同浓度大黄素对两种细胞内bcl-2及NF-κB基因表达的影响,从而探讨大黄素抑制白血病细胞株K562、U937增殖的有关机制。
方法:
1细胞培养:将K562、U937细胞按常规用RPMI 1640培养液培养,培养液内含10%新生牛血清(FBS)、100μg/mL青霉素、100U/mL链霉素和2mmol/L谷氨酰胺。置37℃,饱和度5%CO2环境下培养、传代,每2-3天传代一次。待细胞进入对数生长期后进行实验。
2细胞增殖抑制实验:分别测定不同浓度大黄素对K562、U937细胞作用48小时的增殖抑制率。取对数生长期的细胞加入不同浓度的大黄素,培养48小时后,加入CCK-8试剂。在相同条件下继续培养4小时后,在450nm波长下检测吸光度。根据吸光度(A值)计算细胞增殖抑制率。抑制率(%)=(A对照组-A实验组)/A对照组×100%。
3荧光染色观察细胞形态改变:分别收集IC50浓度的大黄素作用48h的K562、U937细胞,同时设立不加大黄素的空白对照组。将细胞用PBS洗后重悬,加入Hochest 33342荧光试剂染色。置荧光显微镜下计数400个细胞,观察细胞的形态学变化。
4流式细胞术检测细胞周期分布及凋亡率:取对数生长期的K562、U937细胞,加入不同浓度的大黄素作用于K562、U937细胞,48h后收集细胞,PBS洗后用70%乙醇4℃固定细胞,PBS再洗后加入RNA酶,10分钟后用终浓度为50μg/ml的PI染色30 min。流式细胞仪测定细胞周期,计算细胞周期变化及凋亡率。
5酶标仪检测caspase3/7活性:将K562、U937细胞接种于96孔板上。处理组的培养液中加入大黄素,使大黄素终浓度为IC50浓度。在37℃、5%CO_2体积分数的条件下培养48h后,加入100μl caspase3/7试剂,4h后酶标仪检测各组细胞在405nm处的吸光度(A值)。
6 RT-PCR检测bcl-2、NF-κB的表达:Trizol法提取细胞总RNA,采用随机引物法以M-MLV合成cDNA,以特异的引物扩增目的基因,琼脂糖凝胶电泳后Goldview染色,以β-action为内参,分析mRNA相对表达水平。
结果:
1大黄素能抑制K562、U937细胞生长并具有浓度依赖性,对K562细胞的IC50为51.58μmol/L,对U937细胞的IC50为48.00μmol/L。
2大黄素处理后,荧光显微镜下出现荧光标记的细胞增多,呈现亮蓝色。
3流式细胞仪检测结果:大黄素处理后,K562细胞主要表现为S期细胞增多、G0/G1期及G2/M期细胞减少(P<0.05);U937细胞主要表现为G0/G1期细胞增多、G2/M期及S期细胞减少(P<0.05)。两种细胞的凋亡率也随浓度的增加而增加(P<0.05)。
4酶标仪检测caspase3/7活性:大黄素处理后K562、U937细胞内的caspase3/7酶活性增加,与对照组相比有显著性差异(P<0.05)。
5 RT-PCR检测bcl-2、NF-κB的表达:大黄素处理后,K562、U937细胞内的bcl-2、NF-κB的表达均较对照组下调。
结论:大黄素对K562细胞、U937细胞生长抑制作用明显,可能通过下调bcl-2、NF-κB的表达,使细胞周期进程被阻滞,同时还促进肿瘤细胞发生凋亡。
Objective: Leukemia is a group of malignant clonal diseases derived from the hematopoietic stem cells (HSC), or from leukemic stem cells (LSC). These cells lose their normal ability of differentiation and maturation and accumulated in bone marrow and other hematopoietic tissues, such as liver and spleen. Leukemia cells can also infiltrate in other organs such as central nervous system (CNS) and testis. Growing of normal hematopoietic cells is suppressed by leukemia cells. The incidence of leukemia in our country is 2.76 per 100 thousands people. The mortality of leukemia occupies the top 6th for male and 8~(th) for female among the overall mortalities of adult malignant tumors. However, it rises to highest among children malignant tumors. Although several new effective drugs have been developed and the skills for hematopoietic stem cell transplantation improved during last decade, there are still many leukemia patients who can not achieve complete remission or relapse sooner or later after the complete remission. The treatment of leukemia becomes more difficult with the appearance of the primary or secondary drug resistance, especially multidrug resistance (MDR). Therefore, it is a long-term and pressing task to find new effective drugs without or with slight side-effect for the treatment of leukemia.
Emodin is a kind of hydroxyanthraquinone chemical compound. It has many functions, such as anti-inflammation, bacteriostasis, immune regulation, inhibiting the secretion of trypsin, protecting the hepatic function and renal function, as well as anti-tumor effect. The anti-tumor effect of Emodin, including anti-proliferation and inducing apoptosis of tumor cells, reversing multidrug resistance, becomes the focus of medical research recent years.
The present study is thus designed to explore the effects of Emodin, at different concentrations, on the proliferation inhibition of leukemia cell lines K562 and U937, by observing the morphological changes, apoptosis bodies, measuring the change of cell cycle distributions and the apoptosis rates, and detecting the expression levels of bcl-2 and NF-κB mRNA by reverse transcriptase polymerase chain reaction (RT-PCR).
Methods:
1 Cell culture: K562 cells and U937 cells were cultured in RPMI-1640 medium which supplemented with 10% newborn bovine serum, at 37℃, 5% CO_2, and fully humidified atmosphere. Cells at logarithmic growth phase were treated with Emodin (at different final concentrations for 48 hours) as different treatment groups or without Emodin treatment as control group for 48 hours, then, they used for the following experiments.
2 Cells proliferation assay: A cell counting kit-8 (CCK-8) was used to measure the growing inhibition effect of Emodin on K562 cells or U937 cells. After the cells were treated with or without Emodin for 48 hours, 10μl of CCK8 solution were added to each group of cells, incubated at 37℃for another 2 hours. The absorbance of each sample was measured at 450 nm by using an enzyme-labeling measuring instrument. The inhibition rates were calculated based on the following formula: the inhibition rate (%) = (the absorbance value of control group - the absorbance value of experiment group)/the absorbance value of control group×100 % . The 50% inhibiting concentration (IC50) were also calculated from the result of this experiment.
3 Hoechst 33342 staining was performed to measure the index of cell apoptosis: K562 cells and U937 cells which had been treated with Emodin at IC50 concentration for 48h were collected, washed with PBS, then stained with Hoechst 33342. At least 400 cells were examined under a fluorescence microscope to observe morphological changes of apoptosis.
4 Flow cytometry (FCM) was used to measure the changes of cell cycle distribution and apoptosis rate: For FCM analysis, K562 cells and U937 cells were treated with Emodin at different concentrations for 48h. The cells were collected, washed with PBS and fixed with 70% ethanol. After the cells were washed with PBS again, RNAase were added to destroy RNA, then stained with propidium iodide (PI) for 30 minutes. 1×10~6 fixed cells were examined by FCM to measure the change of cell cycle distribution and apoptosis rate.
5 Measurement of enzyme activity of caspase3/7: K562 cells and U937 cells were treated with Emodin at different concentrations for 48h. Then 100μl of caspase3/7 enzyme activity measurement reagent were added to each cell culture and the cells were cultured for another 2 hours. The absorbance value was measured at 405 nm by using enzyme-labeling measuring instrument.
6 RT-PCR was performed to measure the mRNA expression levels of Bcl-2 and NF-κB: Total RNA was extracted from each group of cells by Trizol. The reverse transcription reaction was performed to synthesize cDNA by using M-MLV enzyme and random primer. The cDNA and the special primers were then used to amplify the target genes by PCR. PCR products were examined by agarose gel electrophoresis with Goldview staining, and the relative expression levels of Bcl-2 and NF-κB mRNA were calculated according to the expression level ofβ-action.
Results:
1 Emodin inhibited the growth of K562cells and U937 cells in a dose dependent manner and the IC50 of Emodin for K562 cells was 51.58μmol/L and 48.00μmol/L for U937 cells.
2 After cells had been treated with Emodin for 48 hours, morphological changes of cell apoptosis were observed clearly. The percentage of cells with bright blue fluorescence increased in the Emodin treated groups compared with that of control group, observed under a fluorescence microscope.
3 FCM examination results showed that the percentage of cells in S phase increased and the percentage of cells in G0/G1 phase and G2/M phase decreased in Emodin treated K562 cells compared with that of control cells (all P values are <0.05) in a dose-dependence manner. In U937 cell line cells, the percentage of cells in G0/G1 phase increased and the percentages of cells of S phase and G2/M phase decreased in Emodin treated cells compared with that of control cells (all P values are <0.05). Moreover, Emodin increased significantly the apoptosis rate of both cell lines in a dose-dependent manner (P values are <0.05).
4 The enzyme activity of caspase3/7 increased significance in both cell lines, after the treatment of Emodin (P values are <0.05).
5 RT-PCR results showed that the mRNA expression levels of bcl-2 and NF-κB decreased significantly in both K562 and U937 cells with the treatment of Emodin compared with that of control cells.
Conclusion: Emodin inhibited in vitro the growth of K562 cells and U937 cells efficiently. It probably played its role through down-regulating the expression of bcl-2 and NF-κB mRNA, blocking cells cycle progression and inducing the apoptosis of cells.
引文
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11时玉舫,张莉英,王若翔.Fas和FasL:免疫细胞的自杀和谋杀.上海免疫学杂志, 1997, 17(4) : 197-9, 203
12林红伍.细胞凋亡与肿瘤.医学新知杂志,1997,7(4): 182-4,187
13 Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer,1972,26(4):239-57
14赵克森,金丽娟.休克的细胞和分子基础.北京科学出版社, 2002:255-256
15 Nagata S, Golstein P.The Fas death factor. Science,1995, 267(5203):1449-56
16姜泊,潭哓华,许岸高.细胞凋亡基础与临床.北京人民军医出版社,1999:9215
17王修庚,韦伟,高洪.细胞凋亡与疾病.中国畜牧兽医,2006, 33(9):426-8
18 Lee HZ. Protein kinase C involvement in aloe-emodin- and emodin-induced apoptosis in lung carcinoma cell.Br J Pharmacol,2001,134(5):1093-103
19 Koyama J,Morita I,Tagahara K,et al. Chemopreventive effects of emodin and cassiamin B in mouse skin carcinogenesis. Cancer Lett,2002,182 (2):135-9
20范仁根,单湘湘,宋长志,等.大黄素在体外诱导人肝癌细胞smmc-7721凋亡的实验研究.河北医学,2008,14(11): 1264-1270
21 Yang J,Li H,Chen YY,et al. Anthraquinones sensitize tumor cells to arsenic cytotoxicity in vitro and in vivo via reactive oxygen species-mediated dual regulation of apoptosis.Free Radic Biol Med,2004, 37(12):2027-41
22 Yi J, Yang J, He R, et al. Emodin enhances arsenic trioxide - induced apoptosis via generation of reactive oxygen species and inhibition of survival signaling.Cancer Res,2004,64(1): 108-16
23 Shieh DE,Chen YY,Yen MH, et al.Emodin-induced apoptosis through p53-dependent pathway in humanhepatoma cells.Life Sci,2004,74(18):2279-90
24 Kuo PL ,Hsu YL ,Ng LT ,et al . Rhein inhibits the growth and induces the apoptosis of Hep G2 cells.Planta Med 2004, 70(1):12-6
25连晓岚,胡建达,郑志宏,等.大黄素诱导白血病U937细胞凋亡及机制初探.中国药理学通报, 2007, 23(10):1312-6
26 Lida H,Towatari M,Tanimoto M,et al.Overexpression of cyclin E in acute myelogenous leukemia.Blood,1997,90(9): 3707-13
27 Doi TS,Marino MW,Takahashi T,et al.Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA, 1999, 96(6):2994-9
28 Chaisson ML,Brooling JT,Ladiges W, et al. Hepatocyte-specific inhibition of NF-kappaB leads to apoptosis after TNF treatment,but not after partial hepatectomy.J Clin Invest,2002,110(2):193-202
29 Kucharczak J,Simmons MJ,Fan Y,et al.To be,or not to be: NF-kappaB is the answer-role of Rel/NF-kappaB in the regulation of apoptosis.Oncogene,2003,22(56):8961-82
1徐任生.天然产物化学.第1版.北京:科学出版社,1993, 621-623
2谭仁祥.植物成分分析.第1版.北京:科学出版社,2002, 503-504
3焦东海,蒋小维,阮宜吾,等.全国首届大黄学术研讨会文献概述.中医杂志,1988,29(11):66-8
4 Huang SS, Yeh SF, Hong CY. Effect of anthraquinone derivatives on lipid peroxidation in rat heart mitochondria: Structure-activity relationship. J Nat Prod, 1995, 58 (9): 1365-71
5 Kumar A, Dhawans S, Aggarwal BB. Emodin (3-methyl-1, 6,8-trihydroxyanthraquinone) inhibits TNF-induced NF- kappaB activation, IkappaB degradation, and expression of cell surface adhesion protein in human vascular endothelial cells. Oncogene, 1998, 17 (7):913-8
6 Wang HH, Chung JG. Emodin induced inhibition of growth and DNA damage in the Helicobacter pylori. Curr Microbiol, 1997,35(5):262-6
7 Goel RK, Das Gupta G, Ram SN, et al. Antiulcerogenic and anti-inflammatory effects of emodin, isolated from Rhamnus triquerta wall. Indian J Exp Biol,1991,29(3):230-2
8张骏,翁福海.大黄素对内毒素刺激下的大鼠腹腔巨噬细胞分泌TNF-α及NO的影响.天津医科大学学报,2001,7(2): 189-191
9张骏,翁福海,李会强,等.大黄素对大鼠腹腔巨噬细胞产生的TNF-α、IL-1、IL-6及细胞[Ca2+] i的影响.中草药,2001, 32(8):718-721
10展玉涛,魏红山,王志荣,等.大黄素对大鼠四氯化碳性肝损伤保护作用的实验研究.中国中医药科技, 2000,7(1):30-33
11展玉涛,魏红山,王志荣,等.大黄素抗肝纤维化作用的实验研究.中华肝脏病杂志,2001, 9(4):235-237
12刘冠贤,叶任高,谭志明,等.大黄素延缓狼疮性肾炎肾间质纤维化作用的研究.中国实验临床免疫学杂志,1999,11(3): 24-7
13陈高翔,屈遂林.依那普利及大黄素对人肾成纤维细胞的影响.中国航天工业医药,2000,2(4):325-8
14周成华,武玉清,许正新等.大黄素对小肠运动的影响及其机制.中国药理学通报,2003,19(12):1421-1424
15邱轶伟,马涛,吴双虎,等.大黄素收缩大鼠结肠平滑肌细胞的信号转异机制研究.天津医科大学学报,2005,11(2):205-208
16吕金胜,何凤慈,刘震东,等.大黄素对动物离体回肠收缩作用的影响.中国药业,2000,9(11):25
17胡昌江,马烈,何学梅,等.九制大黄蒽醌衍生物对动物高血脂及血液流变学的影响.中成药, 2001,23(1):31-3
18侯晓东,施瑞城,叶丽萍.大黄素的研究现状和展望.中国热带医学,2005,5(8):8371,9371,0471
19姜晓峰,甄永苏.大黄素逆转肿瘤细胞多药抗药性的作用.药学学报,1999,34(3):164-7
20郑合勇,胡建达,黄绿叶,等.大黄素可能通过抑制Akt信号通路诱导HL-60细胞凋亡.药学学报,2007,42 (11):1142-6
21连晓岚,胡建达,郑志宏,等.大黄素诱导白血病U937细胞凋亡及机制初探.中国药理学通报,2007,23(10):1312-6
22 Kim MS, Park MJ, Kim SJ, et al. Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. Int J Oncol, 2005, 27(3):839-46
23董春燕,马占军,吴红玉,等.大黄素抑制胃癌细胞SGC-7901生长的实验研究.哈尔滨医科大学学报,2008,42(4): 358-60,363
24范仁根,单湘湘,宋长志,等.大黄素在体外诱导人肝癌细胞smmc-7721凋亡的实验研究.河北医学,2008,14(11): 1264-1270
25吕盈盈,钱家鸣,邱辉忠.大黄素对结肠癌血管内皮生长因子受体的影响及对结肠癌抑制作用的研究.中国中西医结合消化杂志,2005,13(5):310-13
26 Yang J, Li H, Chen YY, et al. Anthraquinones sensitize tumor cells to arsenic cytotoxicity in vitro and in vivo via reactive oxygen species-mediated dual regulation of apoptosis. Free Radic Biol Med,2004,37(12):2027-41
27 Su YT, Chang HL, Shyue SK, et al. Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway. Biochem Pharmacol, 2005, 70(2):229-41
28 Srinivas G, Anto RJ, Srinivas P, et al. Emodin induces apoptosis of human cervical cancer cells through poly(ADP- ribose) polymerase cleavage and activation of caspase-9. Eur J Pharmacol, 2003, 473(2-3):117-25
29 Zhu F, Liu XG, Liang NC. Effect of emodin and apigenin on invasion of human ovarian carcinoma HO-8910PM cells in vitro. Ai Zheng, 2003, 22(4):358-62
30 Yi J, Yang J, He R, et al. Emodin enhances arsenic trioxide- induced apoptosis via generation of reactive oxygen species and inhibition of survival signaling. Cancer Res,2004,64(1):108-16
31 Cha TL,Qiu L,Chen CT,et al.Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth. Cancer Res, 2005, 65(6):2287-95
32 Koyama J, Morita I, Tagahara K, et al. Chemopreventive effects of emodin and cassiamin B in mouse skin carcinogenesis. Cancer Lett, 2002,182(2):135-9
33 Kuo YC , Sun CM , Ou JC , et al. A tumor cell growth inhibitor from Polygonum hypoleucum Ohwi. Life Sci,1997, 61(23):2335-44
34 Gilmore TD. Clinically relevant findings. J Clin Invest,1997, 100(12):2935-6
35 Li JJ, Westergaard C, Ghosh P, et al . Inhibitors of both nuclear factor-kappaB and activator protein-1 activation block the neoplastic transformation response. Cancer Res,1997,57 (16):3569-76
36杨洁,汤雪明,李慧,等.大黄素提高HeLa细胞对三氧化二砷促凋亡敏感性的研究.实验生物学报,2003,36(6): 465-475
37 Lee HZ. Protein kinase C involvement in aloe-emodin- and emodin-induced apoptosis in lung carcinoma cell. Br J Pharmacol, 2001, 134(5):1093-103
38 Chen YC, Shen SC, Lee WR, et al. Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase-3 cascade but independent of reactive oxygen species production. BiochemPharmacol, 2002, 64(12):1713-24
39贺学强,林鸿,郑宝轩,等.大黄素对肝癌细胞SMMC-7721抑制作用及P53、C-myc蛋白的表达.中国中医药信息杂志, 2005, 12(1):21-22
40肖金玲,吕福祯,李家宁.大黄素对AGZY-83A细胞内Ki-67抗原表达的影响.哈尔滨医科大学学报,2005,39(2):158-162
41王心华,甄永苏.大黄素抑制人高转移巨细胞肺癌PG细胞的肿瘤转移相关性质.癌症,2001,20(8):789-793
42 Shieh DE, Chen YY, Yen MH, et al . Emodin-induced apoptosis through p53-dependent pathway in human hepatoma cells. Life Sci, 2004, 74(18):2279-90
43 Kuo PL , Hsu YL , Ng LT , et al . Rhein inhibits the growth and induces the apoptosis of Hep G2 cells. Planta Med 2004, 70(1):12-6
44彭黎明等.细胞凋亡的基础与临床.人民卫生出版社.2000, 37
45彭黎明等.细胞凋亡的基础与临床.人民卫生出版社.2000, 43
46刘景生.细胞信息与调控.人民卫生出版社. 1998, 172-175
47 Jing X, Ueki N, Cheng J, et al. Induction of apoptosis in hepatocellular carcinoma cell lines by emdion. Jpn J Cancer Res, 2002, 93(8):874-82
48彭黎明等.细胞凋亡的基础与临床.人民卫生出版社.2000, 64
49 Wang XH, Wu SY, Zhen YS. Inhibitory effects of emodin onangiogenesis. Yao Xue Xue Bao,2004,39(4):254-8
50 Huang Q, Shen HM, Shui G, et al. Emodin inhibits tumor cell adhesion through disruption of the membrane lipid Raft-associated integrin signaling pathway. Cancer Res, 2006, 66(11):5807-15
51 Huang Q, Shen HM, Ong CN. Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/ Rac1 pathway.Cell Mol Life Sci,2005, 62(10):1167-75
52 Kwak HJ, Park MJ, Park CM, et al. Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2(KDR/Flk-1) phosphorylation. Int J Cancer 2006, 118(11):2711-20
53胡凯文,侯丽,陈信义,等.大黄酸/大黄素抗多药耐药肿瘤细胞研究.中国中医基础医学杂志,1998,45(11):19-20
54 Brown M, Bellon M, Nicot C. Emodin and DHA potently increase arsenic trioxide interferon-alpha-induced cell death of HTLV-I-transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1. Blood,2007,109(4): 1653-9
55 Jing Y, Yang J, Wang Y, et al. Alteration of subcellular redox equilibrium and the consequent oxidative modification of nuclear factor kappa B are critical for anticancer cytotoxicity by emodin, a reactive oxygen species-producing agent. Free Radic Biol Med,2006,40(12):2183-2197
56 Fu ZY, Han JX, Huang HY. Effects of emodin on geneexpression profile in small cell lung cancer NCI-H446 cells. Chin Med J (Engl),2007,120(19):1710-5
57 Zhang L, Hung MC. Sensitization of HER-2/ neu- overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by tyrosine kinase inhibitor emodin. Oncogene,1996,12(3):571-6
58 Yi J, Yang J, He R, et al. Emodin enhances arsenic trioxide- induced apoptosis via generation of reactive oxygen species and inhibition of survival signaling. Cancer Res, 2004, 64(1):108-16
2谭仁祥.植物成分分析.第1版.北京:科学出版社,2002, 503-504
3邱学德,刘乔保,孙力莉等.大黄素对膀胱肿瘤细胞株BIU87和T24的作用研究.云南医药, 2004, 25(3):192-4
4 Kim MS, Park MJ, Kim SJ, et al. Emodin suppresseshyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. Int J Oncol, 2005, 27(3):839-46
5范仁根,单湘湘,宋长志,等.大黄素在体外诱导人肝癌细胞smmc-7721凋亡的实验研究.河北医学,2008, 14(11): 1264-70
6廖子君,宋永春,陈晓泉.大黄素对人肺腺癌A-549细胞增殖周期影响的实验研究.中华肿瘤防治杂志,2007,14(5): 342-344
7董春燕,马占军,吴红玉,等.大黄素抑制胃癌细胞SGC-7901生长的实验研究.哈尔滨医科大学学报,2008,42(4): 358-60,363
8郑合勇,胡建达,黄绿叶,等.大黄素可能通过抑制Akt信号通路诱导HL-60细胞凋亡.药学学报,2007,42(11):1142-6
9连晓岚,胡建达,郑志宏,等.大黄素诱导白血病U937细胞凋亡及机制初探.中国药理学通报,2007, 23(10):1312-6
10陈英玉,郑合勇,胡建达,等.大黄素抑制HL-60/ADR耐药细胞增殖和诱导凋亡的作用.中国实验血液学杂志,2007,15(5): 955-960
11时玉舫,张莉英,王若翔.Fas和FasL:免疫细胞的自杀和谋杀.上海免疫学杂志, 1997, 17(4) : 197-9, 203
12林红伍.细胞凋亡与肿瘤.医学新知杂志,1997,7(4): 182-4,187
13 Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer,1972,26(4):239-57
14赵克森,金丽娟.休克的细胞和分子基础.北京科学出版社, 2002:255-256
15 Nagata S, Golstein P.The Fas death factor. Science,1995, 267(5203):1449-56
16姜泊,潭哓华,许岸高.细胞凋亡基础与临床.北京人民军医出版社,1999:9215
17王修庚,韦伟,高洪.细胞凋亡与疾病.中国畜牧兽医,2006, 33(9):426-8
18 Lee HZ. Protein kinase C involvement in aloe-emodin- and emodin-induced apoptosis in lung carcinoma cell.Br J Pharmacol,2001,134(5):1093-103
19 Koyama J,Morita I,Tagahara K,et al. Chemopreventive effects of emodin and cassiamin B in mouse skin carcinogenesis. Cancer Lett,2002,182 (2):135-9
20范仁根,单湘湘,宋长志,等.大黄素在体外诱导人肝癌细胞smmc-7721凋亡的实验研究.河北医学,2008,14(11): 1264-1270
21 Yang J,Li H,Chen YY,et al. Anthraquinones sensitize tumor cells to arsenic cytotoxicity in vitro and in vivo via reactive oxygen species-mediated dual regulation of apoptosis.Free Radic Biol Med,2004, 37(12):2027-41
22 Yi J, Yang J, He R, et al. Emodin enhances arsenic trioxide - induced apoptosis via generation of reactive oxygen species and inhibition of survival signaling.Cancer Res,2004,64(1): 108-16
23 Shieh DE,Chen YY,Yen MH, et al.Emodin-induced apoptosis through p53-dependent pathway in humanhepatoma cells.Life Sci,2004,74(18):2279-90
24 Kuo PL ,Hsu YL ,Ng LT ,et al . Rhein inhibits the growth and induces the apoptosis of Hep G2 cells.Planta Med 2004, 70(1):12-6
25连晓岚,胡建达,郑志宏,等.大黄素诱导白血病U937细胞凋亡及机制初探.中国药理学通报, 2007, 23(10):1312-6
26 Lida H,Towatari M,Tanimoto M,et al.Overexpression of cyclin E in acute myelogenous leukemia.Blood,1997,90(9): 3707-13
27 Doi TS,Marino MW,Takahashi T,et al.Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA, 1999, 96(6):2994-9
28 Chaisson ML,Brooling JT,Ladiges W, et al. Hepatocyte-specific inhibition of NF-kappaB leads to apoptosis after TNF treatment,but not after partial hepatectomy.J Clin Invest,2002,110(2):193-202
29 Kucharczak J,Simmons MJ,Fan Y,et al.To be,or not to be: NF-kappaB is the answer-role of Rel/NF-kappaB in the regulation of apoptosis.Oncogene,2003,22(56):8961-82
1徐任生.天然产物化学.第1版.北京:科学出版社,1993, 621-623
2谭仁祥.植物成分分析.第1版.北京:科学出版社,2002, 503-504
3焦东海,蒋小维,阮宜吾,等.全国首届大黄学术研讨会文献概述.中医杂志,1988,29(11):66-8
4 Huang SS, Yeh SF, Hong CY. Effect of anthraquinone derivatives on lipid peroxidation in rat heart mitochondria: Structure-activity relationship. J Nat Prod, 1995, 58 (9): 1365-71
5 Kumar A, Dhawans S, Aggarwal BB. Emodin (3-methyl-1, 6,8-trihydroxyanthraquinone) inhibits TNF-induced NF- kappaB activation, IkappaB degradation, and expression of cell surface adhesion protein in human vascular endothelial cells. Oncogene, 1998, 17 (7):913-8
6 Wang HH, Chung JG. Emodin induced inhibition of growth and DNA damage in the Helicobacter pylori. Curr Microbiol, 1997,35(5):262-6
7 Goel RK, Das Gupta G, Ram SN, et al. Antiulcerogenic and anti-inflammatory effects of emodin, isolated from Rhamnus triquerta wall. Indian J Exp Biol,1991,29(3):230-2
8张骏,翁福海.大黄素对内毒素刺激下的大鼠腹腔巨噬细胞分泌TNF-α及NO的影响.天津医科大学学报,2001,7(2): 189-191
9张骏,翁福海,李会强,等.大黄素对大鼠腹腔巨噬细胞产生的TNF-α、IL-1、IL-6及细胞[Ca2+] i的影响.中草药,2001, 32(8):718-721
10展玉涛,魏红山,王志荣,等.大黄素对大鼠四氯化碳性肝损伤保护作用的实验研究.中国中医药科技, 2000,7(1):30-33
11展玉涛,魏红山,王志荣,等.大黄素抗肝纤维化作用的实验研究.中华肝脏病杂志,2001, 9(4):235-237
12刘冠贤,叶任高,谭志明,等.大黄素延缓狼疮性肾炎肾间质纤维化作用的研究.中国实验临床免疫学杂志,1999,11(3): 24-7
13陈高翔,屈遂林.依那普利及大黄素对人肾成纤维细胞的影响.中国航天工业医药,2000,2(4):325-8
14周成华,武玉清,许正新等.大黄素对小肠运动的影响及其机制.中国药理学通报,2003,19(12):1421-1424
15邱轶伟,马涛,吴双虎,等.大黄素收缩大鼠结肠平滑肌细胞的信号转异机制研究.天津医科大学学报,2005,11(2):205-208
16吕金胜,何凤慈,刘震东,等.大黄素对动物离体回肠收缩作用的影响.中国药业,2000,9(11):25
17胡昌江,马烈,何学梅,等.九制大黄蒽醌衍生物对动物高血脂及血液流变学的影响.中成药, 2001,23(1):31-3
18侯晓东,施瑞城,叶丽萍.大黄素的研究现状和展望.中国热带医学,2005,5(8):8371,9371,0471
19姜晓峰,甄永苏.大黄素逆转肿瘤细胞多药抗药性的作用.药学学报,1999,34(3):164-7
20郑合勇,胡建达,黄绿叶,等.大黄素可能通过抑制Akt信号通路诱导HL-60细胞凋亡.药学学报,2007,42 (11):1142-6
21连晓岚,胡建达,郑志宏,等.大黄素诱导白血病U937细胞凋亡及机制初探.中国药理学通报,2007,23(10):1312-6
22 Kim MS, Park MJ, Kim SJ, et al. Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. Int J Oncol, 2005, 27(3):839-46
23董春燕,马占军,吴红玉,等.大黄素抑制胃癌细胞SGC-7901生长的实验研究.哈尔滨医科大学学报,2008,42(4): 358-60,363
24范仁根,单湘湘,宋长志,等.大黄素在体外诱导人肝癌细胞smmc-7721凋亡的实验研究.河北医学,2008,14(11): 1264-1270
25吕盈盈,钱家鸣,邱辉忠.大黄素对结肠癌血管内皮生长因子受体的影响及对结肠癌抑制作用的研究.中国中西医结合消化杂志,2005,13(5):310-13
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