阻断PI3K/Akt通路对云南宣威肺腺癌XWLC-05细胞的放射敏感性研究
|
摘要
【研究目的】
探讨PI3K/Akt特异性抑制剂Ly294002对云南宣威肺腺癌XWLC-05细胞株的放射增敏作用。
【研究方法】
1.克隆形成实验测定XWLC-05细胞在不同剂量X线照射下的存活分数,分别用单靶多击数学模型拟合细胞存活曲线,并求出放射生物学参数D_0、D_q、N、SF_2、SER。
2.四氮唑兰比色法(MTT法)检测X线4Gy照射24h、48h后不同浓度Ly294002对XWLC-05细胞的抑制率,评价细胞放射敏感性。
3.流式细胞术测定不同条件下Ly294002对XWLC-05细胞的周期分布和细胞凋亡情况的影响,评价Ly294002的作用机制。
【研究结果】
1.克隆形成实验:XWLC-05细胞在对照组各个剂量点的存活分数均高于实验组,对照组D0、Dq、N、SF2的值均大于实验组,SER值为1.05,对照组和实验组存活分数经成组t检验有显著差异(t=2.856,p=0.036)。
2.MTT法实验:不同浓度(5、10、20、50μmol/l)Ly294002作用XWLC-05细胞24小时及48小时后,对照组抑制率小于实验组,Ly294002作用24小时后,对照组和实验组抑制率经成组T检验有显著差异(t=-17.489,p=0.003),Ly294002作用48小时后对照组和实验组抑制率经成组T检验无显著差异(t=-2.201,p＞0.05)。
3.流式细胞检测:Ly294002作用12小时后,未照射实验组G_2/M期细胞比例大于对照组,照射实验组G_2/M期细胞比例小于对照组,对照组和实验组G_2/M期细胞经成组t检验无显著差异。Ly294002作用24小时和36小时后,实验组G_2/M期细胞比例均大于对照组,对照组和实验组G_2/M期细胞经成组t检验有显著差异(p＜0.05)。Ly294002作用12小时、24小时和36小时后,各组凋亡结果不明显,经秩和检验,对照组和实验组细胞凋亡结果无明显差异(p＞0.05)。
【结论】
1.Ly294002对XWLC-05细胞有放射增敏作用。
2.不同浓度Ly294002作用XWLC-05细胞24小时后,对细胞的抑制皇浓度依从性,随着Ly294002浓度的增加,抑制率增加;且照射组抑制率大于单纯Ly294002组;提示24小时可能为Ly294002最佳作用时间。
3.XWLC-05细胞经照射后出现G2/M期细胞阻滞,经Ly294002作用后G2/M期细胞阻滞增加,凋亡率不明显,提示Ly294002可能通过增加G2/M期细胞数增加XWLC-05细胞的放射敏感性。
Purpose
To investigate the radiosensitive effect of PI3K/Akt's specific inhibitor-Ly294002 on adenocarcinoma of lung cancer cell at xuanwei,yunnan province.
Materials and methods
1.Clonogenic survival assay was performed to determine survival fraction of XWLC-05 cell at different doses.The parameters D_0,D_q,N,SF_2 and SER from multi-target hit mathematical model were calculated to evaluate radiosensitivity of the cells and were fitted cell survival curve.
2.Tetrazolylazo-colorimetry was detected to inhibition rates of XWLC-05 cells as different concentrations of Ly294002 after 24 hours and 48 hours with 4Gy irradiation,Cell radiosensitivity was evaluated.
3.Flow cytometry was performed to check the impact on the XWLC-05 cells cycle and apoptosis on different conditions of Ly294002 in order to evaluated the mechanism of Ly294002.
Results
1.Clonogenic survival assay:The XWLC-05 cells's survival fraction of the control group in different points were higher than experimental group.The control group's values of D_0,D_q, SF_2 were higher than the experimental group.The value of SER is 1.05.The survival fraction between the control group and the experimental group were significantly different(p＜0.05).
2.Detection of MTT colorimetric assay:With different concentrations(5,10,20,50μmol/l), inhibition rate of the control group inhibition rate was less than that of the experimental group after 24 hours and 48 hours.By the data t test group,the inhibiting results processed for 24 hours with Ly294002,between the control group and the experimental group were significantly different(p＜0.05).The cells are processed for 24 hours with Ly294002 are of statistical significance(p＜0.05).The inhibition were processed for 24 hours by Ly294002,the control group and the experimental group were of no statistical significance(p＞0.05).
3.Detection of the Flow cytometry assay:Having processed for 24 hours with Ly294002, the G_2/M phase cell ratio of the experimental group of no irradiation was greater than the control group,the G_2/M phase cell ratio of the experimental group of irradiation wasless than the control group(p＞0.05).Having processed for 24 hours and 36 hours with Ly294002,the G_2/M phase cell ratio of the experimental group of irradiation was more than the control group(p＜0.05).The result of apoptosis was not obvious after the cells were processed for 12 hours,24 hours and 36 hours with Ly294002,the control group and experimental group apoptosis result there was no significant difference(p＞0.05).
Conclusions
1.Ly294002 have an radiosensitive effect on XWLC-05 cell.
2.After 24 hours,the role of different concentrations Ly294002 inhibited on XWLC-05 cells was in a dose-compliance.With the increasing concentration of Ly294002,inhibition rate increase.Comparing with the control group,the inhibitory rate of the irradiated group was more greatly increasing;The best time processing with Ly294002 may be 24h.
3.The G_2/M phase of XWLC-05 cells was blocked after irradiating,the G_2/M phase cells block were increased by Ly294002,The rate of apoptosis was not obvious,It was suggested that the mechanism of Ly294002 on XWLC-05 cell line's radio-sensitizing effect may be blocking cells during G_2/M phase.
探讨PI3K/Akt特异性抑制剂Ly294002对云南宣威肺腺癌XWLC-05细胞株的放射增敏作用。
【研究方法】
1.克隆形成实验测定XWLC-05细胞在不同剂量X线照射下的存活分数,分别用单靶多击数学模型拟合细胞存活曲线,并求出放射生物学参数D_0、D_q、N、SF_2、SER。
2.四氮唑兰比色法(MTT法)检测X线4Gy照射24h、48h后不同浓度Ly294002对XWLC-05细胞的抑制率,评价细胞放射敏感性。
3.流式细胞术测定不同条件下Ly294002对XWLC-05细胞的周期分布和细胞凋亡情况的影响,评价Ly294002的作用机制。
【研究结果】
1.克隆形成实验:XWLC-05细胞在对照组各个剂量点的存活分数均高于实验组,对照组D0、Dq、N、SF2的值均大于实验组,SER值为1.05,对照组和实验组存活分数经成组t检验有显著差异(t=2.856,p=0.036)。
2.MTT法实验:不同浓度(5、10、20、50μmol/l)Ly294002作用XWLC-05细胞24小时及48小时后,对照组抑制率小于实验组,Ly294002作用24小时后,对照组和实验组抑制率经成组T检验有显著差异(t=-17.489,p=0.003),Ly294002作用48小时后对照组和实验组抑制率经成组T检验无显著差异(t=-2.201,p＞0.05)。
3.流式细胞检测:Ly294002作用12小时后,未照射实验组G_2/M期细胞比例大于对照组,照射实验组G_2/M期细胞比例小于对照组,对照组和实验组G_2/M期细胞经成组t检验无显著差异。Ly294002作用24小时和36小时后,实验组G_2/M期细胞比例均大于对照组,对照组和实验组G_2/M期细胞经成组t检验有显著差异(p＜0.05)。Ly294002作用12小时、24小时和36小时后,各组凋亡结果不明显,经秩和检验,对照组和实验组细胞凋亡结果无明显差异(p＞0.05)。
【结论】
1.Ly294002对XWLC-05细胞有放射增敏作用。
2.不同浓度Ly294002作用XWLC-05细胞24小时后,对细胞的抑制皇浓度依从性,随着Ly294002浓度的增加,抑制率增加;且照射组抑制率大于单纯Ly294002组;提示24小时可能为Ly294002最佳作用时间。
3.XWLC-05细胞经照射后出现G2/M期细胞阻滞,经Ly294002作用后G2/M期细胞阻滞增加,凋亡率不明显,提示Ly294002可能通过增加G2/M期细胞数增加XWLC-05细胞的放射敏感性。
Purpose
To investigate the radiosensitive effect of PI3K/Akt's specific inhibitor-Ly294002 on adenocarcinoma of lung cancer cell at xuanwei,yunnan province.
Materials and methods
1.Clonogenic survival assay was performed to determine survival fraction of XWLC-05 cell at different doses.The parameters D_0,D_q,N,SF_2 and SER from multi-target hit mathematical model were calculated to evaluate radiosensitivity of the cells and were fitted cell survival curve.
2.Tetrazolylazo-colorimetry was detected to inhibition rates of XWLC-05 cells as different concentrations of Ly294002 after 24 hours and 48 hours with 4Gy irradiation,Cell radiosensitivity was evaluated.
3.Flow cytometry was performed to check the impact on the XWLC-05 cells cycle and apoptosis on different conditions of Ly294002 in order to evaluated the mechanism of Ly294002.
Results
1.Clonogenic survival assay:The XWLC-05 cells's survival fraction of the control group in different points were higher than experimental group.The control group's values of D_0,D_q, SF_2 were higher than the experimental group.The value of SER is 1.05.The survival fraction between the control group and the experimental group were significantly different(p＜0.05).
2.Detection of MTT colorimetric assay:With different concentrations(5,10,20,50μmol/l), inhibition rate of the control group inhibition rate was less than that of the experimental group after 24 hours and 48 hours.By the data t test group,the inhibiting results processed for 24 hours with Ly294002,between the control group and the experimental group were significantly different(p＜0.05).The cells are processed for 24 hours with Ly294002 are of statistical significance(p＜0.05).The inhibition were processed for 24 hours by Ly294002,the control group and the experimental group were of no statistical significance(p＞0.05).
3.Detection of the Flow cytometry assay:Having processed for 24 hours with Ly294002, the G_2/M phase cell ratio of the experimental group of no irradiation was greater than the control group,the G_2/M phase cell ratio of the experimental group of irradiation wasless than the control group(p＞0.05).Having processed for 24 hours and 36 hours with Ly294002,the G_2/M phase cell ratio of the experimental group of irradiation was more than the control group(p＜0.05).The result of apoptosis was not obvious after the cells were processed for 12 hours,24 hours and 36 hours with Ly294002,the control group and experimental group apoptosis result there was no significant difference(p＞0.05).
Conclusions
1.Ly294002 have an radiosensitive effect on XWLC-05 cell.
2.After 24 hours,the role of different concentrations Ly294002 inhibited on XWLC-05 cells was in a dose-compliance.With the increasing concentration of Ly294002,inhibition rate increase.Comparing with the control group,the inhibitory rate of the irradiated group was more greatly increasing;The best time processing with Ly294002 may be 24h.
3.The G_2/M phase of XWLC-05 cells was blocked after irradiating,the G_2/M phase cells block were increased by Ly294002,The rate of apoptosis was not obvious,It was suggested that the mechanism of Ly294002 on XWLC-05 cell line's radio-sensitizing effect may be blocking cells during G_2/M phase.
引文
1 孙大业,郭林燕和马力耕等编著．细胞信号转导．第三版．北京：科学出版社,2001：73～90．
2 Kandel ES, Hay N. The regulation and activitives of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell. Res.1999, 253: 210-229.
3 Meier R, Hemmings BA. Regulation of protein kinase B. J. Recept ingnal Transduct Res. 1999,19: 121—128.
4 Schlessinger J. Cell signaling by receptor tyrosine Itinases. Cell, 2000,103: 211—225.
5 Rodgers EE, Theibert AB. Functions of PI 3-kina} in development of the nervous system. Int J Dev Neurosci., 2002, 20(3-5):187～197.
6 Tan J, Hallahan DE. Growth factor-independent activation of protein kinase B contributes to theinherent resistance of vascular endothelium to radiation-induced apoptotic response. Cancer Res.2003 Nov I5:63(22):7663～7667.
7 Okumura E, Fukuhara T, Yoshida H, et al. Akt inhibits Mytl in the signalling pathway that leads to meiotic G2/M-phase transition. Nat Cell Biol. 2002 Feb:4(2): 111—116.
8 Kandel ES, Skeen J, Majewski N, et al. Activation of Akt/protein kinase B overcomes a G2/M cell cycle checkpoint induced by DNA damage. Mol Cell Biol. 2002 Nov:22(22):7831 ～7841.
9 Canguilhem B, Pradines A, Baudouin C, et al. RhoB protects human keratinocytes from UVB-induced apoptosis through epidermal growth factor receptor signaling. J Biol Chem. 2005 Dec 30,280(52):43257— 63.
10 Miglietta L, Franzone P, Centurioni MG, et al. A Phase II Trial with Cisplatin-Paclitaxel Cytotoxic Treatment and Concurrent External and Endocavitary Radiation Therapy in Locally Advanced or Recurrent Cervical Cancer.Oncology. 2006 Jan 26;70(1):19-24.
11 Yamamoto N, Nishimura Y, Nakagawa K,et al. Phase I/II study of weekly docetaxel dose escalation in combination with fixed weekly cisplatin and concurrent thoracic radiotherapy in locally advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2006 Jan 17:1—7.
12 Kolfschoten GM, Hulscher TM, Duyndam MC, et al. Variation in the kinetics of caspase-3 activation, Bcl-2 phosphorylation and apoptotic morphology in unselected human ovarian cancer cell lines as a response to docetaxel. Biochem Pharmacol. 2002,63(4): 733—43.
13 Ricotti L, Tesei A, De Paola F, et al. In vitro schedule-dependent interaction between docetaxel and gemcitabine in human gastric cancer cell lines. Clin Cancer Res. 2003,9(2):900～5.
14 Scagliotti GV, Turrisi AT 3rd. Docetaxel-based combined-modality chemoradiotherapy for locally advanced non-small cell lung cancer. Oncologist. 2003,8(4),361～74.
15 Araki S, Miyagi Y, Kawanishi K, et al. Neoadjuvant treatment with docetaxel and the effects of irradiation for human ovarian adenocarcinoma and cervical squamous cell carcinoma in vitro. Acta Med Okayama.2002,56(1):13～8.
16 Ollikainen T, Knuuttila A, Suhonen S, et al. In vitro sensitivity of normal human mesothelial and malignant mesothelioma cell lines to four new chemotherapeutic agents. Anticancer Drugs. 2000,11(2):93～99.
17 Parkin DM,Bray F,Ferlay J,Pisani P. Global Cancer Statistics,2002.CA Cancer J Clin 2005;55:74-108.
18 吕任齐,赵体德．云南省-县市肺癌死亡率趋势分析．中国肿瘤[J],2002,11,(12)：701～701．
19 George D, Soren M, Paul M. Biologic basic for combining drugs and radiation[J].Semin Radiat Oncol,2006,16(1):2～9.
20 Cantley LC. The phosphoinositide 3-kinase pathway. Science,2002,296:1655～1657.
21 Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-AKT): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J,1998,335(Pt 1):1～13.
22 Vanhaesebroeck B, and Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J,2000,346(Pt 3):561～576.
23 Gupta AK, Bakanauskas VJ, Cemiglia GJ, et al. The Ras radiation resistance pathway. Cancer Res,2001,61:4278～4282.
24 Kozma SC,Thomsag.Regulation of cell size in growth,development and human disease; PI3K, PKB and S6K [J].Bioassays,2002,24(1),65～71.
25 Neri L M,borgatti P,Capitani S, et al.The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system[J]. Biochim Biophys Acta,2002,1584(2-3),73～80.
26 Cheng JQ .Godwin AK ,Bellacosa A , et al.AKT2,a putative oncogene encoding a member of a subfamily of portein-serine/threonine kinases,is a mplified in human ovarianc arcinomas[J].Proc Natl Acad Sci USA, 1992 ,89 (19):9267～9271.
27 Bellacosa A ,de Feo D ,GodwinA K, et al. Molecular alterations of the AM oncogene in ovarian and berast carcinomas[J] .Int J Cancer,1995,64 (4): 280～285.
28 Cheng JQ ,Ruggeri B ,Klein WM,et al .Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 experssion and tumorigenicity by antisense RNA[J].Prue Natl Acad Sci USA, 1996,93 (8):3636 -3641.
29 Ringel M D,Hayre N ,Saito J ,et al. Overexpression and overactivation of Akt in thyroid carcinoma[J].CancerRes,2001,61(8):6105～6111.
30 Yuan Z Q,Sun M ,Feldman R I,et al. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer[J]. Oncogene,2000,19(8):2324～2330.
31 Saxj K,Eldeiry WS.p53 downstream targets and chemosensitivity[J]. Cell Death Differ ,2003,10(4);413～417.
32 Nnewton HR. Molecular neur-ooncology and development of targeted therapeutic strategies for brain tumors. Part2 : PI3K/Akt/PTEN, mTOR, SHH/PTCH and angtogenests [J] Expert Rev Anticancer Ther,2004,4(1):105～128.
33 Weinert T. Enhanced:a DNA damage checkpoint meets the cell cycle engine[J]. Science, 1997,277(5331):1450～1451.
34 Shtivelman E,Sussman J, Stokoe D. Role for PI 3-kinase and PKB activity in the G2/M phase of the cell cycle[J]. Carr Biol, 2002, 12(11);919～924.
35 Henry MK, Lynch JT , Eapen AK ,et al. DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway[J]. Blood ,2001,98(3):834-841.
36 Maker S, Eccless A . Phosphoinositide 3-kinase signaling pathways in tumor progression, invasion and angiogenesis[J].Tumori,2004,90(1):2～8.
37 Edwarda E. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to Ionizing radiation[J]. Cancer Res,2002,62(16):4671～4677.
38 Fang J, Xia C,Cao Z, et al. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways[J] ,FASEB J,2005,19(3);342～353.
39 Cantley LC. The phosphoinositide 3-kinase pathway. Science,2002,296:1655～～1657.
40 Gupta AK, Cemiglia GJ, Mick S,et al. Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using Ly294002. Int J Radiat Oncol Biol Phys,2003,56:846～853.
41 刘泰福,等主编,现代放射肿瘤学.上海:复旦大学出版社、上海医科大学出版社。2001.
42 Ashkenazi A,Dixit VM.Death receptors:signaling and modulation[J].Science.1998,281(5381):1305-1308.
43 Igor BR,Eugenia V,G J,Mick S,et al.If not apoptosis,then what? Treatment-induced senescence and mitotic catastrophe in tumor cells[J].Drug Resistance Updates,2001,4:303-313.
44 Bemstein JL;Seminara D;Borresen Dale AL.Workshop on The Epidemiology of the ATM Gene:Impact on Breast Cancer Risk and Treatment,Present Status and Future Focus,Lillehammer,Norway,29June 2002[J].Breast Cancer Res.2002,4(6):249-252.
45 夏曙,于世英.抑制PI3K/Akt提高药物对HeLa细胞放射增敏作用的研究.中华放射肿瘤学杂志.2006,5:419-422.
46 傅深,孙宜,章青,邵雨卉,刘泰福.阻断PI3K/AKT通路对乳腺癌细胞放射敏感性影响的研究.中华放射肿瘤学杂志。2006,15(6):467-470.
47 Silvestri I,Guide C,Imperatore C,et al.The micronucleas assay:an evaluation of its use in determining tumor cell radiosensitivity invitro[J].J Euro radiat Oncol,1997,(Sup 2):15.
48 Liang J,Slingerland JM.Multiple role of the PI3K/PKB(AKT)pathway in cell cycle progression [J].Pancreas 2004,28(3):353-358.
49 Zhou H,Kim YS,Peletier A,et al.Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR-and HER2-overexpressing breast cancer cell line proliferation,radiosensitization,and resistance.Int J Radiat Oncol Biol Phys,2004,58:344-352.
50 Lin WC,Kao HW,Robinson D,et al.Tyrosine kinases and gastric cancer.Oncogene,2000,19:5680-5689.
51 Easty DJ,Bennett DC.Melanoma Res,Protein tyrosine kinases in malignant melanoma.2000,10:401-411.
52 Latnenl,laihom.Cell:UV damage responses functions of tumor suppressor p53[J].Biochim Biophys Acta,2005,1755(2):71-89.
53 Dashbc,el Deiryws.Cell cycle checkpoint control mech anisms that can bedisrupted in cancer[J].Methods Mobiol,2004,280:99-161.
54 Howells LM,Hudson EA,Manson MM.Inhibition of phosphatiaylino sitot 3-kinase/protein kinase B signaling is not sufficient to account for inable-3-carbinol-induced apoptosis in some breast and prostate tumor cell[J].Clin cancer Res,2005,11(23):8521-8527.
55 Torres Roca JF,Steven Eschrich.Prediction of radiation sensitivity using a gene expression classifier[J].Cancer Res.2005,65(16):7169-7176.
56 FAN S,MA YX,GAO M,et al.The multisubstrate adapter Gabl regulates hepatocyte growth factor(scatterf actor)-c-Met signaling for cells urvival and DNA repair[J].Mol Cell Biol,2001,21(15),4968-4984.
57 傅深,章青,孙宜等.不同亚型AKT/PKB在肿瘤细胞凋亡中的作用.肿瘤,2005,25:339-340.
58 闫凤彩,王秦秦,阮永华等.肺癌细胞系XWLC-05的建立及其生物学特性研究[J]癌症2007,26(1):21-25.
1 Carpenter CL,Cantley LC.Phosphoinositide 3-kinase and the regulation of cell growth.Biochim-Biophys-Acta,1996;1288(1):M11-16.
2 Bemstein JL;Seminara D;Borresen Dale AL.Workshop on The Epidemiology of the ATM Gene:Impact on Breast Cancer Risk and Treatment,Present Status and Future Focus,Lillehammer,Norway,29 June 2002[J].Breast Cancer Res.2002,4(6):249-252.
3 Lee CM,Fuhrman CB,Planelles V.Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines[J].Clin Cancer Res.2006,12(1):250-256.
4 Xu J;Gao M;Fan S.Effect of Akt inhibition on scatter factor-regulated gene expression in DU-145human prostate cancer cells[J].Oncogene.2007,26(20):2925-2938.
5 Balsara BR,Pei J,Mitsuuchi Y,et al.Frequent activation of AKT in non-small cell lung carcinomas and p reneop lastic bronchial lesions.Carcinogenesis,2004,25(11):2053-2059.
6 Philipp V,Carsten B,Bernd N.et al.Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase[J].J Biol Chem,2005,280(6):5121-5127.
7 Testa JR,Bellacosa A.AKT p lays a central role in tumorigenesis.Proc Natl Acad Sci USA,2001,98(20):10983-10985.
8 李中文,阮培刚,邹彦.甘氨双唑钠对Ⅱ、Ⅲ期非小细胞肺癌放疗增敏作用的临床观察[J].遵义医学院学报,2007,9:314-315.
9 Perez CA,Pajak TF,Rubin P,et al.Long-term observations of the pattems of failure in patients with unreseetable non-oat cell carcinoma of the lung treated with definitive radiotherapy.Report by the Radiation Thera-py Ontology Group(73-01)[J].Cancer,1987,59:1874-1881.
10 Fletcher CH.Clini dose-response of human malignant epithelial tumor[J].Br J Raadiol,1973,46:233-237.
11 Yee SB,Song YS,Jeong SH,et al.A novel chenodeoxycholic derivative HS-1200 enhances radiation-induced apoptosis in MCF-7 cells[J].Oncol Rep,2007,17(4):919-923.
12 Pradier O.Rave Frank M,Lehmann J et al.Int J Cancer,2001,91(6):840-845.
13 任振义,白春学等.泰索帝对Lewis肺癌放疗增敏作用的实验研究[J].辐射研究与辐射工艺学报.2002,8:192-195.
14 Stevens CW,Lee JS,Cox J,et al.Novel approaches to locally advanced unresectablenon-small cell lung cancer.Radiother Oncol,2000,55(1):11-18.
15 黄静,黄金昶.扶正增效方对肺腺癌细胞放射增敏的基因表达谱分析[J].中日友好医院学报,2006,20(6):348-351.
16 Akimoto T,Hunte NR,Buchmiller L,et al.Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas[J].Clin Cancer Res,1999,5:2884- 2890.
17 Barker FG,Simmons ML,Chang SM,et al.EGFR overexpression and radiation response in glioblastoma multiforme[J].hat J Radiat Oncol Biol Phys,2001,51:410-418.
18 Baumann M,Krause M,Zips D,et al.Selective inhibition of the epidermal growth factor tyrosine kinase by BIBX 1382BS improves growth delay but not local control after fractionated irradiation in human FaDu squamous cell carcinoma in nude mice[J].Int J Radiat Biol,2003,79:547-559.
19 Solomon BM,Hagekyriakou J,Trivett MK,et al.EGFR blockade with ZD1839(Iressa)potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma[J].Int J Radiat Oncol Biol Phys,2003,55:713-723.
20 Chinnaiyan P,Huang S,Vallabhaneni G,et al.Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib(Tarceva)[J].Cancer Res,2005,65(8):3328-3335.
21 Milas L.Cyclooxygenase-2(Cox-2)enzyme inhibitors as potential enhancers of tumour radioresponse[J].Semin Radiat Oncol,2001,11:290-299.
22 Furuta Y,Hall ER,Sanduja S,er al.Prostaglandin production by murine tumours as a predictor for therapeutic response to indomethacin[J].Cancer Res,1988,48:3002-3007.
23 Huber PE,Bischof M,Jenne J,et al.Trimodal cancer treatment:beneficial effects of combined antiangiogenesis,radiation,and chemotherapy[J].Cancer Res,2005,65(9):3643-3655.
25 Lee CG,Heijn M,di Tomaso E:Anti-vascular endothelial growth factor reatment augments tumor radiation response under normoxic or hypoxic conditions[J].Cancer Res,2000,60:5565-5570.
25 Geng L,Donnelly E,McMahon G.Inhibition of vascular endothelial growth factor receptor signaling ledas to reversal of tulor resistance to radiotherapy[J].Cancer Res,2001,61:2413-2419.
27 Sonveaux P,Brouet A,Havaux X.Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway:Implications for tumor radiotherapy[J].Cacner Res,2003,63:1012-1019.
28 Lee SH,Kim HS,Park WS,et al.Non-small cell lung cancers frequently express phosphorylated Akt;an irnmunohistochemical study[J].APMIS,2002,110(7-8):587-592.
28 Blackhall FH,Pintilie M,Michael M,et al.Expression and prognostic significance of kit,protein kinase B,and mitogen-activated protein kinase in patients with small cell lung cancer[J].Clin Cancer Res,2003,9(6)2241-2247.
29 Nguyen DM,Chen GA,Reddy R,Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B(Akt)-mediated signaling pathway[J].J Thorac Cardiovasc Surg,2004,127(2):365-375.
30 傅深,蒋国梁,刘泰福.PI3K/Akt传导路径在细胞放疗敏感性中的意义[J].中华放射肿瘤学杂志,2006,15(2):140-143.
31 Green LM,Murray DK,Bant AM,et al.Response of thyroid follicular cells to gamma irradiation compared to proton irradiation.I.Initial characterization of DNA damage,micronucleus formation,apoptosis,cell survival,and cell cycle phase redistribution[J].Radiat Res,2001,155(1):32-42.
32 闫宇邱,孙伟建,周平坤.放射增敏剂的作用机制及临床研究进展[J].中华放射医学与防护杂志,2004,24(3):292-294.
33 马文丽,郑文岭.分子肿瘤学[M].北京:科技出版社出版,2003,135.
34 Steel GG,Deacon JM,Duchesne GM,et al.The dose-rate effect in human tumour cells [J].RadiotherOncol,1987,9(4):299-310.
35 Newton H R.Molecular neuro-oneology and development of targeted therapeutic strategies for brain tumors.Part 2:PI3K/Akt/PTEN,mTOR,SHH/PTCH and angiogenesis[J].E,rpert Rev Anticancer Th8r.2004,4(1):105-128.
36 Weinert T.Enhanced:a DNA damage checkpoint meets the cell cycle engine [J].Science,1997,277(5331):1450-1451.
37 Meyn RE.StephensLC,Ang KK,et al.Heterogeneity in the development of apoptosis in irradiated murine tumours of different histologies[J].Int J Radiat Biol.1993,64(5):583-591.
38 Braker S,Eccled SA.PhosphoinOsitide 3-kinase signalling pathways in tumor progression,invasion and angiogenesis[J].Tumori,2004,90(1):2-8.
39 Edwards E.Phosphatidy linositol 3-kinase/Akt signaling in the response of vascular endothelium to lonizing radiation[J].Cafleer Res,2002,62(16):4671-4677.
40 Fang J,Xia C,et al.Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways[J]+FASEB J,2005,19(3):342-353.
2 Kandel ES, Hay N. The regulation and activitives of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell. Res.1999, 253: 210-229.
3 Meier R, Hemmings BA. Regulation of protein kinase B. J. Recept ingnal Transduct Res. 1999,19: 121—128.
4 Schlessinger J. Cell signaling by receptor tyrosine Itinases. Cell, 2000,103: 211—225.
5 Rodgers EE, Theibert AB. Functions of PI 3-kina} in development of the nervous system. Int J Dev Neurosci., 2002, 20(3-5):187～197.
6 Tan J, Hallahan DE. Growth factor-independent activation of protein kinase B contributes to theinherent resistance of vascular endothelium to radiation-induced apoptotic response. Cancer Res.2003 Nov I5:63(22):7663～7667.
7 Okumura E, Fukuhara T, Yoshida H, et al. Akt inhibits Mytl in the signalling pathway that leads to meiotic G2/M-phase transition. Nat Cell Biol. 2002 Feb:4(2): 111—116.
8 Kandel ES, Skeen J, Majewski N, et al. Activation of Akt/protein kinase B overcomes a G2/M cell cycle checkpoint induced by DNA damage. Mol Cell Biol. 2002 Nov:22(22):7831 ～7841.
9 Canguilhem B, Pradines A, Baudouin C, et al. RhoB protects human keratinocytes from UVB-induced apoptosis through epidermal growth factor receptor signaling. J Biol Chem. 2005 Dec 30,280(52):43257— 63.
10 Miglietta L, Franzone P, Centurioni MG, et al. A Phase II Trial with Cisplatin-Paclitaxel Cytotoxic Treatment and Concurrent External and Endocavitary Radiation Therapy in Locally Advanced or Recurrent Cervical Cancer.Oncology. 2006 Jan 26;70(1):19-24.
11 Yamamoto N, Nishimura Y, Nakagawa K,et al. Phase I/II study of weekly docetaxel dose escalation in combination with fixed weekly cisplatin and concurrent thoracic radiotherapy in locally advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2006 Jan 17:1—7.
12 Kolfschoten GM, Hulscher TM, Duyndam MC, et al. Variation in the kinetics of caspase-3 activation, Bcl-2 phosphorylation and apoptotic morphology in unselected human ovarian cancer cell lines as a response to docetaxel. Biochem Pharmacol. 2002,63(4): 733—43.
13 Ricotti L, Tesei A, De Paola F, et al. In vitro schedule-dependent interaction between docetaxel and gemcitabine in human gastric cancer cell lines. Clin Cancer Res. 2003,9(2):900～5.
14 Scagliotti GV, Turrisi AT 3rd. Docetaxel-based combined-modality chemoradiotherapy for locally advanced non-small cell lung cancer. Oncologist. 2003,8(4),361～74.
15 Araki S, Miyagi Y, Kawanishi K, et al. Neoadjuvant treatment with docetaxel and the effects of irradiation for human ovarian adenocarcinoma and cervical squamous cell carcinoma in vitro. Acta Med Okayama.2002,56(1):13～8.
16 Ollikainen T, Knuuttila A, Suhonen S, et al. In vitro sensitivity of normal human mesothelial and malignant mesothelioma cell lines to four new chemotherapeutic agents. Anticancer Drugs. 2000,11(2):93～99.
17 Parkin DM,Bray F,Ferlay J,Pisani P. Global Cancer Statistics,2002.CA Cancer J Clin 2005;55:74-108.
18 吕任齐,赵体德．云南省-县市肺癌死亡率趋势分析．中国肿瘤[J],2002,11,(12)：701～701．
19 George D, Soren M, Paul M. Biologic basic for combining drugs and radiation[J].Semin Radiat Oncol,2006,16(1):2～9.
20 Cantley LC. The phosphoinositide 3-kinase pathway. Science,2002,296:1655～1657.
21 Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-AKT): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J,1998,335(Pt 1):1～13.
22 Vanhaesebroeck B, and Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J,2000,346(Pt 3):561～576.
23 Gupta AK, Bakanauskas VJ, Cemiglia GJ, et al. The Ras radiation resistance pathway. Cancer Res,2001,61:4278～4282.
24 Kozma SC,Thomsag.Regulation of cell size in growth,development and human disease; PI3K, PKB and S6K [J].Bioassays,2002,24(1),65～71.
25 Neri L M,borgatti P,Capitani S, et al.The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system[J]. Biochim Biophys Acta,2002,1584(2-3),73～80.
26 Cheng JQ .Godwin AK ,Bellacosa A , et al.AKT2,a putative oncogene encoding a member of a subfamily of portein-serine/threonine kinases,is a mplified in human ovarianc arcinomas[J].Proc Natl Acad Sci USA, 1992 ,89 (19):9267～9271.
27 Bellacosa A ,de Feo D ,GodwinA K, et al. Molecular alterations of the AM oncogene in ovarian and berast carcinomas[J] .Int J Cancer,1995,64 (4): 280～285.
28 Cheng JQ ,Ruggeri B ,Klein WM,et al .Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 experssion and tumorigenicity by antisense RNA[J].Prue Natl Acad Sci USA, 1996,93 (8):3636 -3641.
29 Ringel M D,Hayre N ,Saito J ,et al. Overexpression and overactivation of Akt in thyroid carcinoma[J].CancerRes,2001,61(8):6105～6111.
30 Yuan Z Q,Sun M ,Feldman R I,et al. Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer[J]. Oncogene,2000,19(8):2324～2330.
31 Saxj K,Eldeiry WS.p53 downstream targets and chemosensitivity[J]. Cell Death Differ ,2003,10(4);413～417.
32 Nnewton HR. Molecular neur-ooncology and development of targeted therapeutic strategies for brain tumors. Part2 : PI3K/Akt/PTEN, mTOR, SHH/PTCH and angtogenests [J] Expert Rev Anticancer Ther,2004,4(1):105～128.
33 Weinert T. Enhanced:a DNA damage checkpoint meets the cell cycle engine[J]. Science, 1997,277(5331):1450～1451.
34 Shtivelman E,Sussman J, Stokoe D. Role for PI 3-kinase and PKB activity in the G2/M phase of the cell cycle[J]. Carr Biol, 2002, 12(11);919～924.
35 Henry MK, Lynch JT , Eapen AK ,et al. DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway[J]. Blood ,2001,98(3):834-841.
36 Maker S, Eccless A . Phosphoinositide 3-kinase signaling pathways in tumor progression, invasion and angiogenesis[J].Tumori,2004,90(1):2～8.
37 Edwarda E. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to Ionizing radiation[J]. Cancer Res,2002,62(16):4671～4677.
38 Fang J, Xia C,Cao Z, et al. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways[J] ,FASEB J,2005,19(3);342～353.
39 Cantley LC. The phosphoinositide 3-kinase pathway. Science,2002,296:1655～～1657.
40 Gupta AK, Cemiglia GJ, Mick S,et al. Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using Ly294002. Int J Radiat Oncol Biol Phys,2003,56:846～853.
41 刘泰福,等主编,现代放射肿瘤学.上海:复旦大学出版社、上海医科大学出版社。2001.
42 Ashkenazi A,Dixit VM.Death receptors:signaling and modulation[J].Science.1998,281(5381):1305-1308.
43 Igor BR,Eugenia V,G J,Mick S,et al.If not apoptosis,then what? Treatment-induced senescence and mitotic catastrophe in tumor cells[J].Drug Resistance Updates,2001,4:303-313.
44 Bemstein JL;Seminara D;Borresen Dale AL.Workshop on The Epidemiology of the ATM Gene:Impact on Breast Cancer Risk and Treatment,Present Status and Future Focus,Lillehammer,Norway,29June 2002[J].Breast Cancer Res.2002,4(6):249-252.
45 夏曙,于世英.抑制PI3K/Akt提高药物对HeLa细胞放射增敏作用的研究.中华放射肿瘤学杂志.2006,5:419-422.
46 傅深,孙宜,章青,邵雨卉,刘泰福.阻断PI3K/AKT通路对乳腺癌细胞放射敏感性影响的研究.中华放射肿瘤学杂志。2006,15(6):467-470.
47 Silvestri I,Guide C,Imperatore C,et al.The micronucleas assay:an evaluation of its use in determining tumor cell radiosensitivity invitro[J].J Euro radiat Oncol,1997,(Sup 2):15.
48 Liang J,Slingerland JM.Multiple role of the PI3K/PKB(AKT)pathway in cell cycle progression [J].Pancreas 2004,28(3):353-358.
49 Zhou H,Kim YS,Peletier A,et al.Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR-and HER2-overexpressing breast cancer cell line proliferation,radiosensitization,and resistance.Int J Radiat Oncol Biol Phys,2004,58:344-352.
50 Lin WC,Kao HW,Robinson D,et al.Tyrosine kinases and gastric cancer.Oncogene,2000,19:5680-5689.
51 Easty DJ,Bennett DC.Melanoma Res,Protein tyrosine kinases in malignant melanoma.2000,10:401-411.
52 Latnenl,laihom.Cell:UV damage responses functions of tumor suppressor p53[J].Biochim Biophys Acta,2005,1755(2):71-89.
53 Dashbc,el Deiryws.Cell cycle checkpoint control mech anisms that can bedisrupted in cancer[J].Methods Mobiol,2004,280:99-161.
54 Howells LM,Hudson EA,Manson MM.Inhibition of phosphatiaylino sitot 3-kinase/protein kinase B signaling is not sufficient to account for inable-3-carbinol-induced apoptosis in some breast and prostate tumor cell[J].Clin cancer Res,2005,11(23):8521-8527.
55 Torres Roca JF,Steven Eschrich.Prediction of radiation sensitivity using a gene expression classifier[J].Cancer Res.2005,65(16):7169-7176.
56 FAN S,MA YX,GAO M,et al.The multisubstrate adapter Gabl regulates hepatocyte growth factor(scatterf actor)-c-Met signaling for cells urvival and DNA repair[J].Mol Cell Biol,2001,21(15),4968-4984.
57 傅深,章青,孙宜等.不同亚型AKT/PKB在肿瘤细胞凋亡中的作用.肿瘤,2005,25:339-340.
58 闫凤彩,王秦秦,阮永华等.肺癌细胞系XWLC-05的建立及其生物学特性研究[J]癌症2007,26(1):21-25.
1 Carpenter CL,Cantley LC.Phosphoinositide 3-kinase and the regulation of cell growth.Biochim-Biophys-Acta,1996;1288(1):M11-16.
2 Bemstein JL;Seminara D;Borresen Dale AL.Workshop on The Epidemiology of the ATM Gene:Impact on Breast Cancer Risk and Treatment,Present Status and Future Focus,Lillehammer,Norway,29 June 2002[J].Breast Cancer Res.2002,4(6):249-252.
3 Lee CM,Fuhrman CB,Planelles V.Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines[J].Clin Cancer Res.2006,12(1):250-256.
4 Xu J;Gao M;Fan S.Effect of Akt inhibition on scatter factor-regulated gene expression in DU-145human prostate cancer cells[J].Oncogene.2007,26(20):2925-2938.
5 Balsara BR,Pei J,Mitsuuchi Y,et al.Frequent activation of AKT in non-small cell lung carcinomas and p reneop lastic bronchial lesions.Carcinogenesis,2004,25(11):2053-2059.
6 Philipp V,Carsten B,Bernd N.et al.Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase[J].J Biol Chem,2005,280(6):5121-5127.
7 Testa JR,Bellacosa A.AKT p lays a central role in tumorigenesis.Proc Natl Acad Sci USA,2001,98(20):10983-10985.
8 李中文,阮培刚,邹彦.甘氨双唑钠对Ⅱ、Ⅲ期非小细胞肺癌放疗增敏作用的临床观察[J].遵义医学院学报,2007,9:314-315.
9 Perez CA,Pajak TF,Rubin P,et al.Long-term observations of the pattems of failure in patients with unreseetable non-oat cell carcinoma of the lung treated with definitive radiotherapy.Report by the Radiation Thera-py Ontology Group(73-01)[J].Cancer,1987,59:1874-1881.
10 Fletcher CH.Clini dose-response of human malignant epithelial tumor[J].Br J Raadiol,1973,46:233-237.
11 Yee SB,Song YS,Jeong SH,et al.A novel chenodeoxycholic derivative HS-1200 enhances radiation-induced apoptosis in MCF-7 cells[J].Oncol Rep,2007,17(4):919-923.
12 Pradier O.Rave Frank M,Lehmann J et al.Int J Cancer,2001,91(6):840-845.
13 任振义,白春学等.泰索帝对Lewis肺癌放疗增敏作用的实验研究[J].辐射研究与辐射工艺学报.2002,8:192-195.
14 Stevens CW,Lee JS,Cox J,et al.Novel approaches to locally advanced unresectablenon-small cell lung cancer.Radiother Oncol,2000,55(1):11-18.
15 黄静,黄金昶.扶正增效方对肺腺癌细胞放射增敏的基因表达谱分析[J].中日友好医院学报,2006,20(6):348-351.
16 Akimoto T,Hunte NR,Buchmiller L,et al.Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas[J].Clin Cancer Res,1999,5:2884- 2890.
17 Barker FG,Simmons ML,Chang SM,et al.EGFR overexpression and radiation response in glioblastoma multiforme[J].hat J Radiat Oncol Biol Phys,2001,51:410-418.
18 Baumann M,Krause M,Zips D,et al.Selective inhibition of the epidermal growth factor tyrosine kinase by BIBX 1382BS improves growth delay but not local control after fractionated irradiation in human FaDu squamous cell carcinoma in nude mice[J].Int J Radiat Biol,2003,79:547-559.
19 Solomon BM,Hagekyriakou J,Trivett MK,et al.EGFR blockade with ZD1839(Iressa)potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma[J].Int J Radiat Oncol Biol Phys,2003,55:713-723.
20 Chinnaiyan P,Huang S,Vallabhaneni G,et al.Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib(Tarceva)[J].Cancer Res,2005,65(8):3328-3335.
21 Milas L.Cyclooxygenase-2(Cox-2)enzyme inhibitors as potential enhancers of tumour radioresponse[J].Semin Radiat Oncol,2001,11:290-299.
22 Furuta Y,Hall ER,Sanduja S,er al.Prostaglandin production by murine tumours as a predictor for therapeutic response to indomethacin[J].Cancer Res,1988,48:3002-3007.
23 Huber PE,Bischof M,Jenne J,et al.Trimodal cancer treatment:beneficial effects of combined antiangiogenesis,radiation,and chemotherapy[J].Cancer Res,2005,65(9):3643-3655.
25 Lee CG,Heijn M,di Tomaso E:Anti-vascular endothelial growth factor reatment augments tumor radiation response under normoxic or hypoxic conditions[J].Cancer Res,2000,60:5565-5570.
25 Geng L,Donnelly E,McMahon G.Inhibition of vascular endothelial growth factor receptor signaling ledas to reversal of tulor resistance to radiotherapy[J].Cancer Res,2001,61:2413-2419.
27 Sonveaux P,Brouet A,Havaux X.Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway:Implications for tumor radiotherapy[J].Cacner Res,2003,63:1012-1019.
28 Lee SH,Kim HS,Park WS,et al.Non-small cell lung cancers frequently express phosphorylated Akt;an irnmunohistochemical study[J].APMIS,2002,110(7-8):587-592.
28 Blackhall FH,Pintilie M,Michael M,et al.Expression and prognostic significance of kit,protein kinase B,and mitogen-activated protein kinase in patients with small cell lung cancer[J].Clin Cancer Res,2003,9(6)2241-2247.
29 Nguyen DM,Chen GA,Reddy R,Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B(Akt)-mediated signaling pathway[J].J Thorac Cardiovasc Surg,2004,127(2):365-375.
30 傅深,蒋国梁,刘泰福.PI3K/Akt传导路径在细胞放疗敏感性中的意义[J].中华放射肿瘤学杂志,2006,15(2):140-143.
31 Green LM,Murray DK,Bant AM,et al.Response of thyroid follicular cells to gamma irradiation compared to proton irradiation.I.Initial characterization of DNA damage,micronucleus formation,apoptosis,cell survival,and cell cycle phase redistribution[J].Radiat Res,2001,155(1):32-42.
32 闫宇邱,孙伟建,周平坤.放射增敏剂的作用机制及临床研究进展[J].中华放射医学与防护杂志,2004,24(3):292-294.
33 马文丽,郑文岭.分子肿瘤学[M].北京:科技出版社出版,2003,135.
34 Steel GG,Deacon JM,Duchesne GM,et al.The dose-rate effect in human tumour cells [J].RadiotherOncol,1987,9(4):299-310.
35 Newton H R.Molecular neuro-oneology and development of targeted therapeutic strategies for brain tumors.Part 2:PI3K/Akt/PTEN,mTOR,SHH/PTCH and angiogenesis[J].E,rpert Rev Anticancer Th8r.2004,4(1):105-128.
36 Weinert T.Enhanced:a DNA damage checkpoint meets the cell cycle engine [J].Science,1997,277(5331):1450-1451.
37 Meyn RE.StephensLC,Ang KK,et al.Heterogeneity in the development of apoptosis in irradiated murine tumours of different histologies[J].Int J Radiat Biol.1993,64(5):583-591.
38 Braker S,Eccled SA.PhosphoinOsitide 3-kinase signalling pathways in tumor progression,invasion and angiogenesis[J].Tumori,2004,90(1):2-8.
39 Edwards E.Phosphatidy linositol 3-kinase/Akt signaling in the response of vascular endothelium to lonizing radiation[J].Cafleer Res,2002,62(16):4671-4677.
40 Fang J,Xia C,et al.Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways[J]+FASEB J,2005,19(3):342-353.