ROZ活化PPARγ促进DDP抑制A549细胞裸鼠移植瘤生长作用
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摘要
目的:观察过氧化物酶体增殖因子活化受体γ(Peroxisome Proliferator activated recettor gammar PPARγ)配体罗格列酮(Rosiglitazone ROZ)与顺铂(Cisplatin DDP)联合应用对人肺腺癌细胞系A549裸鼠移植瘤的作用,探讨ROZ活化PPARγ,下调NFκB、Bcl-2,从而诱导人肺腺癌细胞凋亡的作用机制。
方法:体外培养人肺腺癌A549细胞,建立人肺腺癌(A549)细胞裸鼠移植瘤模型,28只荷瘤裸鼠随机分为7组, A组(生理盐水0.2ml),B组(DDP1mg/kg),C组(DDP4mg/kg),D组(ROZ10mg/kg),E组(ROZ30mg/kg),F组(ROZ10mg/kg +DDP1mg/kg),G组(ROZ 30mg/kg +DDP1mg/kg)。隔天腹腔注射给药,共8次,给药期间每4日测量皮下移植瘤的最长经和最短经,按标准公式:移植瘤体积(V)=最长径×最短径2×0.52计算瘤体积,绘制肿瘤生长曲线。实验末处死裸鼠,剥离皮下移植瘤,称量重量,计算瘤重抑制率;观察ROZ与DDP联合应用对人肺腺癌裸鼠移植瘤的治疗作用及化疗后人肺腺癌裸鼠移植瘤的病理学形态特点。移植瘤组织标本SP免疫组织化学检测PPARγ、NFκB、Bcl-2蛋白的表达。
结果:人肺腺癌裸鼠移植瘤模型治疗实验结果显示:罗格列酮、顺铂及两药合用均能抑制裸鼠移植瘤的生长。DDP1mg/kg组及DDP4mg/kg组对移植瘤的瘤重抑制率分别为30.28%,65.85%,ROZ10mg/kg组及ROZ30mg/kg组对移植瘤的瘤重抑制率分别为38.38%,49.65%,呈剂量依赖性(P<0.01)。联合用药ROZ10mg/kg +DDP1mg/kg组及ROZ30mg/kg +DDP1mg/kg组抑瘤作用进一步增强,瘤重抑制率分别为52.11%,83.80%。ROZ30mg/kg与DDP1mg/kg联合应用具有协同效应(q=1.29)。免疫组化检测结果显示ROZ10mg/kg组及ROZ30mg/kg组与对照组比较, PPARγ蛋白表达上调,NFκB、Bcl-2蛋白表达下调,差异具有显著性(P<0.05)。联合用药组该调节作用进一步增强(P<0.001)。
结论:1)罗格列酮能抑制人肺腺癌裸鼠移植瘤的生长。
2)罗格列酮能增强顺铂对人肺腺癌裸鼠移植瘤的生长抑制作用,呈剂量依赖性。
3)罗格列酮增强顺铂抑制人肺癌裸鼠移植瘤生长作用可能与其上调PPARγ,下调NFκB、Bcl-2蛋白表达相关。
Objective:To observe the synergistic effects of Rosiglitazone and Cisplatin on the growth of lung adenocarcinoma A549 xenogragft in nude mice, and to investigate the mechanism of the therapeutic and synergistic action whether is involved in activating PPARγ.
Methods:Human lung carcinomal cell line (A549) cells were cultured in vitro, then A549 cells were transplanted in nude mice. Twenty-eight xenogragfts in nude mice were established successively. They were then randomly divided into seven groups. A(N.S group),B(Cisplatin 1mg/kg),C(Cisplatin 4mg/kg),D(Rosiglitazone 10mg/kg), E(Rosiglitazon30mg/kg),F(Rosiglitazon10mg/kg+Cisplatin1mg/kg),G(Rosiglitazone30mg/kg+Cisplatin1mg/kg).Seven days after implantation, different treatments were served. The volumes of the xenogragfts were measured respectively during the therapy time. The tumor growth inhibiting rates of each group were calculated. Moreover, the curves of tumor growth were drew. Xenogragft was subjected to histological examination. Subcutaneous xenogragft PPARγ, Bcl-2 and NFκB were determined by immunohistochemistry method.
Results: Therapeutic trial of human lung carcinoma xenografts in nude mouse model indicated that In each treatment group, tumor growth was suppressed significantly, intraperitoneal injection of Cisplatin, Rosiglitazon and their combination resulted in a significant inhibition on the growth of human lung carcinoma xenografts A549 in vivo(P<0.01), The tumor weight inhibitory rate of DDP at 1mg/kg, 4mg/kg was 30.28%, 65.85%,respectively. The tumor weight inhibitory rate of ROZ at 10mg/kg, 30mg/kg was 38.38%, 49.65% respectively. The tumor weight inhibitory rate of combination groups was 52.11%, 83.80%. The effect of inhibiting tumor growth was significantly strengthened. The combination group (Rosiglitazone 30mg/kg+ Cisplatin 1mg/kg) showed synergia effect on inhibiting the growth of the xenografts with a q value of 1.29. Campare to control group, Bcl-2 and NFκB expression of subcutaneous xenografts was obviously down-regulated and the PPARγwas up-regulated by Rosiglitazone (P<0.05) and the combined group(P<0.001).
Conclusion:
1) Rosiglitazone can inhibit the growth of human lung carcinoma xenograft in nude mice.
2) Rosiglitazone combined with Cisplatin can significantly inhibit the growth of human lung carcinoma xenograft in nude mice in dose-dependent manner.
3) The inhibition of growth by Rosiglitazone combined with Cisplatin are associated with up-regulation of PPARγprotein level expression and down-regulation of NFκB、Bcl-2protein level expression.
方法:体外培养人肺腺癌A549细胞,建立人肺腺癌(A549)细胞裸鼠移植瘤模型,28只荷瘤裸鼠随机分为7组, A组(生理盐水0.2ml),B组(DDP1mg/kg),C组(DDP4mg/kg),D组(ROZ10mg/kg),E组(ROZ30mg/kg),F组(ROZ10mg/kg +DDP1mg/kg),G组(ROZ 30mg/kg +DDP1mg/kg)。隔天腹腔注射给药,共8次,给药期间每4日测量皮下移植瘤的最长经和最短经,按标准公式:移植瘤体积(V)=最长径×最短径2×0.52计算瘤体积,绘制肿瘤生长曲线。实验末处死裸鼠,剥离皮下移植瘤,称量重量,计算瘤重抑制率;观察ROZ与DDP联合应用对人肺腺癌裸鼠移植瘤的治疗作用及化疗后人肺腺癌裸鼠移植瘤的病理学形态特点。移植瘤组织标本SP免疫组织化学检测PPARγ、NFκB、Bcl-2蛋白的表达。
结果:人肺腺癌裸鼠移植瘤模型治疗实验结果显示:罗格列酮、顺铂及两药合用均能抑制裸鼠移植瘤的生长。DDP1mg/kg组及DDP4mg/kg组对移植瘤的瘤重抑制率分别为30.28%,65.85%,ROZ10mg/kg组及ROZ30mg/kg组对移植瘤的瘤重抑制率分别为38.38%,49.65%,呈剂量依赖性(P<0.01)。联合用药ROZ10mg/kg +DDP1mg/kg组及ROZ30mg/kg +DDP1mg/kg组抑瘤作用进一步增强,瘤重抑制率分别为52.11%,83.80%。ROZ30mg/kg与DDP1mg/kg联合应用具有协同效应(q=1.29)。免疫组化检测结果显示ROZ10mg/kg组及ROZ30mg/kg组与对照组比较, PPARγ蛋白表达上调,NFκB、Bcl-2蛋白表达下调,差异具有显著性(P<0.05)。联合用药组该调节作用进一步增强(P<0.001)。
结论:1)罗格列酮能抑制人肺腺癌裸鼠移植瘤的生长。
2)罗格列酮能增强顺铂对人肺腺癌裸鼠移植瘤的生长抑制作用,呈剂量依赖性。
3)罗格列酮增强顺铂抑制人肺癌裸鼠移植瘤生长作用可能与其上调PPARγ,下调NFκB、Bcl-2蛋白表达相关。
Objective:To observe the synergistic effects of Rosiglitazone and Cisplatin on the growth of lung adenocarcinoma A549 xenogragft in nude mice, and to investigate the mechanism of the therapeutic and synergistic action whether is involved in activating PPARγ.
Methods:Human lung carcinomal cell line (A549) cells were cultured in vitro, then A549 cells were transplanted in nude mice. Twenty-eight xenogragfts in nude mice were established successively. They were then randomly divided into seven groups. A(N.S group),B(Cisplatin 1mg/kg),C(Cisplatin 4mg/kg),D(Rosiglitazone 10mg/kg), E(Rosiglitazon30mg/kg),F(Rosiglitazon10mg/kg+Cisplatin1mg/kg),G(Rosiglitazone30mg/kg+Cisplatin1mg/kg).Seven days after implantation, different treatments were served. The volumes of the xenogragfts were measured respectively during the therapy time. The tumor growth inhibiting rates of each group were calculated. Moreover, the curves of tumor growth were drew. Xenogragft was subjected to histological examination. Subcutaneous xenogragft PPARγ, Bcl-2 and NFκB were determined by immunohistochemistry method.
Results: Therapeutic trial of human lung carcinoma xenografts in nude mouse model indicated that In each treatment group, tumor growth was suppressed significantly, intraperitoneal injection of Cisplatin, Rosiglitazon and their combination resulted in a significant inhibition on the growth of human lung carcinoma xenografts A549 in vivo(P<0.01), The tumor weight inhibitory rate of DDP at 1mg/kg, 4mg/kg was 30.28%, 65.85%,respectively. The tumor weight inhibitory rate of ROZ at 10mg/kg, 30mg/kg was 38.38%, 49.65% respectively. The tumor weight inhibitory rate of combination groups was 52.11%, 83.80%. The effect of inhibiting tumor growth was significantly strengthened. The combination group (Rosiglitazone 30mg/kg+ Cisplatin 1mg/kg) showed synergia effect on inhibiting the growth of the xenografts with a q value of 1.29. Campare to control group, Bcl-2 and NFκB expression of subcutaneous xenografts was obviously down-regulated and the PPARγwas up-regulated by Rosiglitazone (P<0.05) and the combined group(P<0.001).
Conclusion:
1) Rosiglitazone can inhibit the growth of human lung carcinoma xenograft in nude mice.
2) Rosiglitazone combined with Cisplatin can significantly inhibit the growth of human lung carcinoma xenograft in nude mice in dose-dependent manner.
3) The inhibition of growth by Rosiglitazone combined with Cisplatin are associated with up-regulation of PPARγprotein level expression and down-regulation of NFκB、Bcl-2protein level expression.
引文
[1] Maione P, Rossi A, Airoma G, et al. The role of targeted therapy in non-small cell lung cancer. Crit Rev Oncol Hematol, 2004;51(1):29-44
[2] Okamoto T, Maruyama R, Shoji F, et al. Long-term survivors in stage IV non-small cell lung cancer. Lung Cancer, 2005;47(L): 85-91
[3] Kosmidis PA, Manegold C. Advanced NSCLC: new cytostatic agents. Lung Cancer, 2003; 41 Suppl 1:S123-32
[4] Patel JD, Pasche B, Argiris A. Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase inhibitors: where do we stand, where do we go. Crit Rev Oncol Hematol, 2004;50(3):175-86
[5] Kersten S, Desvergne B, Wshiw. Roles of PPARs in health and disease. Nature, 2000; 405(6785): 421-4
[6] Chaudhary PM, Rononson IB .Expression and activity of P-glycoprotein, a multidrug efflux pump,in human hematopoietic stem cells. Cell,1991Jul 12; 66(1):85
[7] Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signaling pathways through heterodimer formation of their receptors Nature, 1992 Aug 27; 358 (6389):771-4
[8] Marcus SL, Capone JP, Rachubinski RA. Identification of COUP-TFII as a Peroxisome proliferator response element binding factor using genetic seletion I yeast: COUP-TFII activates transcription in yeast but antagonizes PPAR signaling in mammalian cells. Mol Cell Endocrinol, 1996;120(1):31-39
[9] Hamm JK, el Jack AK,Pilch PF.Role of PPAR gamma in regulating adipocyte differenting and insulin - responsive glucose uptake.Ann N Y Acad Sci, 1999; 892: 134-45
[10] Rahimian R,Masih-Khan E,LoM,etal.Hepatic over-expression of peroxisome proliferator activated receptor gamma in the ob/ob mouse model of non-insulin dependent diabetes mellitus.Mol Cell Biochem,.2001;224(1-2):29-37
[11] Koeffler HP. Peroxisome Proliferator-activated receptor gamma and cancers[J]. Clin Cancer Res,.2003;9(1):1-9
[12] Chang TH and Szabo E. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer . Cancer Res, 2000; 60(4):1129-38
[13] Liu H, Zang C, Fenner MH et al. PPARgamma ligands and ATRA inhibit the invasion of human breast cancer cells in vitor. Breast Cancer Res Treat, 2003;79(1):63-74
[14] Heaney AP, Fernando M, Melmed S. PPAR-gamma receptor ligands: novel therapy for pituitary adenomas. J Clin Invest, 2003 May; 111(9):1381-8
[15] Theocharis S, Kanelli H, Politi E et al. Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade . Lung Cancer, 2002; 36(3):249-55
[16] Yoshimura R, Matsuyama M, Segawa Y et al. Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer, 2003; 104(5):597-602
[17] Guan YF, Zhang YH, Breyer RM et al. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. Neoplasia, 1999; 1(4):330-9
[18] Heaney AP, Fernando M, Melmed S. PPAR-gamma receptor ligands :novel therapy for pituitary adenomas. J Clin Invest, 2003 ;111(9):1381-1388
[19] Keshamouni VG, Arenberg DA, Reddy RG, et al. PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-cell lung cancer. Neoplasia, 2005 ;7(3) :294-301
[20] Lee KS, Park SJ, Hwang PH, et al. PPAR-gamma modulates allergic inflammation through up-regulation of PTEN. FASEB J, 2005 ; 19(8) :1033-5
[21] Konturek PC, Kania J, Konturek JW, et al. H.Pylori infection, atrophic gastritis, cytokines, gastrin, COX-2, PPAR gamma and impaired apoptosis in gastric carcinogenesis. Med Sci Monit, 2003 ; 9(7) :SR53-66
[22] Cuan Y, Targeting peroxisome proliferator-activated receptors(PPARs) in kidney and urologic disease . Minerva Urol Nefrol , 2002;54(2): 65-79
[23] Toshinori Murata, Shikun He, Masanori Hangai,et al. PeroxisomeProliferator-Activated ReceptorγLigands Inhibit Choroidal Neovascularization. Investigative Ophthalmology and Visual Science, 2000;41 :2309-2317
[24] Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator activated receptors alpha and gamma. Proc Natl Acad Sci USA,1997 ;94(9): 4318-4323
[25] Dipak Panigraphy, Samuel Singer, Lucy Q.Shen, et al. PPARr ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. Clin Invest, 2002,110: 923-932
[26] Nam DH, Ramachandran S, Song DK, et al. Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone. Mol Hum Reprod, 2007;13(11):829-36.
[27] Aung CS, Faddy HM, Lister EJ,et al.Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation. Biochem Biophys Res Commun, 2006;340(2):656-60.
[28] Alarcon de la lastra C, Sanchez-Fidalgo S, Villegas I, et al. New pharmacological perspectives and therapeutic potential of PPAR-gamma agonists. Curr Pharm Des, 2004; 10(28):3505-24
[29]Krzystyniak KL, Current strategies for anticancer chemoprevention and chemoprotection Acta Pol Pharm, 2002; 59(6): 473-8
[30]周亭芳,庄英帜,曹建国。罗格列酮增强顺铂抑制人肺腺癌细胞增殖作用。中国药理学通报2005,21(1):88-91
[31]廖明初,庄英帜,曹建国。罗格列酮与顺铂联合应用诱导人肺腺癌细胞凋亡的作用研究。南华大学学报,2007,35(1):38-41
[32]戴体俊。合并用药的定量分析。中国药理学通报,1998,14(15);479-80
[33]葛海波,朱雄,王尔华。噻唑烷二酮类胰岛素增敏剂的研究进展。药学进展,2001,1:31-5
[34] Zander T, Kraus JA, Grommes C, et al. Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma. J Neurochem, 2002; 81(5):1052-1060
[35] Takashima T, Fujiwara Y, Higuchi K, et al. PPAR-gamma ligands inhibit growthof human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity. Int J Oncol, 2001; 19(3):465-71
[36] Shimada T, Kojima K, Yoshiura K, et al. Characteristics of the peroxisome proliferator activated receptor gamma(PPAR-gamma) ligand induced apoptosis in colon cancer cells. Cut, 2002; 50(5):658-664
[37] Sato H, Ishihara S, Kawashima K, et al. Expression of peroxisome proliferators-activated receptor(PPARr) gamma in gastric cancer and inhibitory effects of PPAR gamma agonists. Br J Cancer, 2000 NoV; 83(10):1394-1400
[38] Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarooma cells induced by ligands for Peroxisome proliferator-activated recepror-gamma and the retinoid X receptor. Proc Natl Acad Sci USA, 1997; 94(1):237-241
[39] Demetri GD,Fletcher CD,Mueller E,et al. Induction of solid tumor differentiation by the peroxisome proliferator-actived receptors-gamma ligand troglitazone in patients with liposarooma. Proc Natl Acad Sci USA,1996; 96(7):3951-3956
[40] Liu Y, Meng Y, Liu H et al.Growth inhibition and differentiation induced by proliferator activated receptor gamma ligand rosiglitazone in human melanoma cell line a375. Med Oncol, 2006; 23(3):393-402
[41]欧阳高亮,李祺福,洪水根。细胞凋亡与肿瘤的发生发展和治疗。国外医学肿瘤学分册.2000, 27 (5): 266-268
[42] Kerr 3F, Winterord CM, Harmon BV Apoptosis its significance in cancer and cancel therapy. Cancer,1994;73: 2013-2026
[43] Simon SM, Schindler M. Cell biological mechanisms of multidrug resistance in tumors. Proc Natl Acad Sci USA,1994; 91(9):3497-3504
[44] Manish A Shah and Gary K.Schwqrtz. Cell cycle-mediated drug resistance: An emerging concept in cancer therapy [J].Clin Cancer Res, 2001;7:2168-2181
[45] Hastak K, Gupta S, Ahmad N, et al. Role of p53 and NF-kappaB in epigallocatechin-3-gallate -induced apoptosis of LNCaP cells. Oncogene, 2003 ; 22(31): 4851-4859
[46] Gilmore TD, Koedood M, Piffat KA, et al. Rel/NF-kappaB/IkappaB proteins and cancer. Oncogene, 1996;13(7): 1367-78
[47] Vandoros GP, Konstantinopoulos PA, Sotiropoulou-Bonikou G, et al. PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas. J Cancer Res Clin Oncol, 2006 ;132(2):76-84
[48] Zhijian J. Chen et al. Ubiquitin Signaling in the NF-κB Pathway. Nat Cell Biol. 2005 August; 7(8): 758–765
[49] Degterev A, Lugovskoy A, Cardone M, et al. Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol, 2001;3(2):173-82
[50]Miyashita T, Read JC. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood,1993; 81(1):151-7
[51] Campos L, Rouault JP, Sabido O et al. High Expression of bcl-2 protein in acute myeloid leukemia cell is associated with poor response to chemotherapy. Blood, 1993; 81(11): 3091-3096
[52]Li M, Lee TW, Mok Ts, et al, Activation of peroxisome proliferators-activated receptor-gamma by troglitazone (TGZ) inhibits human lung cell growth. Cell Biochem, 2005; 96(4): 760-774
[53]Zhang M, Zou P, Bai M et al. Peroxisome proliferator activated receptor-gamma activated by ligands can inhibit human lung cancer growth through induction of apoptosis. J Huazhong Univ Sci Technolog Med Sci, 2003; 23(2):138-140
[54] Chen GG, Lee JF, Wang SH et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and Nf-kappaB in human colon cancer. Life Sci, 2002; 70(22):2631-46
[1] Suridvold H, Lien S, Identifieation of a novel peroxisome proliferrator-activated receptor PPARγpromoter in man and transactivation by the nuclear receptor ROR. Biophys Res Commun, 2001;287(2); 383
[2] Mejrhaeghe A, Fajas L, Gollilleux F. A function polymorphism in a STAT5B site of the human PPAR gamma 3 gene promoter affect heigh and lipid metabolism in a French population. Arterioscler Thromb Vasc Biol, 2003 Feb 1;23(23):289-94
[3] Alarcon de la Lastra C, Sanchez-Fidalgo S, Villegas I. New Pharmacological Perspectives and Therapeutic Potential of PPAR-gamma. Agonists Current Pharmaceutical Design, 2004;10:3505-3524
[4] Willson TM, Brown PJ, Sternbach DD, et al. The PPARs:from orphan receptors to drug discowery [J]. J Med Chem, 2000;43(4): 527-550
[5] PERE P, JAMES R, LIN Jiandie. Cytokine Stimulation of Energy Expenditure through p38 MAP Kinase Activation of PPARγCoactivator -1[J]. Molecular Cell,2001; 8:971-982
[6] Chen GG, Lee JF, Wang SH et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and Nf-kappaB in human colon cancer. Life Sci, 2002; 70(22):2631-46
[7] LLUIS F, VIVANE E, RAPHAEL R. PPARγcontrols cell proliferation and apoptosis in an RB-dependent manner[J]. Oncogene, 2003;22:4186-4193
[8] Reed JC. Apoptosis mechanisms: implications for cancer drug discovery. Oncology(Huntingt),2004 Nov;18(13 suppl 10): 10-20
[9] Zander T, Kraus JA, Grommas C. Induction of apposes in human and rat glioma by agonists of the nuclear receptor PPAR gamma. Neurochem, 2002;81(5):1052-1060
[10] WANG C, PATTABIRAMAN N, ZHOU J N. Cyclin D1 repression of peroxisome proliferators-activated receptor gamma expression and transactivation[J]. Mol Cell Biol, 2003;23(17):6159-6173
[11] Shimada T, Kojima K, Yoshiura K. Characteristics of the peroxisome proliferrator-activated receptor gamma(PPARγ) ligand induced apoptosis in colin cancer cells. Gut, 2002; 50(50):658
[12] Grommes C, Landreth GE, Heneka MT. Antineoplastic effects of peroxisome proliferrator-activated receptor gamma apoptosis. Lancet Oncol. 2004Jul;5(7):419-29
[13] Zhang M, Zou P, Bai M. Peroxisome proliferrator-activated receptor gamma by ligands can inhibit human lung cancer cell growth through induction of apoptosis. Huazhong Univer Sci Techenolog. Med Sic,2003;23(2):138-40
[14] YU Y, CORRELL O H, VANDEN HEUVEL J P. Conjugated linoleic acid decreases production of pro-inflammatory products in macriophages : evidence for a PPARγ-dependent mechanism[J]. Biochimica Biophysica Acta, 2002;1581:89-99
[15] Tukeuchi S, Okumura T, Motomura W. Troglitazone induce G1 arrest by P27 kipl induction that mediated by inhibition of proteasome in human gastric cell. Cancer Res, 2002; 93: 774-782
[16] LISA D Y, YAN G, JAMIE B. The antiproliferative effects of PPARγligands in normal human mammary epithelial cells[J]. Breast cancer Research and Treatment,2003;78:179-192
[17]Shiau CW, Yang CC, Kulp SK. Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xl/Bcl-2 functions independently of PPAR gamma. Cancer Res, 2005 Feb 15;6(4):1561-1569
[18] Shimada T, Kojima K, Yoshiura K, et al. Characteristics of the peroxisome proliferator activated receptor gamma(PPAR-gamma) ligand induced apoptosis in colon cancer cells[J]. Cut, 2002;50(5):658-664
[19] Back SJ, Wilson LC, Hsil C. Troglitazone, a peroxisome proliferators-activated receptor gamma(PPARγ) ligand, selectively induces the early growth response-1 gene independently of PPARγ. Biol Chem, 2003;278(8):5845-5853
[20] Strakova N, Ehrmann J, Dzubak P. The synthetic ligand of peroxisome proliferation-activated receptor gamma ciglitazone affects human globlastoma cell lines. Pharmacol Efp Ther, 2004; 309(3):1239-1247
[21] Han S, Sidell N, Fisher PB. Up-regulation of P21 gene expression by peroxisome proliferation-activated receptor gamma in human lung carcinoma cells. Clin cancer Res, 2004;10(6):1911-1919
[22] Kaga Hm, Sakisaka S, Harada M. Involvement of P21(WAF/cipl), P27(Kipl), and P18(Ink4c) in troglitazone induced cell cycle arrest in human hepatoma cell line. Hepatology, 2001;33(5):1087-1097
[23] Motomura W, Okumura T, Takahashi N, et al. Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27 KiP1 in human. Panceatic carcinoma cells[J]. Cancer Res, 2000;60(19):5558-5564
[24] Yoshizu mi T, Ohta T, Ninomiya I. Thiazolidinedione , a peroxisome proliferation-activated receptor gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int J Onct, 2004;25(8):1122-1130
[25] Galli A, Ceni E, Crabb DM. Antidiaberic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms. Cut, 2004;53(11):1682-1697
[26] Sunami E, Tsuno NH, Kitayama J. Decreased synthesis of matrix metallop roteinase-7 and adhesion to the extracellular matrix protein of human colon cancer cells treated with troglitazone. Surg Today, 2002;32:343-350
[27] Elnemr A, Ohta T, Iwata K, et al. PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells[J]. Int J Oncol, 2000;17(6):1157-1164
[28] Ceni E, Mello T, Tarocchi M. Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells. Worold J Oncot, 2005;11(8):1122-1130
[29] Margeli A, Kouraklis G, Theocharis S. Peroxisome proliferation-activated receptorC(PPARc) ligand and angiogenesis. Angiogenesis, 2003;6(3):165-169
[30] Panigrahy D, Singer S, Shen LQ, et al. PPARc ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. Clin Invest, 2002;110:923-932
[31] Keshamouni VG, Arenberg DA, Reddy RC, et al. PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neaplasia, 2005 Mar;7(3):294-301
[32] Panigrapy D, Singer S, Shen LQ, et al. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis[J]. J Clin Invest, 2002;110(7):923-932
[2] Okamoto T, Maruyama R, Shoji F, et al. Long-term survivors in stage IV non-small cell lung cancer. Lung Cancer, 2005;47(L): 85-91
[3] Kosmidis PA, Manegold C. Advanced NSCLC: new cytostatic agents. Lung Cancer, 2003; 41 Suppl 1:S123-32
[4] Patel JD, Pasche B, Argiris A. Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase inhibitors: where do we stand, where do we go. Crit Rev Oncol Hematol, 2004;50(3):175-86
[5] Kersten S, Desvergne B, Wshiw. Roles of PPARs in health and disease. Nature, 2000; 405(6785): 421-4
[6] Chaudhary PM, Rononson IB .Expression and activity of P-glycoprotein, a multidrug efflux pump,in human hematopoietic stem cells. Cell,1991Jul 12; 66(1):85
[7] Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signaling pathways through heterodimer formation of their receptors Nature, 1992 Aug 27; 358 (6389):771-4
[8] Marcus SL, Capone JP, Rachubinski RA. Identification of COUP-TFII as a Peroxisome proliferator response element binding factor using genetic seletion I yeast: COUP-TFII activates transcription in yeast but antagonizes PPAR signaling in mammalian cells. Mol Cell Endocrinol, 1996;120(1):31-39
[9] Hamm JK, el Jack AK,Pilch PF.Role of PPAR gamma in regulating adipocyte differenting and insulin - responsive glucose uptake.Ann N Y Acad Sci, 1999; 892: 134-45
[10] Rahimian R,Masih-Khan E,LoM,etal.Hepatic over-expression of peroxisome proliferator activated receptor gamma in the ob/ob mouse model of non-insulin dependent diabetes mellitus.Mol Cell Biochem,.2001;224(1-2):29-37
[11] Koeffler HP. Peroxisome Proliferator-activated receptor gamma and cancers[J]. Clin Cancer Res,.2003;9(1):1-9
[12] Chang TH and Szabo E. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer . Cancer Res, 2000; 60(4):1129-38
[13] Liu H, Zang C, Fenner MH et al. PPARgamma ligands and ATRA inhibit the invasion of human breast cancer cells in vitor. Breast Cancer Res Treat, 2003;79(1):63-74
[14] Heaney AP, Fernando M, Melmed S. PPAR-gamma receptor ligands: novel therapy for pituitary adenomas. J Clin Invest, 2003 May; 111(9):1381-8
[15] Theocharis S, Kanelli H, Politi E et al. Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade . Lung Cancer, 2002; 36(3):249-55
[16] Yoshimura R, Matsuyama M, Segawa Y et al. Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer, 2003; 104(5):597-602
[17] Guan YF, Zhang YH, Breyer RM et al. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. Neoplasia, 1999; 1(4):330-9
[18] Heaney AP, Fernando M, Melmed S. PPAR-gamma receptor ligands :novel therapy for pituitary adenomas. J Clin Invest, 2003 ;111(9):1381-1388
[19] Keshamouni VG, Arenberg DA, Reddy RG, et al. PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-cell lung cancer. Neoplasia, 2005 ;7(3) :294-301
[20] Lee KS, Park SJ, Hwang PH, et al. PPAR-gamma modulates allergic inflammation through up-regulation of PTEN. FASEB J, 2005 ; 19(8) :1033-5
[21] Konturek PC, Kania J, Konturek JW, et al. H.Pylori infection, atrophic gastritis, cytokines, gastrin, COX-2, PPAR gamma and impaired apoptosis in gastric carcinogenesis. Med Sci Monit, 2003 ; 9(7) :SR53-66
[22] Cuan Y, Targeting peroxisome proliferator-activated receptors(PPARs) in kidney and urologic disease . Minerva Urol Nefrol , 2002;54(2): 65-79
[23] Toshinori Murata, Shikun He, Masanori Hangai,et al. PeroxisomeProliferator-Activated ReceptorγLigands Inhibit Choroidal Neovascularization. Investigative Ophthalmology and Visual Science, 2000;41 :2309-2317
[24] Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator activated receptors alpha and gamma. Proc Natl Acad Sci USA,1997 ;94(9): 4318-4323
[25] Dipak Panigraphy, Samuel Singer, Lucy Q.Shen, et al. PPARr ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. Clin Invest, 2002,110: 923-932
[26] Nam DH, Ramachandran S, Song DK, et al. Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone. Mol Hum Reprod, 2007;13(11):829-36.
[27] Aung CS, Faddy HM, Lister EJ,et al.Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation. Biochem Biophys Res Commun, 2006;340(2):656-60.
[28] Alarcon de la lastra C, Sanchez-Fidalgo S, Villegas I, et al. New pharmacological perspectives and therapeutic potential of PPAR-gamma agonists. Curr Pharm Des, 2004; 10(28):3505-24
[29]Krzystyniak KL, Current strategies for anticancer chemoprevention and chemoprotection Acta Pol Pharm, 2002; 59(6): 473-8
[30]周亭芳,庄英帜,曹建国。罗格列酮增强顺铂抑制人肺腺癌细胞增殖作用。中国药理学通报2005,21(1):88-91
[31]廖明初,庄英帜,曹建国。罗格列酮与顺铂联合应用诱导人肺腺癌细胞凋亡的作用研究。南华大学学报,2007,35(1):38-41
[32]戴体俊。合并用药的定量分析。中国药理学通报,1998,14(15);479-80
[33]葛海波,朱雄,王尔华。噻唑烷二酮类胰岛素增敏剂的研究进展。药学进展,2001,1:31-5
[34] Zander T, Kraus JA, Grommes C, et al. Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma. J Neurochem, 2002; 81(5):1052-1060
[35] Takashima T, Fujiwara Y, Higuchi K, et al. PPAR-gamma ligands inhibit growthof human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity. Int J Oncol, 2001; 19(3):465-71
[36] Shimada T, Kojima K, Yoshiura K, et al. Characteristics of the peroxisome proliferator activated receptor gamma(PPAR-gamma) ligand induced apoptosis in colon cancer cells. Cut, 2002; 50(5):658-664
[37] Sato H, Ishihara S, Kawashima K, et al. Expression of peroxisome proliferators-activated receptor(PPARr) gamma in gastric cancer and inhibitory effects of PPAR gamma agonists. Br J Cancer, 2000 NoV; 83(10):1394-1400
[38] Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarooma cells induced by ligands for Peroxisome proliferator-activated recepror-gamma and the retinoid X receptor. Proc Natl Acad Sci USA, 1997; 94(1):237-241
[39] Demetri GD,Fletcher CD,Mueller E,et al. Induction of solid tumor differentiation by the peroxisome proliferator-actived receptors-gamma ligand troglitazone in patients with liposarooma. Proc Natl Acad Sci USA,1996; 96(7):3951-3956
[40] Liu Y, Meng Y, Liu H et al.Growth inhibition and differentiation induced by proliferator activated receptor gamma ligand rosiglitazone in human melanoma cell line a375. Med Oncol, 2006; 23(3):393-402
[41]欧阳高亮,李祺福,洪水根。细胞凋亡与肿瘤的发生发展和治疗。国外医学肿瘤学分册.2000, 27 (5): 266-268
[42] Kerr 3F, Winterord CM, Harmon BV Apoptosis its significance in cancer and cancel therapy. Cancer,1994;73: 2013-2026
[43] Simon SM, Schindler M. Cell biological mechanisms of multidrug resistance in tumors. Proc Natl Acad Sci USA,1994; 91(9):3497-3504
[44] Manish A Shah and Gary K.Schwqrtz. Cell cycle-mediated drug resistance: An emerging concept in cancer therapy [J].Clin Cancer Res, 2001;7:2168-2181
[45] Hastak K, Gupta S, Ahmad N, et al. Role of p53 and NF-kappaB in epigallocatechin-3-gallate -induced apoptosis of LNCaP cells. Oncogene, 2003 ; 22(31): 4851-4859
[46] Gilmore TD, Koedood M, Piffat KA, et al. Rel/NF-kappaB/IkappaB proteins and cancer. Oncogene, 1996;13(7): 1367-78
[47] Vandoros GP, Konstantinopoulos PA, Sotiropoulou-Bonikou G, et al. PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas. J Cancer Res Clin Oncol, 2006 ;132(2):76-84
[48] Zhijian J. Chen et al. Ubiquitin Signaling in the NF-κB Pathway. Nat Cell Biol. 2005 August; 7(8): 758–765
[49] Degterev A, Lugovskoy A, Cardone M, et al. Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol, 2001;3(2):173-82
[50]Miyashita T, Read JC. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood,1993; 81(1):151-7
[51] Campos L, Rouault JP, Sabido O et al. High Expression of bcl-2 protein in acute myeloid leukemia cell is associated with poor response to chemotherapy. Blood, 1993; 81(11): 3091-3096
[52]Li M, Lee TW, Mok Ts, et al, Activation of peroxisome proliferators-activated receptor-gamma by troglitazone (TGZ) inhibits human lung cell growth. Cell Biochem, 2005; 96(4): 760-774
[53]Zhang M, Zou P, Bai M et al. Peroxisome proliferator activated receptor-gamma activated by ligands can inhibit human lung cancer growth through induction of apoptosis. J Huazhong Univ Sci Technolog Med Sci, 2003; 23(2):138-140
[54] Chen GG, Lee JF, Wang SH et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and Nf-kappaB in human colon cancer. Life Sci, 2002; 70(22):2631-46
[1] Suridvold H, Lien S, Identifieation of a novel peroxisome proliferrator-activated receptor PPARγpromoter in man and transactivation by the nuclear receptor ROR. Biophys Res Commun, 2001;287(2); 383
[2] Mejrhaeghe A, Fajas L, Gollilleux F. A function polymorphism in a STAT5B site of the human PPAR gamma 3 gene promoter affect heigh and lipid metabolism in a French population. Arterioscler Thromb Vasc Biol, 2003 Feb 1;23(23):289-94
[3] Alarcon de la Lastra C, Sanchez-Fidalgo S, Villegas I. New Pharmacological Perspectives and Therapeutic Potential of PPAR-gamma. Agonists Current Pharmaceutical Design, 2004;10:3505-3524
[4] Willson TM, Brown PJ, Sternbach DD, et al. The PPARs:from orphan receptors to drug discowery [J]. J Med Chem, 2000;43(4): 527-550
[5] PERE P, JAMES R, LIN Jiandie. Cytokine Stimulation of Energy Expenditure through p38 MAP Kinase Activation of PPARγCoactivator -1[J]. Molecular Cell,2001; 8:971-982
[6] Chen GG, Lee JF, Wang SH et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and Nf-kappaB in human colon cancer. Life Sci, 2002; 70(22):2631-46
[7] LLUIS F, VIVANE E, RAPHAEL R. PPARγcontrols cell proliferation and apoptosis in an RB-dependent manner[J]. Oncogene, 2003;22:4186-4193
[8] Reed JC. Apoptosis mechanisms: implications for cancer drug discovery. Oncology(Huntingt),2004 Nov;18(13 suppl 10): 10-20
[9] Zander T, Kraus JA, Grommas C. Induction of apposes in human and rat glioma by agonists of the nuclear receptor PPAR gamma. Neurochem, 2002;81(5):1052-1060
[10] WANG C, PATTABIRAMAN N, ZHOU J N. Cyclin D1 repression of peroxisome proliferators-activated receptor gamma expression and transactivation[J]. Mol Cell Biol, 2003;23(17):6159-6173
[11] Shimada T, Kojima K, Yoshiura K. Characteristics of the peroxisome proliferrator-activated receptor gamma(PPARγ) ligand induced apoptosis in colin cancer cells. Gut, 2002; 50(50):658
[12] Grommes C, Landreth GE, Heneka MT. Antineoplastic effects of peroxisome proliferrator-activated receptor gamma apoptosis. Lancet Oncol. 2004Jul;5(7):419-29
[13] Zhang M, Zou P, Bai M. Peroxisome proliferrator-activated receptor gamma by ligands can inhibit human lung cancer cell growth through induction of apoptosis. Huazhong Univer Sci Techenolog. Med Sic,2003;23(2):138-40
[14] YU Y, CORRELL O H, VANDEN HEUVEL J P. Conjugated linoleic acid decreases production of pro-inflammatory products in macriophages : evidence for a PPARγ-dependent mechanism[J]. Biochimica Biophysica Acta, 2002;1581:89-99
[15] Tukeuchi S, Okumura T, Motomura W. Troglitazone induce G1 arrest by P27 kipl induction that mediated by inhibition of proteasome in human gastric cell. Cancer Res, 2002; 93: 774-782
[16] LISA D Y, YAN G, JAMIE B. The antiproliferative effects of PPARγligands in normal human mammary epithelial cells[J]. Breast cancer Research and Treatment,2003;78:179-192
[17]Shiau CW, Yang CC, Kulp SK. Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xl/Bcl-2 functions independently of PPAR gamma. Cancer Res, 2005 Feb 15;6(4):1561-1569
[18] Shimada T, Kojima K, Yoshiura K, et al. Characteristics of the peroxisome proliferator activated receptor gamma(PPAR-gamma) ligand induced apoptosis in colon cancer cells[J]. Cut, 2002;50(5):658-664
[19] Back SJ, Wilson LC, Hsil C. Troglitazone, a peroxisome proliferators-activated receptor gamma(PPARγ) ligand, selectively induces the early growth response-1 gene independently of PPARγ. Biol Chem, 2003;278(8):5845-5853
[20] Strakova N, Ehrmann J, Dzubak P. The synthetic ligand of peroxisome proliferation-activated receptor gamma ciglitazone affects human globlastoma cell lines. Pharmacol Efp Ther, 2004; 309(3):1239-1247
[21] Han S, Sidell N, Fisher PB. Up-regulation of P21 gene expression by peroxisome proliferation-activated receptor gamma in human lung carcinoma cells. Clin cancer Res, 2004;10(6):1911-1919
[22] Kaga Hm, Sakisaka S, Harada M. Involvement of P21(WAF/cipl), P27(Kipl), and P18(Ink4c) in troglitazone induced cell cycle arrest in human hepatoma cell line. Hepatology, 2001;33(5):1087-1097
[23] Motomura W, Okumura T, Takahashi N, et al. Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27 KiP1 in human. Panceatic carcinoma cells[J]. Cancer Res, 2000;60(19):5558-5564
[24] Yoshizu mi T, Ohta T, Ninomiya I. Thiazolidinedione , a peroxisome proliferation-activated receptor gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int J Onct, 2004;25(8):1122-1130
[25] Galli A, Ceni E, Crabb DM. Antidiaberic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms. Cut, 2004;53(11):1682-1697
[26] Sunami E, Tsuno NH, Kitayama J. Decreased synthesis of matrix metallop roteinase-7 and adhesion to the extracellular matrix protein of human colon cancer cells treated with troglitazone. Surg Today, 2002;32:343-350
[27] Elnemr A, Ohta T, Iwata K, et al. PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells[J]. Int J Oncol, 2000;17(6):1157-1164
[28] Ceni E, Mello T, Tarocchi M. Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells. Worold J Oncot, 2005;11(8):1122-1130
[29] Margeli A, Kouraklis G, Theocharis S. Peroxisome proliferation-activated receptorC(PPARc) ligand and angiogenesis. Angiogenesis, 2003;6(3):165-169
[30] Panigrahy D, Singer S, Shen LQ, et al. PPARc ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. Clin Invest, 2002;110:923-932
[31] Keshamouni VG, Arenberg DA, Reddy RC, et al. PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neaplasia, 2005 Mar;7(3):294-301
[32] Panigrapy D, Singer S, Shen LQ, et al. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis[J]. J Clin Invest, 2002;110(7):923-932