黄芩苷抗肿瘤作用分子机制的实验研究
摘要
1.黄芩苷对S_(180)荷瘤小鼠抑瘤作用机制的研究
目的:探讨黄芩苷对S_(180)荷瘤小鼠的抑瘤作用机制。
方法:取60只小鼠复制S_(180)瘤模型,随机分成5组:黄芩苷大、中、小剂量组,对照组,环磷酰胺组。观察黄芩苷对S_(180)荷瘤小鼠的抑制率、脾指数及胸腺指数,NK(natural killer,NK)细胞活性及血清肿瘤坏死因子-a(tumor necrosis facter-a,TNF-a)、白介素-2(interleukin-2,IL-2)的含量,肿瘤组织血管内皮生长因子(vascularendothelial growth factor,VEGF)的表达。
结果:各种剂量的黄芩苷对小鼠S_(180)肉瘤均有明显的抑制效应,且呈现剂量依赖性,大、中、小剂量组小鼠抑瘤率分别为56.0%、48.0%、36.0%,与对照组比较均有显著性差异(P＜0.05)。此外,与对照组比较,黄芩苷大、中剂量组的脾指数有显著性差异(P＜0.05);大、中、小剂量组的胸腺指数、NK细胞活性、血清TNF-a、IL-2含量均有显著性差异(P＜0.05)。Western blot结果表明,VEGF在黄芩苷大、中、小剂量组小鼠瘤组织中的表达与对照组比较,有显著性差异(P＜0.05)。
结论:黄芩苷能够抑制S_(180)荷瘤小鼠肿瘤生长;并能明显升高S_(180)荷瘤小鼠脾细胞NK细胞活性及血清TNF-a、IL-2的含量,对小鼠的免疫功能有调节作用;同时黄芩苷可以下调S_(180)荷瘤小鼠肿瘤组织VEGF的表达。
2.黄芩苷对HepG-2细胞诱导凋亡作用的研究
目的:研究黄芩苷体外对HepG-2细胞抑制增殖、诱导凋亡的作用,并初步探讨其作用机制。
方法:采用体外细胞培养方法,应用MTT法检测黄芩苷对HepG-2细胞的抗增殖作用及细胞毒活性;通过倒置显微镜、HE染色、扫描电镜(scannin electron microscope,SEM)观察凋亡细胞的形态学及超微结构的改变;应用流式细胞术(flow cytometry,FCM)分析细胞周期和凋亡率,观察黄芩苷对HepG-2细胞的诱导凋亡作用;通过免疫细胞化学(S-P法)检测凋亡相关基因bcl-2、bax、p53蛋白表达的改变;采用Westernblot技术检测Caspase-3蛋白表达情况,初步探讨黄芩苷在体外对HepG-2细胞诱导凋亡作用的可能机制。
结果:(1)MTT比色法结果表明,黄芩苷在体外对HepG-2细胞有明显的抑制作用,且这种抑制作用呈现浓度和时间依赖性。(2)形态学观察:倒置显微镜、扫描电镜及HE染色结果表明,黄芩苷作用于肿瘤细胞后,可诱导较典型的细胞凋亡形态学变化及超微结构改变,如细胞胞体缩小,胞质浓缩,微绒毛结构减少甚至消失,胞核向外呈锐角突起,染色质高度浓缩,电子密度增高,边集于核膜下或呈新月形,有的出现核固缩,核碎裂以及凋亡小体形成等。(3)免疫细胞化学(S-P法)检测凋亡相关基因bel-2、p53蛋白表达明显减少、bax表达明显增加;Bcl-2/Bax比例明显降低。(4)流式细胞仪分析结果,50μg/ml黄芩苷作用于HepG-2细胞48 h后,出现明显的细胞凋亡峰,其凋亡率为27.01%,与对照组细胞的凋亡率5.47%相比差异有显著性(P＜0.01)。且G2/M期细胞明显减少,而S期细胞比率显著上升,多数细胞阻滞在S期。(5)Western blot结果显示,随着药物浓度的增加Caspase-3酶原蛋白条带逐渐变细,并且可见到蛋白裂解产物(Caspase-3蛋白)逐渐增多。
结论:黄芩苷对HepG-2细胞具有较强的抑制增殖和诱导凋亡的作用;黄芩苷诱导HepG-2细胞凋亡的机制可能与下调p53基因表达和降低Bcl-2/Bax比例,从而促进Caspase-3的活化有关。
1.Study on the inhibition effect mechanism of baicalin in S_(180) mice
Objectives:To study the inhibition effect mechanism of baicalin in S_(180) mice.
Methods:The S_(180) sarcomas was transplanted in 60 KM mice,then they were divided randomly into 5 groups to receive different treatment(high,medium and low dose group of baicalin chloroform extract,cyclophosphosphamide group and control group.The inhibition ratios of the tumor,the spleen index and thymus index were calculated out,the activities of NK cell and the contents of TNF-a,IL-2 in serum were detected.And the levels of VEGF protein was assayed with Western blot.
Results:Baicalin could increase the levels of the inhibition ratios of the tumor weight,the spleen index and thymus index in mice,and the effects were in a dose dependent manner.The inhibition ratios of tumor in high,medium and low dose group of baicalin were 56.0%,48.0%,36.0%,and the difference was significant compared with the control group(P＜0.05).The research also finds that the difference of the thymus index,the activities of NK cell and the contents of TNF-a,IL-2 in serum were significant in high,medium and low dose group of baicalin comparing with the control group (P＜0.05).Western blot disclosed that bicalin also could markly downregulate the expression of VEGF gene and compared with control group the difference was significant (P＜0.05).
Conclusions:The baicalin could suppres mouse S180 tumor growth and increase the activities of NK cell and the contents of TNF-a,IL-2 in serum significantly.It also could regulate the mice immunity and markly downregulate the expression of VEGF gene.
2.Study on the apoptosis-inducing effect mechanism of baicalin on HepG-2 cell line
Objective:To study the inhibition proliferation and the apoptosis-inducing effect of Baicalin and the perhaps mechanism.
Methods:The HepG-2 cell were cultured in vitro.To detect the change of the correlated index.The antiproliferation and cytotoxic efficiency of Baicalin on HepG-2 cell was assessed with MTT assay.The cell apoptosis effect was observed by inverted microscope,HE staining and scannin electron microscope(SEM).The cell growth cycle and apoptosis ratio were measured by flow cytometry(FCM).The expressions of caspase-3 protein was detected by Western blot.
Results:(1) MTT assay disclosed that Baicalin inhibited the proliferation of HepG-2 cell and the effects were in a time-and-concentration dependent manner.(2) Inverted microscope,HE staining and SEM disclosed that Baicalin induced the typical apoptosis change in cell morphology.(3) FCM disclosed that the ratio of apoptosis was significanfly different as compared with that of control group compared with the control group 5.47%,deviation was significant(P＜0.01) in 48 hours.the tumor cells on G2/M stage decrease obviously and on S stage,the cells increase notablely.(4) Immunocytochemistry disclosed bcl-2,p53 were significantly decreased and bax increased.(5) Western blot disclosed that followed by the increase of Baicalin,caspase-3 protein expression was step up gradually.
Conclusions:Baicalin could make some effect on inhibiting proliferation and apoptosis- inducing on HepG-2 cell line,perhaps related to activating of Caspase-3.
目的:探讨黄芩苷对S_(180)荷瘤小鼠的抑瘤作用机制。
方法:取60只小鼠复制S_(180)瘤模型,随机分成5组:黄芩苷大、中、小剂量组,对照组,环磷酰胺组。观察黄芩苷对S_(180)荷瘤小鼠的抑制率、脾指数及胸腺指数,NK(natural killer,NK)细胞活性及血清肿瘤坏死因子-a(tumor necrosis facter-a,TNF-a)、白介素-2(interleukin-2,IL-2)的含量,肿瘤组织血管内皮生长因子(vascularendothelial growth factor,VEGF)的表达。
结果:各种剂量的黄芩苷对小鼠S_(180)肉瘤均有明显的抑制效应,且呈现剂量依赖性,大、中、小剂量组小鼠抑瘤率分别为56.0%、48.0%、36.0%,与对照组比较均有显著性差异(P＜0.05)。此外,与对照组比较,黄芩苷大、中剂量组的脾指数有显著性差异(P＜0.05);大、中、小剂量组的胸腺指数、NK细胞活性、血清TNF-a、IL-2含量均有显著性差异(P＜0.05)。Western blot结果表明,VEGF在黄芩苷大、中、小剂量组小鼠瘤组织中的表达与对照组比较,有显著性差异(P＜0.05)。
结论:黄芩苷能够抑制S_(180)荷瘤小鼠肿瘤生长;并能明显升高S_(180)荷瘤小鼠脾细胞NK细胞活性及血清TNF-a、IL-2的含量,对小鼠的免疫功能有调节作用;同时黄芩苷可以下调S_(180)荷瘤小鼠肿瘤组织VEGF的表达。
2.黄芩苷对HepG-2细胞诱导凋亡作用的研究
目的:研究黄芩苷体外对HepG-2细胞抑制增殖、诱导凋亡的作用,并初步探讨其作用机制。
方法:采用体外细胞培养方法,应用MTT法检测黄芩苷对HepG-2细胞的抗增殖作用及细胞毒活性;通过倒置显微镜、HE染色、扫描电镜(scannin electron microscope,SEM)观察凋亡细胞的形态学及超微结构的改变;应用流式细胞术(flow cytometry,FCM)分析细胞周期和凋亡率,观察黄芩苷对HepG-2细胞的诱导凋亡作用;通过免疫细胞化学(S-P法)检测凋亡相关基因bcl-2、bax、p53蛋白表达的改变;采用Westernblot技术检测Caspase-3蛋白表达情况,初步探讨黄芩苷在体外对HepG-2细胞诱导凋亡作用的可能机制。
结果:(1)MTT比色法结果表明,黄芩苷在体外对HepG-2细胞有明显的抑制作用,且这种抑制作用呈现浓度和时间依赖性。(2)形态学观察:倒置显微镜、扫描电镜及HE染色结果表明,黄芩苷作用于肿瘤细胞后,可诱导较典型的细胞凋亡形态学变化及超微结构改变,如细胞胞体缩小,胞质浓缩,微绒毛结构减少甚至消失,胞核向外呈锐角突起,染色质高度浓缩,电子密度增高,边集于核膜下或呈新月形,有的出现核固缩,核碎裂以及凋亡小体形成等。(3)免疫细胞化学(S-P法)检测凋亡相关基因bel-2、p53蛋白表达明显减少、bax表达明显增加;Bcl-2/Bax比例明显降低。(4)流式细胞仪分析结果,50μg/ml黄芩苷作用于HepG-2细胞48 h后,出现明显的细胞凋亡峰,其凋亡率为27.01%,与对照组细胞的凋亡率5.47%相比差异有显著性(P＜0.01)。且G2/M期细胞明显减少,而S期细胞比率显著上升,多数细胞阻滞在S期。(5)Western blot结果显示,随着药物浓度的增加Caspase-3酶原蛋白条带逐渐变细,并且可见到蛋白裂解产物(Caspase-3蛋白)逐渐增多。
结论:黄芩苷对HepG-2细胞具有较强的抑制增殖和诱导凋亡的作用;黄芩苷诱导HepG-2细胞凋亡的机制可能与下调p53基因表达和降低Bcl-2/Bax比例,从而促进Caspase-3的活化有关。
1.Study on the inhibition effect mechanism of baicalin in S_(180) mice
Objectives:To study the inhibition effect mechanism of baicalin in S_(180) mice.
Methods:The S_(180) sarcomas was transplanted in 60 KM mice,then they were divided randomly into 5 groups to receive different treatment(high,medium and low dose group of baicalin chloroform extract,cyclophosphosphamide group and control group.The inhibition ratios of the tumor,the spleen index and thymus index were calculated out,the activities of NK cell and the contents of TNF-a,IL-2 in serum were detected.And the levels of VEGF protein was assayed with Western blot.
Results:Baicalin could increase the levels of the inhibition ratios of the tumor weight,the spleen index and thymus index in mice,and the effects were in a dose dependent manner.The inhibition ratios of tumor in high,medium and low dose group of baicalin were 56.0%,48.0%,36.0%,and the difference was significant compared with the control group(P＜0.05).The research also finds that the difference of the thymus index,the activities of NK cell and the contents of TNF-a,IL-2 in serum were significant in high,medium and low dose group of baicalin comparing with the control group (P＜0.05).Western blot disclosed that bicalin also could markly downregulate the expression of VEGF gene and compared with control group the difference was significant (P＜0.05).
Conclusions:The baicalin could suppres mouse S180 tumor growth and increase the activities of NK cell and the contents of TNF-a,IL-2 in serum significantly.It also could regulate the mice immunity and markly downregulate the expression of VEGF gene.
2.Study on the apoptosis-inducing effect mechanism of baicalin on HepG-2 cell line
Objective:To study the inhibition proliferation and the apoptosis-inducing effect of Baicalin and the perhaps mechanism.
Methods:The HepG-2 cell were cultured in vitro.To detect the change of the correlated index.The antiproliferation and cytotoxic efficiency of Baicalin on HepG-2 cell was assessed with MTT assay.The cell apoptosis effect was observed by inverted microscope,HE staining and scannin electron microscope(SEM).The cell growth cycle and apoptosis ratio were measured by flow cytometry(FCM).The expressions of caspase-3 protein was detected by Western blot.
Results:(1) MTT assay disclosed that Baicalin inhibited the proliferation of HepG-2 cell and the effects were in a time-and-concentration dependent manner.(2) Inverted microscope,HE staining and SEM disclosed that Baicalin induced the typical apoptosis change in cell morphology.(3) FCM disclosed that the ratio of apoptosis was significanfly different as compared with that of control group compared with the control group 5.47%,deviation was significant(P＜0.01) in 48 hours.the tumor cells on G2/M stage decrease obviously and on S stage,the cells increase notablely.(4) Immunocytochemistry disclosed bcl-2,p53 were significantly decreased and bax increased.(5) Western blot disclosed that followed by the increase of Baicalin,caspase-3 protein expression was step up gradually.
Conclusions:Baicalin could make some effect on inhibiting proliferation and apoptosis- inducing on HepG-2 cell line,perhaps related to activating of Caspase-3.
引文
[1]Francesco Fabbril,Silvia Carlonil,Giovanni Brigliadoril.Hepatocellular carcinoma in extremely elderly patients:an analysis of clinical characteristics,prognosis and patient survival[J].World J Gastroenterol,2006,12(1):48-53.
[2]Llovet JM,Fuster J,Bruix J.The Barcelona approach:diagnosis,staging and treatment of hepatocellular carcinoma[J].Liver Transpl,2004,10:115-120.
[3]Tammela T,Enholm B,Alitalo K,et al.The biology of vascular endothelial growth factors[J].Cardiovasc Res,2005,65(3):550-563.
[4]Tanaka A,Suemaru K,Otsuka T,et al.Hoek's formula,a cystatin C-based prediction formula for determining the glomerular filtration rate,is the most effective method for original adjusting the dosage of vancomycin[J],Int J Clin Pharmacol Ther,2007,45(11):592-597.
[5]Toyoda K,Uda K,Shirakawa A,et al.Combined and staged endovascular recanalization of cervical and intracranial arteries in hyperacute ischemic stroke.[J].Intern Med,2007,46(23):1935-1936.
[6]Donala K,Senger D,Livingston V,et al.Vascular permeability factor(VEGF,VPE)in tumor biology[J].Cancer Metastasis Rev,1993,12:303-324.
[7]Malsonpiewe PC,SuriC,Jones PF,et al.Angiopoietin22,a natural antagonist for tie22 that disrupts in vivo angiogenesis[J].Science,1997,277(5322):55-60.
[8]Suri C,Jones PF,Patan S,et al.Requisite role of angiopoietin21:a ligand for the Tie2receptor during embryonic angiogenesis[J].Cell,1996,87(7):1171-1180.
[9]Valenzuela DM,Griffiths J,Rojas J,et al.Angiopoietin 3 and 4:diverging gene counterparts in mouse and man[J].Proc Natl Acad Sci USA,1999,96(5):1904-1909.
[10]Moenner M,G usse M.The widespread expression of angiogenin in diferent human cells suggests a biological function not only related to angiogenesis.Eur J Biochem,1994,226:483-490.
[11]Choprav,Dinh TV.Serum levels of interleukins,growth factors and angiogenin in patients with endometrial cancer[J].J Cancer Res Clin Oncol,1997,123:167-172.
[12]中华人民共和国卫生部药典委员会.中国药典一部[M].北京:化学工业出版社, 2005.211-212.
[13]Craig B.Apoptosis in the pathogenesis and treatment of disease[J].Science,1995,267:1456-1460.
[14]厉红元,车艺,汤为学,等.姜黄素对人肝癌细胞增殖和凋亡的影响[J].中华肝脏病杂志,2002,10(6):449-451.
[15]王娟,王顺启,倪虹,等.莪术挥发油抑制人肝癌细胞株SMMC-7721生长的实验研究[J].天津中医药,2003,20(1):48-50.
[16]杨小平,张星.青蒿酯钠诱导人肿瘤细胞凋亡及其分子机制的探讨[J].中草药,2002.33(9):819-821.
[17]朱秀琴,王国申,张学军,等.中药阿魏酸钠对人肝癌细胞生存性及凋亡的影响[J].世界华人消化杂志,1999,7(8):715-755.
[18]吕晓英,曾令福,郑保春,等.红毛五加多糖诱导胃癌细胞凋亡[J].第四军医大学学报,2000,21(11):325-326.
[19]谭宇蕙,陈冠林,郭椒杰,等.小果碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用.中国药理学通报,2001,17(1):40-43.
[20]刘军,柳惠图,梁云燕,等.复方中药白龙对GI期人胃癌细胞中抑癌基因的影响及与PKA信号通路的相关性[J].中国中西医结合杂志,1999,19(10):613-616.
[21]AG Zhao,HL Zhao,XJ Jin,et al.Effects of Chinese Jianpi herbs on cell apoptosis and related gene expression in human gastric cancer grafted onto nude mice[J].World J Gastroenterol,2002,8(5):792-796.
[22]杨娟,傅军鹏.黄芩活性成分及药效研究近况[J].实用医药杂志,2004,21(3):271-273.
[23]汤立建,赵良才,李庆林,等.黄芩黄酮类成分抗肿瘤作用及机制研究进展[J]中国中药杂志,2007,32(1):23-26.
[24]马波,李梦龙,周在德,等.黄酮体化合物抗肿瘤活性的量子化学研究[J].化学研究与应用,2002,14(2):149-151.
[25]Schluter B,Bergmarm U,Johtek C,et al.Impairment of specific host defence mechanism in patients with chronic post-traumatic osteomyelitis[J].Trauma,1991,31: 68 -72.
[26]Patel PM,Flemming CL,Russell SJ,et al.Cytokine gene transfer as a therapeutic strategy[J].J Immunother,1993,14:310-315.
[27]Hagiwara,Toyoda K,Torisu R,et al.Progressive stroke involving bilateral medial medulla expanding to spinal cord due to vertebral artery dissection[J].Cerebrovasc Dis,2007,24(6):540-542.
[28]Takanashi Y,Tucker SL.Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer[J].Arch Surg,1997,132:541-546.
[29]Zachary I,Gliki G.Sigaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family[J].Cardiovasc Res,2001,49(3):568- 581.
[30]Nruchrist C,E rovic BM,et al.Vascular endothelial growth factor receptor 2(VEGFR2) expression in squamous cell carcinomas of the head and neck[J].Laryngoscope,2001,3:1835-1840.
[31]Gabrilovich D,Ishida T,Oyama T,et al.Vascular endothelial growth factor in hibits the development of dendritic cells and dramatically afects the diferentiation of multiple hematopoietic lineages in vivo[J].Blood,1998,92:4150-4166.
[32]Holash J,Wiegand SJ,Yancopoulos GD.New model of tumor angiogenesis:dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF[J].Oncogene,1999,18(38):5356-5362.
[33]陈治.VEGF基因表达调节机制的研究进展[J].国外医学生理病理科学与临床分册,2000,20(3):1902-1921.
[34]Chow NH,Liu HS,et al.Expression of vascular endothelial growth factor in primary superficial bladder cancer[J].Anticancer Res,1999,19:4593-4597.
[35]Ahmad SA,Liu W,Jung YD,et al.The effects of angiopoietin21 and 22 on tumor growth and angiogenesis in human colon cancer[J].Cancer Res,2001,61(4):1255-1259.
[36]Hayes AJ,Huang WQ,Mallah J.Angiopoietin-1 and its receptor Tie-participate in the regulation of capillary-like tubule formation and survival of endothelial cells[J].Microvasc Res,1999,58(3):224-237.
[1]Kerr J F R,Wyllie A H,Currie AR,et al.Apoptosis a basic biological phenomenon with wide-ranging implication in tissue kinetics[J].Br J Cancer,1972,26:239-257.
[2]Gorczyca W,Gong J,Ardelt B,et al.The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents[J].Cancer Res,1993,53:3186-3192.
[3]王娟,王顺启,倪虹,等.莪术挥发油抑制人肝癌细胞株SMMC-7721生长的实验研究[J].天津中医药,2003,20(1):48-50.
[4]谭宇蕙,陈冠林,郭椒杰等.小果碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用.中国药理学通报,2001,17(1):40-43.
[5]ladanowski A,konopa J,Adriamycin and daunonvycininduce programmed cell death (apoptosis) in tumor cells[J].Biochem Pharmacol,1993,46(3):375-382.
[6]李林,夏丽娟,蒋超,等.三尖杉酯碱和高三尖杉酯碱诱导人早幼粒白血病细胞的程序化死亡[J].药学学报,1994,29(9):667-672.
[7]Huschtacha LI,Jeither TM,Anderson EE,et al.Indentification of apoptotic and necrotic human leukemia cells by flow cytometry[J].Exp Cell Res,1994,212:161-172.
[8]LU Q L,Richard P,leslie W,et al.Bcl-2 expression in adult and embryonic non-haematopoietic tissues[J].J P athol,1993,4:136-139.
[9]Yinn X M,Oltval Z N,Korsmeyer S J.BH1 and BH2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax[J].Nature,1994,369:321-323.
[10]Oltvai Z N,Milliman C L,Korsmeyer S J.Bcl-2 heterodimerizes in vivo with a conserved homolog,bax,that accelerates programmed cell death[J].Cell,1993,74(4):609-619.
[11]Sedlak T W,Oltval Z N,Yang E,et al.Multiple bcl-2 family members demonstrate selective dimerizations with bax.Proc Natl Acad Sci,1995,92(17):7834-7838.
[12]Yang E,Zha J,Jockel J,et al.Bad,a heterodimeric partner for Bcl-xL and bcl-2,displaces bax and promotes cell death[J].Cell,1995,80(2):285-291.
[13]Rosse T,Olivier R,Monney L.Bcl-2 prolongs cell survival after Bax-induced resease of cytochrome c[J].Nature,1998,391:496-499.
[14]Srinivasula S M,Ahmad M,Fernades-Alnenri T.Autoactivation of procaspase -9 by Apaf-1-mediated oligomerization[J].Mol Cell,1998,1:949-957.
[15]范临夏,陶晓南,蔡曦光,等.苦参碱诱导A549细胞凋亡的机制研究[J].第四军医大学学报,2007,28(15):1359-1362.
[16]张卫东,赵惠儒,阎影,等.斑蝥素诱导HepG-2细胞凋亡及其分子机制的研究[J].中华肿瘤杂志,2005,27(6):330-334.
[17]Lu HF,Sue CC,Yu CS,et al.Diallyl disulfide induced apoptosis undergo caspase-3 activity in human bladder cancer T24 cells Food[J].Chem Toxicol,2004,42(10):1543-1552.
[18]Hofmanova J,Vaculova A,Kozubik A.Polyunsaturated fatty acids sensitise human colon adenocarcinoma HT 29 cells to death receptor-mediated apoptosis[J].Cancer Lett,2005,218(1):33-41.
[19]Hastak K,Gupta S,Ahmad N,et al.Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCap cells[J].Oncogene,2003,22:4851-4859.
[20]Voutsadakis IA.Apoptosis and the pathogenesis of Lymphoma[J].Acta Oncol,2000,39(2):151-156.
[21]Swanton E,Savory P,Cosulich S.Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18:1781-1787.
[22]Toshikatsu S,Fumio I,Yokosuka O,et al.expression of p53 and P21 wafl proteins in gastyic and esphageal cancer comparion with mutation of the p53gene[J].Digestive Diseas and science,1998,43(2):279-286.
[23]Nakazawa Y,Kamijo T,Koike K,et al.ARF tumor suppressor induces mitochondria-dependent apoptosis by modulation of mitochondrial Bcl-2 family proteins[J].J Biol Chem.2003,278(30):27888-27895.
[24]Chipuk J E,Kuwana T,Bouchier-Hayes L,et al.Direct Activation of Bax by p53mediates mitochondrial membrane permeabilization and apoptosis[J].Science,2004,303(5660):1010-1014.
[25]林英城,吴名耀,李德锐,等.三氧化二砷诱导鼻咽癌CNE1细胞凋亡及其作用机制的实验研究[J].肿瘤防治研究,2005,32(8):467-469.
[1]Zhang TH,Liu JF,Zhang Y,et al.Ceramide induces apoptosis in human lung adenocarcinoma A549 cells through mitogen-activated protein kinases[J].Acta Pharmacol Sin,2007,28(3):439-445.
[2]Gao L,Shah BE,Chen J,et al.Effects of spider Macrothele raven venom on cell proliferation and cytotoxicity in HeLa cells[J].Acta Pharmacol Sin,2005,26(3):369-376.
[3]Fernades Alnemri T,Litwack G,Alnemri ES.CPP32,a novel human apoptotic protein with homologyo Caenorhabditis elegans cell death protein Ced-3 and mammalian in terlerkin1beta-converting enzyme[J].J Biol hem,1994,269:30761-30764.
[4]Saikumar P,Dong Z,Mikhailov V,et al.Aoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489-506.
[5]Roy S,Bayly CI,Gareau Y,et al.Maintenance of caspase-3 proenzyme dormancy by an intrinsic"safety catah"regulatory trieptide[J].ProcNatl Acad Sci USA,2001,98(11):6132-6137.
[6]Ashkenazi A,Dixit VM,Death receptors:signaling and modulation[J].Science,1998,281(5381):1305-1308.
[7]Morishima N,Nakanishi K,Takenouchi H,et al.Anendoplasmic reticulum stress-specific caspase cascade in apoptosis.Cytochrome c-independent activation of caspase-9 by caspase-12[J].J Biol Chem,2002,277(37):34287-34294.
[8]方强,宋波.caspase抑制剂研究进展[J].国外医学·生理、病理科学与临床分册,2001,21(6):459-465.
[9]Han YX,Giroux A,Erich L,et al.Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors[J].Bioorg Med Chem Lett,2004,14(3):805-810.
[10]Guo ZM,Xian M,Zhang W,et al.N-nitrosoanilines:a new class of caspase-3inhibitors[J].Bioorg Med Chem,2001,9(1):99-101.
[11]张亚辉,李佳,周忠良.Caspase3:治疗神经退行性疾病的新靶点[J].生物化学与生物物理进展,2003,30(2):175-181.
[12]崔银珠.caspase抑制剂有望成为一类新药[J].国外医药合成药、生化药、制剂分册,2002,23(3):148-152.
[13]高红,王常林,蔡炜蒿,等.在肾母细胞瘤的表达及意义[J].中国当代儿科杂志,2004,6(1):29-40.
[14]李长青,金春顺,张凌 喉鳞状细胞癌中PTEN和caspase3的表达及临床意义临床[J].耳鼻咽喉科杂志,2004,18(12):728-730.
[15]赵洪礼,戈全治,董萍.肿瘤特异性凋亡基因诱导A375细胞凋亡信号转导机制研究[J].沈阳部队医药,2006,19(3):363-365.
[16]顾颖,李凌.五味子乙素促进多柔比星诱导肝癌细胞SMMC7721凋亡的研究[J].实用肿瘤杂志,2006,21(5):412-416.
[17]杨琳,吴东,瑛辛彦.癌前病变Caspase-3表达下调与胃黏膜癌变的关联[J].中华肿瘤杂志.2006.28(5):357-360.
[18]Chung C W,Song Y H,Kim I K,et al.Proapoptic effects of tau cleavege product generated by caspase-3[J].Neurobiol Dis,2001,8(1):16-19.
[19]张杰,李孝生.Survivin与Caspase-3的关系及其在泌尿系肿瘤中的表达[J].国际泌尿系统杂志,2007,27(1):34-37.
[20]吴运生,程清洲.大肠癌及腺瘤中Caspase-3和BCL-2的表达及临床意义[J].数理医学杂志,2003,16(4):300-302.
[21]Takayama S,Krajewski S,Krajewska M,et al.Expression and location of Hsp70/Hsebingding anti-apoptotie protein BAG-1 and its variants in normal tissues and tumor cell lines[J].Cancer Res,1998,58(14):3116-3131.
[22]Gliki G,Wheeler-Jones C,Zachary I,et al.Vascular endothelial growth factor induces protein kinase C(PKC) dependent Akt/PKB activation and phosphatidylinositol 3-kinase-mediates PKC delta phosphorylation:role of PKC in angiogenesis[J].Cell Biol Int,2002,26(9):751 - 759.
[23]Zachary I,Gliki G.Sigaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family[J].Cardiovasc Res,2001,49(3):568- 581.
[24]Yahata Y,Shirakata Y,Tokumaru S,et al.Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor induced human dermal microvascular endothelial cell migration and tube formation[J].J Biol Chem,2003,278(41):40026 - 40031.
[1]孙雪飞.藤梨根提取液抗肺癌作用的实验研究[J].山东大学学报(医学版),2006,44(12):1268-1272.
[2]Li XK,Motwani M,Tong W,et al.A chinese herbal ex.tract,inhibits cell growth by suppressing the expression of cyclineB1 and inhibiting CDC2 kinase activity in human cancer cells[J].Mol Pharmacol,2000,58(6):1287-1293.
[4]lizuka N,Miyamoto K,Okita K,et al.Inhibitory efect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer celllines[J].CancerLett,2000,148(1):19-25.
[5]林桂凤,刘银燕.去甲斑蝥素诱导肿瘤细胞凋亡机制的研究[J].中国药房,2007,18(16):1266-1267.
[6]Oltvai ZN,Milliman CL,Korsmeyer SJ.Bcl-2 heterodimerizes in vivo with a conserved homolog,bax,that accelerates programmed cell death[J].Cell,1993,74(4):609-619.
[7]周彩虹.中药金安粉针剂对小鼠Lewis肺癌的抑制作用及其机制探讨[J].中国病理生理杂志,2003,19(5):672-675.
[8]张曼颖,安继红,李昌辉.刺五加叶皂甙诱导肺癌细胞凋亡的研究[J].吉林大学学报(医学版),2002,28(1):37-39.
[9]Silva R,Mesquita AR,Bessa J,et al.Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate:The role of glycogen-synthase-kinase-3beta[J].Neuroscience,2007,27(5):759-762.
[10]李勇.大蒜素对人胃腺癌BGC-823细胞影响的研究[J].中国中西医结合外科杂志,2001,7(5):307-310.
[11]Wilson LC.Nonsteroidal anti-inflammatory drugac-tivated gene(NAG21) is induced by genistein through the expression of p53 in colorectal cancer cells[J].Nt J Cancer,2003,105(6):747-751.
[12]郭伟剑,于尔辛.健脾理气药诱导人肝癌细胞SMMC7721凋亡的研究[J].世界华人消化杂志,2000,8(1):52-55.
[13]许相范.抗癌口服液体外对人胃癌MGC-803细胞株凋亡相关基因作用的研究[J].中华综合临床医学杂志,2003,5(1):14-15.
[14]段小梅.基因家族对细胞凋亡的调控[J].中国医学文摘肿瘤学,2001,15(1):80-83.
[15]袁怀波,凌庆枝,糜漫天,等.葛根黄酮提取物对HL-60细胞bcl-2和bax基因表达的影响[J].食品科学,2005,26(11):241-243.
[16]李英,徐功立,李颖,等.鸦胆子油乳诱导白血病U937细胞凋亡的实验研究[J].中华血液学杂志,2004,25(6):381-382.
[17]姚保泰,吴敏,王博,等.盐酸小檗碱抑制实验性大鼠胃癌前病变细胞Bcl-2表达作用的研究[J].中国中医药杂志,2005,20(3):186-187.
[18]左小东,秦叔逵.华蟾素对肿瘤细胞周期及bcl-2蛋白表达的影响[J].现代中西医结合杂志,2003,12(6):567-568.
[19]马靖,符乃阳.甘草提取物体外选择性诱导几种人肿瘤细胞凋亡[J].癌症,2001,20(8):806-811.
[20]何承伟,梁念慈,莫丽儿,等.半边旗抗肿瘤有效成分6F对HL-60细胞c-myc、bcl-2及PCNA表达的抑制作用[J].广东医学院学报,2002,20(3):165-166.
[21]戴馨仪,陈林香,周贷翰,等.清金得生片抗肿瘤机理研究[J].中药新药与临床药理,2002,13(6):360-362.
[22]刘京生,苗智慧,董力,等.水蛭抗肿瘤作用的实验研究[J].时珍国医国药,2001,12(10):884-885.
[23]刘京生.雄黄诱导肿瘤细胞凋亡的实验研究[J].河北中医,2000,22(11):874-876.
[24]何建成,刘永琦.诱导细胞凋亡和抗凋亡药物研究进展[J].中国中医基础医学杂志,2001,15(5):77-78.
[25]邵晋晨,吴继锋.端粒酶与细胞周期及细胞凋亡关系的研究进展[J].国外医学、生理、病理科学与临床分册,2002,22(1):36-39.
[26]孟志强.多种药物对肝癌细胞端粒酶活性的影响[J].癌症,2000,19(2):317-320.
[27]陈伟忠,林勇,谢渭芬,等.苦参碱对肝癌细胞端粒酶活性调控及细胞周期的影响[J].第二军医大学学报,2002,23(5):498-500.
[28]曾建新,王文亮,王知力,等.砷诱导的肝癌细胞凋亡及端粒酶活性改变[J].卫生毒理学杂志,2002,16(2):88-90.
[29]黎丹戎,唐东平,张丽生,等.茶多酚对肝癌细胞生长及端粒酶活性抑制的研究[J].肿瘤防治研究,2001,28(5):367-368.
[30]李伏娥,朱陵群,叶红军,等.苦参碱诱导人胃癌细胞凋亡及对端粒酶活性的影响[J].中国现代医学杂志,2005,15(12):1809-1812.
[31]Moragoda L.Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells.Anticancer Res,2001,21(2):873-876.
[32]Pan M H,Ling Y C,Lin-Shian Sy,et al.Inducttion of apoptosis by the oolong tea polyphenol theasinensin A through cytochromec releaseand activation of caspase-9 and caspase-3 in human U937 cells[J].J Agric Food Chem,2000,48(12):6337-6346.
[32]程卫东,徐瑞峰.中药诱导肝癌细胞凋亡的研究进展[J].甘肃中医,2004,17(4):44-47.
[33]李红喆.中药诱导肿瘤细胞凋亡[M].抗癌,2003,21-22.
[34]刘珊林,施冬云.硒对肝癌细胞凋亡作用的研究[J].生物物理学报,1998,14(3):553-557.
[35]高艳景,辛华.大蒜素抑制EGF上调人肝癌细胞中EGFR表达的研究[J].山东中医药大学学报,2000,24(3):231-237.
[2]Llovet JM,Fuster J,Bruix J.The Barcelona approach:diagnosis,staging and treatment of hepatocellular carcinoma[J].Liver Transpl,2004,10:115-120.
[3]Tammela T,Enholm B,Alitalo K,et al.The biology of vascular endothelial growth factors[J].Cardiovasc Res,2005,65(3):550-563.
[4]Tanaka A,Suemaru K,Otsuka T,et al.Hoek's formula,a cystatin C-based prediction formula for determining the glomerular filtration rate,is the most effective method for original adjusting the dosage of vancomycin[J],Int J Clin Pharmacol Ther,2007,45(11):592-597.
[5]Toyoda K,Uda K,Shirakawa A,et al.Combined and staged endovascular recanalization of cervical and intracranial arteries in hyperacute ischemic stroke.[J].Intern Med,2007,46(23):1935-1936.
[6]Donala K,Senger D,Livingston V,et al.Vascular permeability factor(VEGF,VPE)in tumor biology[J].Cancer Metastasis Rev,1993,12:303-324.
[7]Malsonpiewe PC,SuriC,Jones PF,et al.Angiopoietin22,a natural antagonist for tie22 that disrupts in vivo angiogenesis[J].Science,1997,277(5322):55-60.
[8]Suri C,Jones PF,Patan S,et al.Requisite role of angiopoietin21:a ligand for the Tie2receptor during embryonic angiogenesis[J].Cell,1996,87(7):1171-1180.
[9]Valenzuela DM,Griffiths J,Rojas J,et al.Angiopoietin 3 and 4:diverging gene counterparts in mouse and man[J].Proc Natl Acad Sci USA,1999,96(5):1904-1909.
[10]Moenner M,G usse M.The widespread expression of angiogenin in diferent human cells suggests a biological function not only related to angiogenesis.Eur J Biochem,1994,226:483-490.
[11]Choprav,Dinh TV.Serum levels of interleukins,growth factors and angiogenin in patients with endometrial cancer[J].J Cancer Res Clin Oncol,1997,123:167-172.
[12]中华人民共和国卫生部药典委员会.中国药典一部[M].北京:化学工业出版社, 2005.211-212.
[13]Craig B.Apoptosis in the pathogenesis and treatment of disease[J].Science,1995,267:1456-1460.
[14]厉红元,车艺,汤为学,等.姜黄素对人肝癌细胞增殖和凋亡的影响[J].中华肝脏病杂志,2002,10(6):449-451.
[15]王娟,王顺启,倪虹,等.莪术挥发油抑制人肝癌细胞株SMMC-7721生长的实验研究[J].天津中医药,2003,20(1):48-50.
[16]杨小平,张星.青蒿酯钠诱导人肿瘤细胞凋亡及其分子机制的探讨[J].中草药,2002.33(9):819-821.
[17]朱秀琴,王国申,张学军,等.中药阿魏酸钠对人肝癌细胞生存性及凋亡的影响[J].世界华人消化杂志,1999,7(8):715-755.
[18]吕晓英,曾令福,郑保春,等.红毛五加多糖诱导胃癌细胞凋亡[J].第四军医大学学报,2000,21(11):325-326.
[19]谭宇蕙,陈冠林,郭椒杰,等.小果碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用.中国药理学通报,2001,17(1):40-43.
[20]刘军,柳惠图,梁云燕,等.复方中药白龙对GI期人胃癌细胞中抑癌基因的影响及与PKA信号通路的相关性[J].中国中西医结合杂志,1999,19(10):613-616.
[21]AG Zhao,HL Zhao,XJ Jin,et al.Effects of Chinese Jianpi herbs on cell apoptosis and related gene expression in human gastric cancer grafted onto nude mice[J].World J Gastroenterol,2002,8(5):792-796.
[22]杨娟,傅军鹏.黄芩活性成分及药效研究近况[J].实用医药杂志,2004,21(3):271-273.
[23]汤立建,赵良才,李庆林,等.黄芩黄酮类成分抗肿瘤作用及机制研究进展[J]中国中药杂志,2007,32(1):23-26.
[24]马波,李梦龙,周在德,等.黄酮体化合物抗肿瘤活性的量子化学研究[J].化学研究与应用,2002,14(2):149-151.
[25]Schluter B,Bergmarm U,Johtek C,et al.Impairment of specific host defence mechanism in patients with chronic post-traumatic osteomyelitis[J].Trauma,1991,31: 68 -72.
[26]Patel PM,Flemming CL,Russell SJ,et al.Cytokine gene transfer as a therapeutic strategy[J].J Immunother,1993,14:310-315.
[27]Hagiwara,Toyoda K,Torisu R,et al.Progressive stroke involving bilateral medial medulla expanding to spinal cord due to vertebral artery dissection[J].Cerebrovasc Dis,2007,24(6):540-542.
[28]Takanashi Y,Tucker SL.Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer[J].Arch Surg,1997,132:541-546.
[29]Zachary I,Gliki G.Sigaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family[J].Cardiovasc Res,2001,49(3):568- 581.
[30]Nruchrist C,E rovic BM,et al.Vascular endothelial growth factor receptor 2(VEGFR2) expression in squamous cell carcinomas of the head and neck[J].Laryngoscope,2001,3:1835-1840.
[31]Gabrilovich D,Ishida T,Oyama T,et al.Vascular endothelial growth factor in hibits the development of dendritic cells and dramatically afects the diferentiation of multiple hematopoietic lineages in vivo[J].Blood,1998,92:4150-4166.
[32]Holash J,Wiegand SJ,Yancopoulos GD.New model of tumor angiogenesis:dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF[J].Oncogene,1999,18(38):5356-5362.
[33]陈治.VEGF基因表达调节机制的研究进展[J].国外医学生理病理科学与临床分册,2000,20(3):1902-1921.
[34]Chow NH,Liu HS,et al.Expression of vascular endothelial growth factor in primary superficial bladder cancer[J].Anticancer Res,1999,19:4593-4597.
[35]Ahmad SA,Liu W,Jung YD,et al.The effects of angiopoietin21 and 22 on tumor growth and angiogenesis in human colon cancer[J].Cancer Res,2001,61(4):1255-1259.
[36]Hayes AJ,Huang WQ,Mallah J.Angiopoietin-1 and its receptor Tie-participate in the regulation of capillary-like tubule formation and survival of endothelial cells[J].Microvasc Res,1999,58(3):224-237.
[1]Kerr J F R,Wyllie A H,Currie AR,et al.Apoptosis a basic biological phenomenon with wide-ranging implication in tissue kinetics[J].Br J Cancer,1972,26:239-257.
[2]Gorczyca W,Gong J,Ardelt B,et al.The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents[J].Cancer Res,1993,53:3186-3192.
[3]王娟,王顺启,倪虹,等.莪术挥发油抑制人肝癌细胞株SMMC-7721生长的实验研究[J].天津中医药,2003,20(1):48-50.
[4]谭宇蕙,陈冠林,郭椒杰等.小果碱对人胃癌MGC-803细胞生长抑制及诱导凋亡的作用.中国药理学通报,2001,17(1):40-43.
[5]ladanowski A,konopa J,Adriamycin and daunonvycininduce programmed cell death (apoptosis) in tumor cells[J].Biochem Pharmacol,1993,46(3):375-382.
[6]李林,夏丽娟,蒋超,等.三尖杉酯碱和高三尖杉酯碱诱导人早幼粒白血病细胞的程序化死亡[J].药学学报,1994,29(9):667-672.
[7]Huschtacha LI,Jeither TM,Anderson EE,et al.Indentification of apoptotic and necrotic human leukemia cells by flow cytometry[J].Exp Cell Res,1994,212:161-172.
[8]LU Q L,Richard P,leslie W,et al.Bcl-2 expression in adult and embryonic non-haematopoietic tissues[J].J P athol,1993,4:136-139.
[9]Yinn X M,Oltval Z N,Korsmeyer S J.BH1 and BH2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax[J].Nature,1994,369:321-323.
[10]Oltvai Z N,Milliman C L,Korsmeyer S J.Bcl-2 heterodimerizes in vivo with a conserved homolog,bax,that accelerates programmed cell death[J].Cell,1993,74(4):609-619.
[11]Sedlak T W,Oltval Z N,Yang E,et al.Multiple bcl-2 family members demonstrate selective dimerizations with bax.Proc Natl Acad Sci,1995,92(17):7834-7838.
[12]Yang E,Zha J,Jockel J,et al.Bad,a heterodimeric partner for Bcl-xL and bcl-2,displaces bax and promotes cell death[J].Cell,1995,80(2):285-291.
[13]Rosse T,Olivier R,Monney L.Bcl-2 prolongs cell survival after Bax-induced resease of cytochrome c[J].Nature,1998,391:496-499.
[14]Srinivasula S M,Ahmad M,Fernades-Alnenri T.Autoactivation of procaspase -9 by Apaf-1-mediated oligomerization[J].Mol Cell,1998,1:949-957.
[15]范临夏,陶晓南,蔡曦光,等.苦参碱诱导A549细胞凋亡的机制研究[J].第四军医大学学报,2007,28(15):1359-1362.
[16]张卫东,赵惠儒,阎影,等.斑蝥素诱导HepG-2细胞凋亡及其分子机制的研究[J].中华肿瘤杂志,2005,27(6):330-334.
[17]Lu HF,Sue CC,Yu CS,et al.Diallyl disulfide induced apoptosis undergo caspase-3 activity in human bladder cancer T24 cells Food[J].Chem Toxicol,2004,42(10):1543-1552.
[18]Hofmanova J,Vaculova A,Kozubik A.Polyunsaturated fatty acids sensitise human colon adenocarcinoma HT 29 cells to death receptor-mediated apoptosis[J].Cancer Lett,2005,218(1):33-41.
[19]Hastak K,Gupta S,Ahmad N,et al.Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCap cells[J].Oncogene,2003,22:4851-4859.
[20]Voutsadakis IA.Apoptosis and the pathogenesis of Lymphoma[J].Acta Oncol,2000,39(2):151-156.
[21]Swanton E,Savory P,Cosulich S.Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts[J].Oncogene,1999,18:1781-1787.
[22]Toshikatsu S,Fumio I,Yokosuka O,et al.expression of p53 and P21 wafl proteins in gastyic and esphageal cancer comparion with mutation of the p53gene[J].Digestive Diseas and science,1998,43(2):279-286.
[23]Nakazawa Y,Kamijo T,Koike K,et al.ARF tumor suppressor induces mitochondria-dependent apoptosis by modulation of mitochondrial Bcl-2 family proteins[J].J Biol Chem.2003,278(30):27888-27895.
[24]Chipuk J E,Kuwana T,Bouchier-Hayes L,et al.Direct Activation of Bax by p53mediates mitochondrial membrane permeabilization and apoptosis[J].Science,2004,303(5660):1010-1014.
[25]林英城,吴名耀,李德锐,等.三氧化二砷诱导鼻咽癌CNE1细胞凋亡及其作用机制的实验研究[J].肿瘤防治研究,2005,32(8):467-469.
[1]Zhang TH,Liu JF,Zhang Y,et al.Ceramide induces apoptosis in human lung adenocarcinoma A549 cells through mitogen-activated protein kinases[J].Acta Pharmacol Sin,2007,28(3):439-445.
[2]Gao L,Shah BE,Chen J,et al.Effects of spider Macrothele raven venom on cell proliferation and cytotoxicity in HeLa cells[J].Acta Pharmacol Sin,2005,26(3):369-376.
[3]Fernades Alnemri T,Litwack G,Alnemri ES.CPP32,a novel human apoptotic protein with homologyo Caenorhabditis elegans cell death protein Ced-3 and mammalian in terlerkin1beta-converting enzyme[J].J Biol hem,1994,269:30761-30764.
[4]Saikumar P,Dong Z,Mikhailov V,et al.Aoptosis:definition,mechanism,and relevance to disease[J].Am J Med,1999,107(5):489-506.
[5]Roy S,Bayly CI,Gareau Y,et al.Maintenance of caspase-3 proenzyme dormancy by an intrinsic"safety catah"regulatory trieptide[J].ProcNatl Acad Sci USA,2001,98(11):6132-6137.
[6]Ashkenazi A,Dixit VM,Death receptors:signaling and modulation[J].Science,1998,281(5381):1305-1308.
[7]Morishima N,Nakanishi K,Takenouchi H,et al.Anendoplasmic reticulum stress-specific caspase cascade in apoptosis.Cytochrome c-independent activation of caspase-9 by caspase-12[J].J Biol Chem,2002,277(37):34287-34294.
[8]方强,宋波.caspase抑制剂研究进展[J].国外医学·生理、病理科学与临床分册,2001,21(6):459-465.
[9]Han YX,Giroux A,Erich L,et al.Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors[J].Bioorg Med Chem Lett,2004,14(3):805-810.
[10]Guo ZM,Xian M,Zhang W,et al.N-nitrosoanilines:a new class of caspase-3inhibitors[J].Bioorg Med Chem,2001,9(1):99-101.
[11]张亚辉,李佳,周忠良.Caspase3:治疗神经退行性疾病的新靶点[J].生物化学与生物物理进展,2003,30(2):175-181.
[12]崔银珠.caspase抑制剂有望成为一类新药[J].国外医药合成药、生化药、制剂分册,2002,23(3):148-152.
[13]高红,王常林,蔡炜蒿,等.在肾母细胞瘤的表达及意义[J].中国当代儿科杂志,2004,6(1):29-40.
[14]李长青,金春顺,张凌 喉鳞状细胞癌中PTEN和caspase3的表达及临床意义临床[J].耳鼻咽喉科杂志,2004,18(12):728-730.
[15]赵洪礼,戈全治,董萍.肿瘤特异性凋亡基因诱导A375细胞凋亡信号转导机制研究[J].沈阳部队医药,2006,19(3):363-365.
[16]顾颖,李凌.五味子乙素促进多柔比星诱导肝癌细胞SMMC7721凋亡的研究[J].实用肿瘤杂志,2006,21(5):412-416.
[17]杨琳,吴东,瑛辛彦.癌前病变Caspase-3表达下调与胃黏膜癌变的关联[J].中华肿瘤杂志.2006.28(5):357-360.
[18]Chung C W,Song Y H,Kim I K,et al.Proapoptic effects of tau cleavege product generated by caspase-3[J].Neurobiol Dis,2001,8(1):16-19.
[19]张杰,李孝生.Survivin与Caspase-3的关系及其在泌尿系肿瘤中的表达[J].国际泌尿系统杂志,2007,27(1):34-37.
[20]吴运生,程清洲.大肠癌及腺瘤中Caspase-3和BCL-2的表达及临床意义[J].数理医学杂志,2003,16(4):300-302.
[21]Takayama S,Krajewski S,Krajewska M,et al.Expression and location of Hsp70/Hsebingding anti-apoptotie protein BAG-1 and its variants in normal tissues and tumor cell lines[J].Cancer Res,1998,58(14):3116-3131.
[22]Gliki G,Wheeler-Jones C,Zachary I,et al.Vascular endothelial growth factor induces protein kinase C(PKC) dependent Akt/PKB activation and phosphatidylinositol 3-kinase-mediates PKC delta phosphorylation:role of PKC in angiogenesis[J].Cell Biol Int,2002,26(9):751 - 759.
[23]Zachary I,Gliki G.Sigaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family[J].Cardiovasc Res,2001,49(3):568- 581.
[24]Yahata Y,Shirakata Y,Tokumaru S,et al.Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor induced human dermal microvascular endothelial cell migration and tube formation[J].J Biol Chem,2003,278(41):40026 - 40031.
[1]孙雪飞.藤梨根提取液抗肺癌作用的实验研究[J].山东大学学报(医学版),2006,44(12):1268-1272.
[2]Li XK,Motwani M,Tong W,et al.A chinese herbal ex.tract,inhibits cell growth by suppressing the expression of cyclineB1 and inhibiting CDC2 kinase activity in human cancer cells[J].Mol Pharmacol,2000,58(6):1287-1293.
[4]lizuka N,Miyamoto K,Okita K,et al.Inhibitory efect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer celllines[J].CancerLett,2000,148(1):19-25.
[5]林桂凤,刘银燕.去甲斑蝥素诱导肿瘤细胞凋亡机制的研究[J].中国药房,2007,18(16):1266-1267.
[6]Oltvai ZN,Milliman CL,Korsmeyer SJ.Bcl-2 heterodimerizes in vivo with a conserved homolog,bax,that accelerates programmed cell death[J].Cell,1993,74(4):609-619.
[7]周彩虹.中药金安粉针剂对小鼠Lewis肺癌的抑制作用及其机制探讨[J].中国病理生理杂志,2003,19(5):672-675.
[8]张曼颖,安继红,李昌辉.刺五加叶皂甙诱导肺癌细胞凋亡的研究[J].吉林大学学报(医学版),2002,28(1):37-39.
[9]Silva R,Mesquita AR,Bessa J,et al.Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate:The role of glycogen-synthase-kinase-3beta[J].Neuroscience,2007,27(5):759-762.
[10]李勇.大蒜素对人胃腺癌BGC-823细胞影响的研究[J].中国中西医结合外科杂志,2001,7(5):307-310.
[11]Wilson LC.Nonsteroidal anti-inflammatory drugac-tivated gene(NAG21) is induced by genistein through the expression of p53 in colorectal cancer cells[J].Nt J Cancer,2003,105(6):747-751.
[12]郭伟剑,于尔辛.健脾理气药诱导人肝癌细胞SMMC7721凋亡的研究[J].世界华人消化杂志,2000,8(1):52-55.
[13]许相范.抗癌口服液体外对人胃癌MGC-803细胞株凋亡相关基因作用的研究[J].中华综合临床医学杂志,2003,5(1):14-15.
[14]段小梅.基因家族对细胞凋亡的调控[J].中国医学文摘肿瘤学,2001,15(1):80-83.
[15]袁怀波,凌庆枝,糜漫天,等.葛根黄酮提取物对HL-60细胞bcl-2和bax基因表达的影响[J].食品科学,2005,26(11):241-243.
[16]李英,徐功立,李颖,等.鸦胆子油乳诱导白血病U937细胞凋亡的实验研究[J].中华血液学杂志,2004,25(6):381-382.
[17]姚保泰,吴敏,王博,等.盐酸小檗碱抑制实验性大鼠胃癌前病变细胞Bcl-2表达作用的研究[J].中国中医药杂志,2005,20(3):186-187.
[18]左小东,秦叔逵.华蟾素对肿瘤细胞周期及bcl-2蛋白表达的影响[J].现代中西医结合杂志,2003,12(6):567-568.
[19]马靖,符乃阳.甘草提取物体外选择性诱导几种人肿瘤细胞凋亡[J].癌症,2001,20(8):806-811.
[20]何承伟,梁念慈,莫丽儿,等.半边旗抗肿瘤有效成分6F对HL-60细胞c-myc、bcl-2及PCNA表达的抑制作用[J].广东医学院学报,2002,20(3):165-166.
[21]戴馨仪,陈林香,周贷翰,等.清金得生片抗肿瘤机理研究[J].中药新药与临床药理,2002,13(6):360-362.
[22]刘京生,苗智慧,董力,等.水蛭抗肿瘤作用的实验研究[J].时珍国医国药,2001,12(10):884-885.
[23]刘京生.雄黄诱导肿瘤细胞凋亡的实验研究[J].河北中医,2000,22(11):874-876.
[24]何建成,刘永琦.诱导细胞凋亡和抗凋亡药物研究进展[J].中国中医基础医学杂志,2001,15(5):77-78.
[25]邵晋晨,吴继锋.端粒酶与细胞周期及细胞凋亡关系的研究进展[J].国外医学、生理、病理科学与临床分册,2002,22(1):36-39.
[26]孟志强.多种药物对肝癌细胞端粒酶活性的影响[J].癌症,2000,19(2):317-320.
[27]陈伟忠,林勇,谢渭芬,等.苦参碱对肝癌细胞端粒酶活性调控及细胞周期的影响[J].第二军医大学学报,2002,23(5):498-500.
[28]曾建新,王文亮,王知力,等.砷诱导的肝癌细胞凋亡及端粒酶活性改变[J].卫生毒理学杂志,2002,16(2):88-90.
[29]黎丹戎,唐东平,张丽生,等.茶多酚对肝癌细胞生长及端粒酶活性抑制的研究[J].肿瘤防治研究,2001,28(5):367-368.
[30]李伏娥,朱陵群,叶红军,等.苦参碱诱导人胃癌细胞凋亡及对端粒酶活性的影响[J].中国现代医学杂志,2005,15(12):1809-1812.
[31]Moragoda L.Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells.Anticancer Res,2001,21(2):873-876.
[32]Pan M H,Ling Y C,Lin-Shian Sy,et al.Inducttion of apoptosis by the oolong tea polyphenol theasinensin A through cytochromec releaseand activation of caspase-9 and caspase-3 in human U937 cells[J].J Agric Food Chem,2000,48(12):6337-6346.
[32]程卫东,徐瑞峰.中药诱导肝癌细胞凋亡的研究进展[J].甘肃中医,2004,17(4):44-47.
[33]李红喆.中药诱导肿瘤细胞凋亡[M].抗癌,2003,21-22.
[34]刘珊林,施冬云.硒对肝癌细胞凋亡作用的研究[J].生物物理学报,1998,14(3):553-557.
[35]高艳景,辛华.大蒜素抑制EGF上调人肝癌细胞中EGFR表达的研究[J].山东中医药大学学报,2000,24(3):231-237.