姜黄素诱导肺癌细胞脱落凋亡的作用及机理研究
摘要
姜黄素是从姜科姜黄属植物姜黄的根茎中提取的一种酚类色素,主要药理作用包括抗炎、抗氧化、降血脂、抗动脉粥样硬化、抗肿瘤、抗HIV病毒等,且毒性很低。姜黄素抗肿瘤的高效,低毒性,多靶点的特性已经成为研究热点,美国国立肿瘤所已将其列为第三代癌化学预防药。尽管姜黄素可以抑制多种肿瘤细胞的生长,诱导多种肿瘤细胞凋亡,但迄今为止,其抗肿瘤作用分子水平的具体机制尚未明确。目前的研究成果认为,姜黄素对细胞凋亡发生过程中的多个环节均有作用,且不同的肿瘤细胞对姜黄素的敏感性和反应类型是不同的,药物引起的不同类型肿瘤细胞的信号转导途径和信号网络的反应方式也不同,因此寻找姜黄素作用于不同细胞的信号靶分子,不仅为肿瘤临床治疗的选择性用药,而且也为针对特异靶点的联合用药,提高抗肿瘤药物的效率,降低细胞的毒性带来深远的意义。
不具备转移特性的实体瘤细胞和正常上皮细胞进入血流后会因失去基质的支持而发生凋亡,这一现象称为脱落凋亡(anoikis)。脱落凋亡的意义在于防止这些脱落的细胞种植于其他不适当的地方。然而,很多容易发生转移的恶性肿瘤细胞,从瘤体上脱落后并不发生凋亡,而是迁徙到其它部位再次生长。这种存在于某些肿瘤细胞中的抗脱落凋亡现象,被认为是肿瘤发生转移的重要原因之一。因此,脱落凋亡为我们深入研究参与细胞存活、死亡和肿瘤转移的多种信号途径提供了一个很好的研究模型,阐明肿瘤细胞抗脱落凋亡的信号转导机制将为治疗肿瘤转移提供新的思路。
Curcumin is hydroxybenzene pigment extract and purify from rhizome of curcuma , the major pharmaceutical effect including anti-inflammation, antioxidant, anti atherosclerosis, anti tumor , anti HIV virus, and another benefit is the toxicity of curcumin is very low. The anti tumor features of curcumin is becoming hot research target for its high efficiency and low toxicity and multi-target, National cancer research center of American already select the curcumin as third generation tumor preventive drug. Although curcumin can suppress the growth of many kinds of tumor cell, and induce the apoptosis of different tumor cell, but until now the detailed molecular mechanism of its anti tumor effect is still unclear. The recent research results suggest that curcumin take effect on multi point of apoptosis process, the sensitivity and pattern of reaction of different tumor cell to curcumin is different, the signal transduction pathway and patterns of signal transduction network reaction induced by
curcumin is different in different tumor cell, so to look for curcumin target signal molecule in different tumor cell is important not only for clinical selective drug in antitumor therapy and also for combine drug therapy for specific target, and this is also important for improve antitumor drug efficiency and reduce cell toxicity of antitumor drug.The apotosis of solid tumor cell without metastasis and normal epithelial cell loss of contact with the extracellular matrix is called anoikis, the features of anoikis is to prevent the fall off cell from planting in other inappropriate place. But those easy metastasis tumor cell can transplant to other place and growth without anoikis happened even after they fall off from solid body of tumor, these phenomena is thought to be the reason of tumor metastasis. So anoikis provide a good research model for signal transduction mechanism about cell growth , death and metastasis. So clarify the mechanism of anoikis signal transduction will provide a new aspect for antitumor metastasis therapy.Lung cancer is the first high incidence tumor in Europe and America with malignance and metastasis feature, so most of research focus on the metastatic mechanism, until now, there is no research reported about whether curcumine can induce lung cancer cell anoikis or not. Based on selected lung cancer cell line with anoikis feature, we use western-blot and other method observe the effect of curcumine on anti-anioikis lung cancer cell and the signal molecules related to cell growth and apoptosis, then we further analysed whether curcumine induced lung cancer cell anoikis depend on the PTEN network or not by gene transfection method.Our experiment take lung cancer cell Calu-3, Spc-Al, A549, PLA801 as
research subject, we observed the lung cancer cell anti-anoikis features, based on these, we study the curcumin' s effects on lung cancer cell growth circle, anti anoikis and phosphorization of related molecule, we also study the signal transduction molecule and transduction pathway in the lung cancer cell anoikis induced by curcumin.In order to explore the cancer suppression gene PTEN' s effect on anti anoikis of lung caner cell, we use Lipofectamine 2000 technique, observe the effect of PTEN at high and low expression on growth state of anti anoikis lung cancer cell, to clarify that whether or not curcumin induced lung cancer cell apoptosis depend on PTEN pathway. Because of the complexity of cancer cell growth and develop, until now, there is no effective anti tumor drug that can both suppress or kill tumor cell and inhibit metastasis at same time. Our results showed the curcumin can efficiently suppress lung cancer cell growth, induced anoikis of lung cancer cell, suggested that curcumin with the ability to inhibit metastasis.Our experiment major founding:1.We screen out three anti-anoikis lung cancer cells: SPC-AK A549n PLA80K Calu-3 cancer cell aniokis.2. Curcumin take effect on A549 cell, inhibit growth circle at G2 stage.3. Curcumin can effectively suppress four lung cancer line, the suppress -ion depend on curcumin concentration.4. Curcumin can induce anoikis in lung cancer cell Spc~Al> A549, PLA801. 5.The molecule mechanism of curcumin induced anoikis(1) The possible way that curcumin induce lung cancer cell anoikis is to suppress the activity of protein tyrosine kinase, some intra cell protein
不具备转移特性的实体瘤细胞和正常上皮细胞进入血流后会因失去基质的支持而发生凋亡,这一现象称为脱落凋亡(anoikis)。脱落凋亡的意义在于防止这些脱落的细胞种植于其他不适当的地方。然而,很多容易发生转移的恶性肿瘤细胞,从瘤体上脱落后并不发生凋亡,而是迁徙到其它部位再次生长。这种存在于某些肿瘤细胞中的抗脱落凋亡现象,被认为是肿瘤发生转移的重要原因之一。因此,脱落凋亡为我们深入研究参与细胞存活、死亡和肿瘤转移的多种信号途径提供了一个很好的研究模型,阐明肿瘤细胞抗脱落凋亡的信号转导机制将为治疗肿瘤转移提供新的思路。
Curcumin is hydroxybenzene pigment extract and purify from rhizome of curcuma , the major pharmaceutical effect including anti-inflammation, antioxidant, anti atherosclerosis, anti tumor , anti HIV virus, and another benefit is the toxicity of curcumin is very low. The anti tumor features of curcumin is becoming hot research target for its high efficiency and low toxicity and multi-target, National cancer research center of American already select the curcumin as third generation tumor preventive drug. Although curcumin can suppress the growth of many kinds of tumor cell, and induce the apoptosis of different tumor cell, but until now the detailed molecular mechanism of its anti tumor effect is still unclear. The recent research results suggest that curcumin take effect on multi point of apoptosis process, the sensitivity and pattern of reaction of different tumor cell to curcumin is different, the signal transduction pathway and patterns of signal transduction network reaction induced by
curcumin is different in different tumor cell, so to look for curcumin target signal molecule in different tumor cell is important not only for clinical selective drug in antitumor therapy and also for combine drug therapy for specific target, and this is also important for improve antitumor drug efficiency and reduce cell toxicity of antitumor drug.The apotosis of solid tumor cell without metastasis and normal epithelial cell loss of contact with the extracellular matrix is called anoikis, the features of anoikis is to prevent the fall off cell from planting in other inappropriate place. But those easy metastasis tumor cell can transplant to other place and growth without anoikis happened even after they fall off from solid body of tumor, these phenomena is thought to be the reason of tumor metastasis. So anoikis provide a good research model for signal transduction mechanism about cell growth , death and metastasis. So clarify the mechanism of anoikis signal transduction will provide a new aspect for antitumor metastasis therapy.Lung cancer is the first high incidence tumor in Europe and America with malignance and metastasis feature, so most of research focus on the metastatic mechanism, until now, there is no research reported about whether curcumine can induce lung cancer cell anoikis or not. Based on selected lung cancer cell line with anoikis feature, we use western-blot and other method observe the effect of curcumine on anti-anioikis lung cancer cell and the signal molecules related to cell growth and apoptosis, then we further analysed whether curcumine induced lung cancer cell anoikis depend on the PTEN network or not by gene transfection method.Our experiment take lung cancer cell Calu-3, Spc-Al, A549, PLA801 as
research subject, we observed the lung cancer cell anti-anoikis features, based on these, we study the curcumin' s effects on lung cancer cell growth circle, anti anoikis and phosphorization of related molecule, we also study the signal transduction molecule and transduction pathway in the lung cancer cell anoikis induced by curcumin.In order to explore the cancer suppression gene PTEN' s effect on anti anoikis of lung caner cell, we use Lipofectamine 2000 technique, observe the effect of PTEN at high and low expression on growth state of anti anoikis lung cancer cell, to clarify that whether or not curcumin induced lung cancer cell apoptosis depend on PTEN pathway. Because of the complexity of cancer cell growth and develop, until now, there is no effective anti tumor drug that can both suppress or kill tumor cell and inhibit metastasis at same time. Our results showed the curcumin can efficiently suppress lung cancer cell growth, induced anoikis of lung cancer cell, suggested that curcumin with the ability to inhibit metastasis.Our experiment major founding:1.We screen out three anti-anoikis lung cancer cells: SPC-AK A549n PLA80K Calu-3 cancer cell aniokis.2. Curcumin take effect on A549 cell, inhibit growth circle at G2 stage.3. Curcumin can effectively suppress four lung cancer line, the suppress -ion depend on curcumin concentration.4. Curcumin can induce anoikis in lung cancer cell Spc~Al> A549, PLA801. 5.The molecule mechanism of curcumin induced anoikis(1) The possible way that curcumin induce lung cancer cell anoikis is to suppress the activity of protein tyrosine kinase, some intra cell protein
引文
1. BLai, A K Kapoor, OP Asthana et al. Efficacy of curcum in the management of chronic anterio ruveitis. Phyo ther Res, junel, 1999, 13 (4): 318～221
2. Jian YT, Mai GF, Wang JD, et al. Preventive and therapeutic effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid. World J Gastroenterol. 2005 Mar 28; 11(12): 1747-52
3. U Pandya, M K Saini, GF Jin et al, Dietary curcum in prevents ocular toxicity of naphthalene in rats. Toxicol Lett, June 5, 2000, 115 (3): 195～204.
4. Swarnakar S, Ganguly K, Kundu P, Banerjee A, Maity P, Sharma AV. Curcumin regulates expression and activity of matrix metalloproteinases-9 and -2 during prevention and healing of indomethacin-induced gastric ulcer. J Biol Chem. 2004 Dec 22;
5. Kang G, Kong PJ, Yuh YJ, Lim SY, Yim SV, Chun W, Kim SS. Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells. J Pharmacol Sci. 2004 Mar; 94(3): 325-8.
6. Huang MT, Lysz T, Ferraro T, Abidi TF, Laskin JD, Conney AH. Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res. 1991 Feb 1; 51(3): 813-912
7. R Motterlini, R Foresti, R Bassi et al, Curcumin, an antioxidant and anti-inf-lammatory agent, induces heme oxygenase-1 and protects endo thelial cells against oxidative stress. Free Radic Biol Med, April 15, 2000, 28 (8): 1303～121
8. TT Phan, P See, ST Lee and SY Chan, Protective effects of curcumin against oxidative damage on sk in cells in vitro: its implication for wound healing. J Trauma, Novemberl, 2001, 51 (5): 927～311
9.石晶,陶沂,胡晋红,等.姜黄素对缺血再灌注大鼠脑组织SOD,MDA和亚硝酸盐含量的影响[J].第二军医大学学报,1999,20(6):38627.
10. Narayanan V enkatesan, Durairal Punithavath i et al, Curcum in prevents adriamycin neph ro toxicity in rats. British Journal of Pharmacology, 2000 (129): 231～2341
11. Dikshit M, Rastogi L, Shukla R, et al; Prevention of ischaemia-induced bioche-mical changes by curcumin quinidine in the cat heart. Indian J Med Res. 1995 Jan; 101: 31-5.
12. Rukkumani R, Sri Balasubashini M, Vishwanathan P, et al. Comparative effects of curcumin and photo-irradiated curcumin on alcohol and polyunsaturated fatty acid-induced hyperlipidemia [J]. Pharmacol Res, 2002, 46 (3): 257-264.
13. Araujo CAC, Leon LL. Biological activities of Curcuma longa L[J]. Mem Inst Oswaldo Cruz, 2001, 96(5): 723-728.
14. Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin induced pulmonary fibrosis in rats[J]. Br J harmacol, 2000, 131 (2): 169-272.
15. Kang HC, Nan JX, Park PH, et al. Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivoand in-vitro[J]. J Pharm Pharmaco, 2002, 54(1): 119-226.
16. M churchill, et al. Inhibition of intestinal tumors by curcumin is associated with changes in the intestinal immune cell profile. J Surg Res, April 1, 2000, 89(2): 691～751
17. MS Hussain et al, Effect on curcumin oncholesterol gallstone induction in mice. Indian J Med Res, October 1, 1992, 96: 288～911
18.沃兴德等,姜黄素对高脂血症作用的实验研究,浙江中西医结合杂志,1994,3(1):241
19. Oda Y. Inhibitory effect of curcumin on SOS functions induced by UV irradiation. Mutat Res. 1995 Oct; 348(2): 67-73.
20. Kumar S, Narain U, Tripathi S et al, Syntheses of Curcumin Bioconjugates and Study of Their Antibacterial Activities against beta-Lactamase-Producing Microorganisms. Bioconjug Chem, 2001, Jul Aug; 12(4): 464～469
21.刘永刚,陈厚昌,蒋毅萍.姜黄素抗肝纤维化的实验研究.时珍国医国药2002,13(5):272-275
22.崔淑香,金东庆,周玲,等.姜黄素抗肿瘤作用试验观察.肿瘤防治杂志2002,9(1):50-52.
23.许建华,赵蓉,柯丹如.姜黄素的体外抗癌作用及其水溶液的稳定性.中国药理学通报,1998,14(5):415-417.
24. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003; 23: 363-398.
25. Adams BK, Ferstl EM, Davis MC, Herold M, Kurtkaya S, et al. Synthesis and biological evaluation of novel curcumin analogs as anticancer and antiangiogenesis agents. Bioorg Med Chem 2004; 12: 3871-3883.
26. Armstrong JS, Hornung B, Lecane P, Jones DP, Knox SJ. Rotenone-induced G2/M cell cycle arrest and apoptosis in a human B lymphoma cell line PW. Biochem Biophys Res Commun 2001; 289: 973-978.
27.陈瑞川,苏金华,马等.光敏化姜黄素诱导胃癌细胞凋亡.癌症,2000,19(4):321-324.
28.焦广宇,周春凌,徐桂强,等.姜黄素、叶绿素辅助治疗胃癌的临床研究.营养学报,2001,23(3):237-238.
29.梁华茂,姜洁,孔北华,等.γ-干扰素对姜黄素抑制人卵巢癌细胞株3AO增殖的影响.山东大学学报(医学版),2002,40(4):307-309.
30.韩锐.抗癌药物研究与实验技术.北京:北京医科大学中国协和医科大学联合出版社,1997,13.
31. Shih CA, Lin JK. Inhibition of 8-hydroxydeoxyguanosine formation by curcumin in mouse fibroblast cells [J]. Carcinogenesis, 1993, 14 (4): 709.
32. Shalini VK, Srinivas I. Fuel smoke condensate induced DNA damage in huan lyml phocytes and protection by turmeric (Curcuma Longa) [J]. Mol Cell Biochem, 1990, 95(1): 21.
33. Abraham SK, Sarma L, Kesavan PC. Protective effects of cholordgenic acid, curcumin and getacarotene against gamma-radiation2induced in vivo chrom-osomal damage[J]. Mutat Res, 1993, 303 (3): 109.
34. Moragoda L, Jaszewski R, Majumdar AP. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res2001, 21(2A): 873-878.
35. Bush JA, Cheung KJ, Li G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp Cell Res, 2001, 271 (2): 305-314.
36. KellyMR, Xu J, Alexander KE, et al. Disparate effects of similar phenol-licphytochemicals as inhibitors of oxidative damage to cellular DNA. Mutat Res, 2001, 485 (4): 309-318.
37. Watabe M, Ito K, Masuda Y, et al. Activation of Aplis required for Bufalin-induced apoptosis in human leukemia U937cells. Oncogene, 1998, 16: 779.
38. Pan MH, Chang WL, Lin-Shiau SY, et al. Induction of apoptosis by garcinol and curcumin through cytochrome C release and activation of caspases in human Leukemia HL-60cells. J Agric Food Chem, 2001, 49 (3): 1464-1474.
39. Anto RJ, Mukhopadhyay A, Denning K, et al. Curcum indiferuloyl methane induces apoptosis through activation of caspase-8, BID cleavage and cytochrome Crelease: its suppression by ectopic expression of Bcl-2and Bcl-xl. Carcinogenesis, 2002, 23(1): 143-150.
40. Moria D, Barthelemy S, Zini R, et al. Curcumin induces the mitochon-drialpe-rmeability transition pore mediated by membrane protein thiol oxidation. Febs Lett, 2001, 4 (1-2): 131-136.
41. Anto RJ, Mukhopadhyay A, Denning K, et al. Curcum indiferuloyl methane induces apoptosis through activation of caspase-8, BID cleavage and cytochrome Crelease: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis, 2002, 23 (1): 143-150.
42.黄俊琼,孙万邦.姜黄素对白血病耐药细胞HL60/ADR的抑制作用.中国免疫学杂志,2002,18(5):334-337.
43. Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, et al. Caspases are activated in a branched protease cascade and control distinct downstream processes in fas-induced apoptosis. J Exp Med 1998; 187: 587-600
44. Lin JK. Suppression of protein kinase C and nuclear oncogene expression as possible action mechanisms of cancer chemoprevention by Curcumin. Arch Pharm Res. 2004 Jul; 27(7): 683-92.
45. Vb S, Tp VK, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappa B and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem. 2004 Dec 7;
46. Kumar AP, Garcia GE, Ghosh R, Rajnarayanan RV, Alworth WL, Slaga TJ. 4-Hydro-xy-3-methoxybenzoic acid methyl ester: a curcumin derivative targets Akt/NF kappa B cell survival signaling pathway: potential for prostate cancer managemen -t .Neoplasia. 2003 May-Jun:5(3):255-66.
47. Chen YR, Tan TH. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin.Oncogene, 1998, 17:173-178.
48. Dorai T, Gehani N, Katz A. Therapeutic potential of curcumin in human prostate cancer. Mol Urol, 2000, 4 (1) :1-6.
49. Huang MT ,Lysz T , Ferraro T , et al . Inhibitory effects of curcumin in vivo lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res, 1991 ,51(3) : 813-819.
50. Lu YP , Chang RL , Lou YR , et al , Effect of curcumin on TPA and u1 raviolet B light-induced expression of c-jun and c-fos in JB6cells and in mouse epidermis[J] . Carcinogenesis ,1994 ,15(10) :2363-2370.
51. Liu JY, Lin SJ , Lin JK. Inhibitory effects of curcumin on protein kinase C activity induced by TPA in NIH3T3 cells[J] . Carcinogenesis , 1993 , 14(5) :857-861.
52. Korutla L , Kumar R. Inhibitory effects of curcumin on epidermal growth factor receptor kinase activity in A431 cells[J]. Biochem Biophys Acta ,1994 ,1224 (3) :597-600.
53. Surh YJ .Molecular mechanisms underlying chemopreventive activities of antiinflammatory phytochemicals : down-regculation of cox-2 and iNOS through suppression of NF-kappa B activation [J] . Mutat Res , 2001, (1):480-481.
54. Li JY, Yu JP, Luo HS, et al Influence of selective cyclooxygenase-2 inhibitor on proliferation of human gastric cancer cells. Ai Zheng. 2002 Jun;21(6):625-9.
55. Zhang F ,Altorki NK, Mestre JR , et al . Curcumin inhibits cyclooxyge- nase-2 transcription in bile acid and phorbol ester-treated human gastrointestinal epithelial cells [J] . Carcinogenesis , 1999 , 20 ( 3) : 445-451.
56. Lin JK, Shih CA. Inhibitory effect of curcumin on xanthine dehyroge-nase/oxidase induced by TPA in NIH3T3 cells [J] . Carcinogenesis , 1994 ,15 (8) :1717-1721.
57. Chen YC , Kuo TC , Lin2Shiau SY, et al . Induction of hsp70 gene expression by modulation of Ca2 + ion and cellular p53 protein by curcumin in colorectalcarcinoma cells[J] .Mol Carcinogenesis, 1996,17 (4) :224-234.
58.Inano H ,0noda M, Inofuku N , et al . Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with gamma-rays [J] . Carcinogenesis ,1999 ,20 (6) : 1011-1018.
59. Shao ZM. Curcumin exerts multiple suppressive effects on human breast carcinoma cells[J] . Int J Cancer ,2002 ,98 (2) :234-240.
60. Surh YJ , Han SS , Keum YS , et al. Inhibitory effects of curcumin and capsaicin on phorbol ester2induced activation of eukaryotic tran- scription factors, NF-kap paB and AP-1 [J]. Biofacters ,2000,12 (124): 107-112.
61.Kim MS. Kang HJ, Moon A. Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. Arch Pharm Res. 2001, 4(4) : 349-354.
62. Pollmann C, Huang X, Mall J, et al. The constitutive photomorph-genesis signalosome directs vascular endothelial growth factor production in tumor cells. Cancer Res, 2001, 61 (23) :8416-8421.
63. Shao ZM , Shen ZZ , Liu CH , et al. Curcumin exerts multiple suppressive effects on human breast carcinoma cells[J].Int J Cancer ,2002,98(2): 234-240.
64.Arbiser JL , Klauber N , Rohan R , et al . Curcumin is an in vivo inhibitor of angiogenesis[J ].Mol Med , 1998,4(6):376-383.
65. Kim MS , Kang HJ , Moon A , et al . Inhibition of invasion and induction of apoptosis by curcumin in H2ras2transformed MCF1-A human breast epithelial [J ]. Arch Pharm Res ,2002, 24(4):349-354.
66. Han SS , Chung ST , Robertson DA , et al . Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1 , C-myc , Bc12XL , NF-kappa B , and p53[J].Clin Immunol, 1999,93 (2) : 152-161.
67. Chaudhuri T, Pal S , Agwarwal ML , et al . Curcumin induces apoptosis inhuman breast cells through p53-dependent Bax induction [J].FEBS Lett, 2002,512 (123) :334-340.
68. Sikora E,Bielak Zmijewska A,PiwockaK, et al. Inhibition ofproliferation and apoptosis of human and rat T lymphocytes by curcumin , a curry pigment [J].Biochem Pharmacol, 1997, 54(8):899-907.
69. Holy JM. Curcumin disrupts mitotic spindle structive and induces mi-cronuclea-tion in MCF27 breast cancer cells[J]. MutatRes, 2002, 518: 71-84.
70. Chuang SE, Yeh PY, Ku YS, et al. Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, andcurcumin in carcinoma cells [J]. Biochem Pharm aco 1, 2002, 63(9): 1709-1716
71. Anuchapreeda S, Leechanachai P, Smith MM, et al. Modulation of P-glyco protein expression and function by curcumin in multidrug resistant human KB cells[J]. Biochem Pharmacol, 2002, 64(4): 573-582.
72. Anto RJ, Mukhopaolhyag A, Denning K, et al. Curcumin induces apoptosis through activation of caspase-8, BID cleavage and cytochrome Crelea-se: its suppression by ectopic expression of Bcl-2 and Bcl-x [J]. Carci nogenesis, 2002, 23 (1): 143-150.
73. Bush JA, Cheng KJ Jr, Li G, et al. Curcumin induces apoptosis in human melanoma cells through Fas Receptor/caspase-8 pathway independent of p53[J]. Exp Cell Res, 2001, 271(2): 305-314.
74.沃兴德,洪行球,高承贤,等.姜黄素长期毒性试验.浙江中医学院学报,2000,24(1):61-62.
75. Shim Js, Kim DH, Jung HJ, et al. Hydrazinocurcumin, a novel synthetic curcumin derivative, is a potent inhibitor of endothelial cell prolix feration. Bioorg Med Chem, 2002, Aug, 10(8): 2439～2441
76. John VD, Kuttan G, Krishnankutty K. Anti-tumour studies of metal chelates of synthetic curcuminoids J Exp Clin Cancer Res, 2002, Jun; 21 (2): 219～241
77. Hahm ER, Cheon G, Lee J, Kim B, et al, New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex. Cancer Lett 2002, Oct 8; 184(1): 89～961
78. Masuda T, Toi Y, Bando H, Maekawa T, et al, Structural identification of new curcumin dimers and their contribution to the antioxidant mechanism of curcumin. J Agri Food Chem, 2002, April 24; 252～301
79. Meredith JE, Jr, Fazeli B, Schwartz MA. The extracellularmatrix as a cell survival factor. Mol Biol Cell 1993; 4: 953-961.
80. Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apopto sis. J Cell Biol 1994; 124: 619-626.
81. Wei L, Yang Y, Zhang X, Yu Q. Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis Oncogene. 2004 Dec 2;23 (56):9052-9061.
82. Fukazawa H, Noguchi K, Masumi A, Murakami Y, Uehara Y. BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/ex -tracellular signal-regulated kinase kinase inhibitors. Mol Cancer Ther. 2004 Oct;3(10):1281-1288.
83. DM , Sun H. PTEN/ MMAC1/ TEP1 suppresses the tumorigenicity and induces Gl cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA , 1998,95:15406 —15411
84. Davies MA, Lu Y, Sano T , Fang X , Tang P , LaPushin R , Koul D et al. Adenoviral transgene expression of MMAC/ PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res, 1998, 58: 5285-5290
85.Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J etal . PTEN, a putative protein tyrosine phosphatase gene mutatedin human brain , breast, and prostate cancer. Science , 1997,275 :1943 —1947
86. Steck PA , Pershouse MA , Jasser SA , Yung WK, Lin H , LigonAH , Langford LA et al. Identification of a candidate tumor suppressor gene , MMA Cl , at chromosome 10q23.3 that is mutatedgene ,MMA Cl.at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet , 1997,15:356 —362
87. Besson A , Robbins SM , Yong VW. PTEN/ MMAC1/ TEP1 in signal transduction and tumorigenesis. Eur J Biochem , 1999, 263:605—611
88. Fang Y, Jin JW, Zha XL. Role of FAKin TNF-α /cycloheximide-induced apoptosis of SMMC-77-1 cells. Acta Biochim BiophysSin ,2001,33:53-58
89. Zhu T , Goh EL , Lobie PE. Growth hormone stimulates the tyrosine phosphorylation and association of pl25 focal adhesion kinase( FAK) with JAK2. Fak is not required for stat-mediated transcription. J Biol Chem , 1998,273:10682—10689
90. Leventhal PS, Shelden EA, Kim B , Feldman EL. Tyrosine phosphorylation of paxillin
and focal adhesion kinase during insulin-like growth factor - I-stimulated lamell -ipodial advance. J Biol Chem ,1997,273:5214 —5218
91.Liliental J , Moon SY, Lesche R , Mamillapalli R , Li D , Zheng Y, Sun H et al . Genetic deletion of the PTEN tumor suppressor gene promotes cell motility by activation of Racl and Cdc42 GTPases. Curr Biol, 2000,10:401 —404
92.Lei QY,Wang LY,Dan ZY. The expression of PTEN in lung cancer and relation to anoikis.ACTA BIOL BIOP SINICA 2002,34 (4): 463 - 468
93. Frisch SM, Vuori K, Ruoslahti E, Chan Hui PY. Control of adhesion-dependent cell survival by focal adhesion kinase. J CellBiol , 1996,134:793-799
94. Ilic D, Almeida EA, Schlaepfer DD, Dazin P, Aizawa S, Damsky CH. Extracellular matrix survival signals transduced by focal adhesion kinase suppress P53-mediated apoptosis. J Cell Biol , 1998,143:547 —560
95.Zha XL. Progress of cell adhesion mediated signal-focal adhesion kinase. Acta Biochim Biophys Sin, 1999, 31:5—8
96. Farias EF, Marzan C, Mira-Y-Lopez R. Cellular retinol-binding protein-I inhibits PI3K/Akt signaling through a retinoic acid receptor-dependent mechanism that regulates p85-p110 heterodimerization. Oncogene. 2004 Dec 20;
97. Eckert LB, Repasky GA, Ulku AS, et al. Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res. 2004 Jul 1;64 (13):4585-4592.
98. Oh A, List HJ, Reiter R, Mani A, Zhang Y, Gehan E, Wellstein A, Riegel AT. The nuclear receptor coactivator AIB1 mediates insulin-like growth factor I-induced phenotypic changes in human breast cancer cells. Cancer Res. 2004 Nov 15;64(22):8299-8308.
99.Fukazawa H, Noguchi K, Murakami Y, Uehara. Mitogen-activated protein/extracellul -ar signal-regulated kinase kinase (MEK) inhibitors restore anoikis sensitivity in human breast cancer cell lines with a constitutively activated extracell -ular-regulated kinase (ERK) pathway. Mol Cancer Ther. 2002 Mar;1(5):303-309.
100. Wei L, Yang Y, Yu Q. Tyrosine kinase-dependent, phosphatidylinositol 3' -kinase, and mitogen-activated protein kinase-independent signaling pathways prevent lung
adenocarcinoma cells from anoikis. Cancer Res. 2001 Mar 15;61(6):2439-2444.
101. Almeida EA, Ilic D, Han Q, Hauck CR, Jin F, Kawakatsu H, Schlaepfer DD, Damsky CH. Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol. 2000 May 1;149(3):741-754.
102. Shelly C, Herrera R. Activation of SGK1 by HGF, Racl and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. J Cell Sci. 2002 May 1;115(Pt 9):1985-1993.
103. Aoudjit F, Vuori K Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-flip and implications for anoikis. J Cell Biol. 2001 Feb 5:152(3):633-43
104. Marconi A, Atzei P, Panza C, Fila C, Tiberio R, Truzzi F, Wachter T, Leverkus M, PincelliC. FLICE/caspase-8 activation triggers anoikis induced by betal-integrin blockade in human keratinocytes. J Cell Sci. 2004 Nov 15;117:5815-5823.
105. Marconi A, Atzei P, Panza C, Fila C, Tiberio R, Truzzi F, Wachter T, Leverkus M, Pincelli C. FLICE/caspase-8 activation triggers anoikis induced by betal-integrin blockade in human keratinocytes. J Cell Sci. 2004 Nov 15;117:5815-5823.
106. Early events in the anoikis program occur in the absence of caspase activation. Wang P, Valentijn AJ, Gilmore AP, Streuli CH.J Biol Chem. 2003 May 30:278(22):19917-25.
107. Wang P, Valentin AJ, Gilmore AP, Streuli CH. Early events in the anoikis program occur in the absence of caspase activation. J Biol Chem. 2003 May30;278(22):19917-25.
108. Pawlak G, Helfman D: Cytoskeletal changes in cell transformation and tumorigenesis. Curr Opin Genet Dev 1999, 11:41-47.
109. Ye X, Krohn RL, Liu W, Joshi SS, Stohs SJ, Bagchi D. The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Mol Cell Bioc hem 1999 Jun;196(1-2):99-108 .
110.Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science. 2001Sep
2. Jian YT, Mai GF, Wang JD, et al. Preventive and therapeutic effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid. World J Gastroenterol. 2005 Mar 28; 11(12): 1747-52
3. U Pandya, M K Saini, GF Jin et al, Dietary curcum in prevents ocular toxicity of naphthalene in rats. Toxicol Lett, June 5, 2000, 115 (3): 195～204.
4. Swarnakar S, Ganguly K, Kundu P, Banerjee A, Maity P, Sharma AV. Curcumin regulates expression and activity of matrix metalloproteinases-9 and -2 during prevention and healing of indomethacin-induced gastric ulcer. J Biol Chem. 2004 Dec 22;
5. Kang G, Kong PJ, Yuh YJ, Lim SY, Yim SV, Chun W, Kim SS. Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells. J Pharmacol Sci. 2004 Mar; 94(3): 325-8.
6. Huang MT, Lysz T, Ferraro T, Abidi TF, Laskin JD, Conney AH. Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res. 1991 Feb 1; 51(3): 813-912
7. R Motterlini, R Foresti, R Bassi et al, Curcumin, an antioxidant and anti-inf-lammatory agent, induces heme oxygenase-1 and protects endo thelial cells against oxidative stress. Free Radic Biol Med, April 15, 2000, 28 (8): 1303～121
8. TT Phan, P See, ST Lee and SY Chan, Protective effects of curcumin against oxidative damage on sk in cells in vitro: its implication for wound healing. J Trauma, Novemberl, 2001, 51 (5): 927～311
9.石晶,陶沂,胡晋红,等.姜黄素对缺血再灌注大鼠脑组织SOD,MDA和亚硝酸盐含量的影响[J].第二军医大学学报,1999,20(6):38627.
10. Narayanan V enkatesan, Durairal Punithavath i et al, Curcum in prevents adriamycin neph ro toxicity in rats. British Journal of Pharmacology, 2000 (129): 231～2341
11. Dikshit M, Rastogi L, Shukla R, et al; Prevention of ischaemia-induced bioche-mical changes by curcumin quinidine in the cat heart. Indian J Med Res. 1995 Jan; 101: 31-5.
12. Rukkumani R, Sri Balasubashini M, Vishwanathan P, et al. Comparative effects of curcumin and photo-irradiated curcumin on alcohol and polyunsaturated fatty acid-induced hyperlipidemia [J]. Pharmacol Res, 2002, 46 (3): 257-264.
13. Araujo CAC, Leon LL. Biological activities of Curcuma longa L[J]. Mem Inst Oswaldo Cruz, 2001, 96(5): 723-728.
14. Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin induced pulmonary fibrosis in rats[J]. Br J harmacol, 2000, 131 (2): 169-272.
15. Kang HC, Nan JX, Park PH, et al. Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivoand in-vitro[J]. J Pharm Pharmaco, 2002, 54(1): 119-226.
16. M churchill, et al. Inhibition of intestinal tumors by curcumin is associated with changes in the intestinal immune cell profile. J Surg Res, April 1, 2000, 89(2): 691～751
17. MS Hussain et al, Effect on curcumin oncholesterol gallstone induction in mice. Indian J Med Res, October 1, 1992, 96: 288～911
18.沃兴德等,姜黄素对高脂血症作用的实验研究,浙江中西医结合杂志,1994,3(1):241
19. Oda Y. Inhibitory effect of curcumin on SOS functions induced by UV irradiation. Mutat Res. 1995 Oct; 348(2): 67-73.
20. Kumar S, Narain U, Tripathi S et al, Syntheses of Curcumin Bioconjugates and Study of Their Antibacterial Activities against beta-Lactamase-Producing Microorganisms. Bioconjug Chem, 2001, Jul Aug; 12(4): 464～469
21.刘永刚,陈厚昌,蒋毅萍.姜黄素抗肝纤维化的实验研究.时珍国医国药2002,13(5):272-275
22.崔淑香,金东庆,周玲,等.姜黄素抗肿瘤作用试验观察.肿瘤防治杂志2002,9(1):50-52.
23.许建华,赵蓉,柯丹如.姜黄素的体外抗癌作用及其水溶液的稳定性.中国药理学通报,1998,14(5):415-417.
24. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003; 23: 363-398.
25. Adams BK, Ferstl EM, Davis MC, Herold M, Kurtkaya S, et al. Synthesis and biological evaluation of novel curcumin analogs as anticancer and antiangiogenesis agents. Bioorg Med Chem 2004; 12: 3871-3883.
26. Armstrong JS, Hornung B, Lecane P, Jones DP, Knox SJ. Rotenone-induced G2/M cell cycle arrest and apoptosis in a human B lymphoma cell line PW. Biochem Biophys Res Commun 2001; 289: 973-978.
27.陈瑞川,苏金华,马等.光敏化姜黄素诱导胃癌细胞凋亡.癌症,2000,19(4):321-324.
28.焦广宇,周春凌,徐桂强,等.姜黄素、叶绿素辅助治疗胃癌的临床研究.营养学报,2001,23(3):237-238.
29.梁华茂,姜洁,孔北华,等.γ-干扰素对姜黄素抑制人卵巢癌细胞株3AO增殖的影响.山东大学学报(医学版),2002,40(4):307-309.
30.韩锐.抗癌药物研究与实验技术.北京:北京医科大学中国协和医科大学联合出版社,1997,13.
31. Shih CA, Lin JK. Inhibition of 8-hydroxydeoxyguanosine formation by curcumin in mouse fibroblast cells [J]. Carcinogenesis, 1993, 14 (4): 709.
32. Shalini VK, Srinivas I. Fuel smoke condensate induced DNA damage in huan lyml phocytes and protection by turmeric (Curcuma Longa) [J]. Mol Cell Biochem, 1990, 95(1): 21.
33. Abraham SK, Sarma L, Kesavan PC. Protective effects of cholordgenic acid, curcumin and getacarotene against gamma-radiation2induced in vivo chrom-osomal damage[J]. Mutat Res, 1993, 303 (3): 109.
34. Moragoda L, Jaszewski R, Majumdar AP. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res2001, 21(2A): 873-878.
35. Bush JA, Cheung KJ, Li G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp Cell Res, 2001, 271 (2): 305-314.
36. KellyMR, Xu J, Alexander KE, et al. Disparate effects of similar phenol-licphytochemicals as inhibitors of oxidative damage to cellular DNA. Mutat Res, 2001, 485 (4): 309-318.
37. Watabe M, Ito K, Masuda Y, et al. Activation of Aplis required for Bufalin-induced apoptosis in human leukemia U937cells. Oncogene, 1998, 16: 779.
38. Pan MH, Chang WL, Lin-Shiau SY, et al. Induction of apoptosis by garcinol and curcumin through cytochrome C release and activation of caspases in human Leukemia HL-60cells. J Agric Food Chem, 2001, 49 (3): 1464-1474.
39. Anto RJ, Mukhopadhyay A, Denning K, et al. Curcum indiferuloyl methane induces apoptosis through activation of caspase-8, BID cleavage and cytochrome Crelease: its suppression by ectopic expression of Bcl-2and Bcl-xl. Carcinogenesis, 2002, 23(1): 143-150.
40. Moria D, Barthelemy S, Zini R, et al. Curcumin induces the mitochon-drialpe-rmeability transition pore mediated by membrane protein thiol oxidation. Febs Lett, 2001, 4 (1-2): 131-136.
41. Anto RJ, Mukhopadhyay A, Denning K, et al. Curcum indiferuloyl methane induces apoptosis through activation of caspase-8, BID cleavage and cytochrome Crelease: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis, 2002, 23 (1): 143-150.
42.黄俊琼,孙万邦.姜黄素对白血病耐药细胞HL60/ADR的抑制作用.中国免疫学杂志,2002,18(5):334-337.
43. Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, et al. Caspases are activated in a branched protease cascade and control distinct downstream processes in fas-induced apoptosis. J Exp Med 1998; 187: 587-600
44. Lin JK. Suppression of protein kinase C and nuclear oncogene expression as possible action mechanisms of cancer chemoprevention by Curcumin. Arch Pharm Res. 2004 Jul; 27(7): 683-92.
45. Vb S, Tp VK, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappa B and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem. 2004 Dec 7;
46. Kumar AP, Garcia GE, Ghosh R, Rajnarayanan RV, Alworth WL, Slaga TJ. 4-Hydro-xy-3-methoxybenzoic acid methyl ester: a curcumin derivative targets Akt/NF kappa B cell survival signaling pathway: potential for prostate cancer managemen -t .Neoplasia. 2003 May-Jun:5(3):255-66.
47. Chen YR, Tan TH. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin.Oncogene, 1998, 17:173-178.
48. Dorai T, Gehani N, Katz A. Therapeutic potential of curcumin in human prostate cancer. Mol Urol, 2000, 4 (1) :1-6.
49. Huang MT ,Lysz T , Ferraro T , et al . Inhibitory effects of curcumin in vivo lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res, 1991 ,51(3) : 813-819.
50. Lu YP , Chang RL , Lou YR , et al , Effect of curcumin on TPA and u1 raviolet B light-induced expression of c-jun and c-fos in JB6cells and in mouse epidermis[J] . Carcinogenesis ,1994 ,15(10) :2363-2370.
51. Liu JY, Lin SJ , Lin JK. Inhibitory effects of curcumin on protein kinase C activity induced by TPA in NIH3T3 cells[J] . Carcinogenesis , 1993 , 14(5) :857-861.
52. Korutla L , Kumar R. Inhibitory effects of curcumin on epidermal growth factor receptor kinase activity in A431 cells[J]. Biochem Biophys Acta ,1994 ,1224 (3) :597-600.
53. Surh YJ .Molecular mechanisms underlying chemopreventive activities of antiinflammatory phytochemicals : down-regculation of cox-2 and iNOS through suppression of NF-kappa B activation [J] . Mutat Res , 2001, (1):480-481.
54. Li JY, Yu JP, Luo HS, et al Influence of selective cyclooxygenase-2 inhibitor on proliferation of human gastric cancer cells. Ai Zheng. 2002 Jun;21(6):625-9.
55. Zhang F ,Altorki NK, Mestre JR , et al . Curcumin inhibits cyclooxyge- nase-2 transcription in bile acid and phorbol ester-treated human gastrointestinal epithelial cells [J] . Carcinogenesis , 1999 , 20 ( 3) : 445-451.
56. Lin JK, Shih CA. Inhibitory effect of curcumin on xanthine dehyroge-nase/oxidase induced by TPA in NIH3T3 cells [J] . Carcinogenesis , 1994 ,15 (8) :1717-1721.
57. Chen YC , Kuo TC , Lin2Shiau SY, et al . Induction of hsp70 gene expression by modulation of Ca2 + ion and cellular p53 protein by curcumin in colorectalcarcinoma cells[J] .Mol Carcinogenesis, 1996,17 (4) :224-234.
58.Inano H ,0noda M, Inofuku N , et al . Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with gamma-rays [J] . Carcinogenesis ,1999 ,20 (6) : 1011-1018.
59. Shao ZM. Curcumin exerts multiple suppressive effects on human breast carcinoma cells[J] . Int J Cancer ,2002 ,98 (2) :234-240.
60. Surh YJ , Han SS , Keum YS , et al. Inhibitory effects of curcumin and capsaicin on phorbol ester2induced activation of eukaryotic tran- scription factors, NF-kap paB and AP-1 [J]. Biofacters ,2000,12 (124): 107-112.
61.Kim MS. Kang HJ, Moon A. Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. Arch Pharm Res. 2001, 4(4) : 349-354.
62. Pollmann C, Huang X, Mall J, et al. The constitutive photomorph-genesis signalosome directs vascular endothelial growth factor production in tumor cells. Cancer Res, 2001, 61 (23) :8416-8421.
63. Shao ZM , Shen ZZ , Liu CH , et al. Curcumin exerts multiple suppressive effects on human breast carcinoma cells[J].Int J Cancer ,2002,98(2): 234-240.
64.Arbiser JL , Klauber N , Rohan R , et al . Curcumin is an in vivo inhibitor of angiogenesis[J ].Mol Med , 1998,4(6):376-383.
65. Kim MS , Kang HJ , Moon A , et al . Inhibition of invasion and induction of apoptosis by curcumin in H2ras2transformed MCF1-A human breast epithelial [J ]. Arch Pharm Res ,2002, 24(4):349-354.
66. Han SS , Chung ST , Robertson DA , et al . Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1 , C-myc , Bc12XL , NF-kappa B , and p53[J].Clin Immunol, 1999,93 (2) : 152-161.
67. Chaudhuri T, Pal S , Agwarwal ML , et al . Curcumin induces apoptosis inhuman breast cells through p53-dependent Bax induction [J].FEBS Lett, 2002,512 (123) :334-340.
68. Sikora E,Bielak Zmijewska A,PiwockaK, et al. Inhibition ofproliferation and apoptosis of human and rat T lymphocytes by curcumin , a curry pigment [J].Biochem Pharmacol, 1997, 54(8):899-907.
69. Holy JM. Curcumin disrupts mitotic spindle structive and induces mi-cronuclea-tion in MCF27 breast cancer cells[J]. MutatRes, 2002, 518: 71-84.
70. Chuang SE, Yeh PY, Ku YS, et al. Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, andcurcumin in carcinoma cells [J]. Biochem Pharm aco 1, 2002, 63(9): 1709-1716
71. Anuchapreeda S, Leechanachai P, Smith MM, et al. Modulation of P-glyco protein expression and function by curcumin in multidrug resistant human KB cells[J]. Biochem Pharmacol, 2002, 64(4): 573-582.
72. Anto RJ, Mukhopaolhyag A, Denning K, et al. Curcumin induces apoptosis through activation of caspase-8, BID cleavage and cytochrome Crelea-se: its suppression by ectopic expression of Bcl-2 and Bcl-x [J]. Carci nogenesis, 2002, 23 (1): 143-150.
73. Bush JA, Cheng KJ Jr, Li G, et al. Curcumin induces apoptosis in human melanoma cells through Fas Receptor/caspase-8 pathway independent of p53[J]. Exp Cell Res, 2001, 271(2): 305-314.
74.沃兴德,洪行球,高承贤,等.姜黄素长期毒性试验.浙江中医学院学报,2000,24(1):61-62.
75. Shim Js, Kim DH, Jung HJ, et al. Hydrazinocurcumin, a novel synthetic curcumin derivative, is a potent inhibitor of endothelial cell prolix feration. Bioorg Med Chem, 2002, Aug, 10(8): 2439～2441
76. John VD, Kuttan G, Krishnankutty K. Anti-tumour studies of metal chelates of synthetic curcuminoids J Exp Clin Cancer Res, 2002, Jun; 21 (2): 219～241
77. Hahm ER, Cheon G, Lee J, Kim B, et al, New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex. Cancer Lett 2002, Oct 8; 184(1): 89～961
78. Masuda T, Toi Y, Bando H, Maekawa T, et al, Structural identification of new curcumin dimers and their contribution to the antioxidant mechanism of curcumin. J Agri Food Chem, 2002, April 24; 252～301
79. Meredith JE, Jr, Fazeli B, Schwartz MA. The extracellularmatrix as a cell survival factor. Mol Biol Cell 1993; 4: 953-961.
80. Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apopto sis. J Cell Biol 1994; 124: 619-626.
81. Wei L, Yang Y, Zhang X, Yu Q. Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis Oncogene. 2004 Dec 2;23 (56):9052-9061.
82. Fukazawa H, Noguchi K, Masumi A, Murakami Y, Uehara Y. BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/ex -tracellular signal-regulated kinase kinase inhibitors. Mol Cancer Ther. 2004 Oct;3(10):1281-1288.
83. DM , Sun H. PTEN/ MMAC1/ TEP1 suppresses the tumorigenicity and induces Gl cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA , 1998,95:15406 —15411
84. Davies MA, Lu Y, Sano T , Fang X , Tang P , LaPushin R , Koul D et al. Adenoviral transgene expression of MMAC/ PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res, 1998, 58: 5285-5290
85.Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J etal . PTEN, a putative protein tyrosine phosphatase gene mutatedin human brain , breast, and prostate cancer. Science , 1997,275 :1943 —1947
86. Steck PA , Pershouse MA , Jasser SA , Yung WK, Lin H , LigonAH , Langford LA et al. Identification of a candidate tumor suppressor gene , MMA Cl , at chromosome 10q23.3 that is mutatedgene ,MMA Cl.at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet , 1997,15:356 —362
87. Besson A , Robbins SM , Yong VW. PTEN/ MMAC1/ TEP1 in signal transduction and tumorigenesis. Eur J Biochem , 1999, 263:605—611
88. Fang Y, Jin JW, Zha XL. Role of FAKin TNF-α /cycloheximide-induced apoptosis of SMMC-77-1 cells. Acta Biochim BiophysSin ,2001,33:53-58
89. Zhu T , Goh EL , Lobie PE. Growth hormone stimulates the tyrosine phosphorylation and association of pl25 focal adhesion kinase( FAK) with JAK2. Fak is not required for stat-mediated transcription. J Biol Chem , 1998,273:10682—10689
90. Leventhal PS, Shelden EA, Kim B , Feldman EL. Tyrosine phosphorylation of paxillin
and focal adhesion kinase during insulin-like growth factor - I-stimulated lamell -ipodial advance. J Biol Chem ,1997,273:5214 —5218
91.Liliental J , Moon SY, Lesche R , Mamillapalli R , Li D , Zheng Y, Sun H et al . Genetic deletion of the PTEN tumor suppressor gene promotes cell motility by activation of Racl and Cdc42 GTPases. Curr Biol, 2000,10:401 —404
92.Lei QY,Wang LY,Dan ZY. The expression of PTEN in lung cancer and relation to anoikis.ACTA BIOL BIOP SINICA 2002,34 (4): 463 - 468
93. Frisch SM, Vuori K, Ruoslahti E, Chan Hui PY. Control of adhesion-dependent cell survival by focal adhesion kinase. J CellBiol , 1996,134:793-799
94. Ilic D, Almeida EA, Schlaepfer DD, Dazin P, Aizawa S, Damsky CH. Extracellular matrix survival signals transduced by focal adhesion kinase suppress P53-mediated apoptosis. J Cell Biol , 1998,143:547 —560
95.Zha XL. Progress of cell adhesion mediated signal-focal adhesion kinase. Acta Biochim Biophys Sin, 1999, 31:5—8
96. Farias EF, Marzan C, Mira-Y-Lopez R. Cellular retinol-binding protein-I inhibits PI3K/Akt signaling through a retinoic acid receptor-dependent mechanism that regulates p85-p110 heterodimerization. Oncogene. 2004 Dec 20;
97. Eckert LB, Repasky GA, Ulku AS, et al. Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res. 2004 Jul 1;64 (13):4585-4592.
98. Oh A, List HJ, Reiter R, Mani A, Zhang Y, Gehan E, Wellstein A, Riegel AT. The nuclear receptor coactivator AIB1 mediates insulin-like growth factor I-induced phenotypic changes in human breast cancer cells. Cancer Res. 2004 Nov 15;64(22):8299-8308.
99.Fukazawa H, Noguchi K, Murakami Y, Uehara. Mitogen-activated protein/extracellul -ar signal-regulated kinase kinase (MEK) inhibitors restore anoikis sensitivity in human breast cancer cell lines with a constitutively activated extracell -ular-regulated kinase (ERK) pathway. Mol Cancer Ther. 2002 Mar;1(5):303-309.
100. Wei L, Yang Y, Yu Q. Tyrosine kinase-dependent, phosphatidylinositol 3' -kinase, and mitogen-activated protein kinase-independent signaling pathways prevent lung
adenocarcinoma cells from anoikis. Cancer Res. 2001 Mar 15;61(6):2439-2444.
101. Almeida EA, Ilic D, Han Q, Hauck CR, Jin F, Kawakatsu H, Schlaepfer DD, Damsky CH. Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol. 2000 May 1;149(3):741-754.
102. Shelly C, Herrera R. Activation of SGK1 by HGF, Racl and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. J Cell Sci. 2002 May 1;115(Pt 9):1985-1993.
103. Aoudjit F, Vuori K Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-flip and implications for anoikis. J Cell Biol. 2001 Feb 5:152(3):633-43
104. Marconi A, Atzei P, Panza C, Fila C, Tiberio R, Truzzi F, Wachter T, Leverkus M, PincelliC. FLICE/caspase-8 activation triggers anoikis induced by betal-integrin blockade in human keratinocytes. J Cell Sci. 2004 Nov 15;117:5815-5823.
105. Marconi A, Atzei P, Panza C, Fila C, Tiberio R, Truzzi F, Wachter T, Leverkus M, Pincelli C. FLICE/caspase-8 activation triggers anoikis induced by betal-integrin blockade in human keratinocytes. J Cell Sci. 2004 Nov 15;117:5815-5823.
106. Early events in the anoikis program occur in the absence of caspase activation. Wang P, Valentijn AJ, Gilmore AP, Streuli CH.J Biol Chem. 2003 May 30:278(22):19917-25.
107. Wang P, Valentin AJ, Gilmore AP, Streuli CH. Early events in the anoikis program occur in the absence of caspase activation. J Biol Chem. 2003 May30;278(22):19917-25.
108. Pawlak G, Helfman D: Cytoskeletal changes in cell transformation and tumorigenesis. Curr Opin Genet Dev 1999, 11:41-47.
109. Ye X, Krohn RL, Liu W, Joshi SS, Stohs SJ, Bagchi D. The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Mol Cell Bioc hem 1999 Jun;196(1-2):99-108 .
110.Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science. 2001Sep