Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/52133
標題: α-胡蘿蔔素在活體內外抑制小鼠肺癌細胞轉移之探討
α-Carotene inhibits metastasis of Lewis lung carcinoma both in vitro and in vivo
作者: 劉懿真
Liu, Yi-Zhen
關鍵字: α-胡蘿蔔素;α-Carotene;轉移;太平洋紫杉醇;小鼠肺癌細胞株;C57BL/6小鼠;Metastasis;Taxol;LLC1;C57BL/6 mice
出版社: 食品暨應用生物科技學系所
引用: Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA: a cancer journal for clinicians 2012, 62(1):10-29. Okuno SH, Jett JR: Small cell lung cancer: current therapy and promising new regimens. Oncologist 2002, 7(3):234-238. D''Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E, Grp EGW: Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010, 21:v116-v119. Schwartz AG, Yang P, Swanson GM: Familial risk of lung cancer among nonsmokers and their relatives. Am J Epidemiol 1996, 144(6):554-562. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF et al: Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer. New Engl J Med 2010, 363(8):733-742. Talmadge JE, Fidler IJ: AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer research 2010, 70(14):5649-5669. Yoon SO, Park SJ, Yun CH, Chung AS: Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. Journal of biochemistry and molecular biology 2003, 36(1):128-137. Deryugina EI, Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer metastasis reviews 2006, 25(1):9-34. Martin MD, Matrisian LM: The other side of MMPs: protective roles in tumor progression. Cancer metastasis reviews 2007, 26(3-4):717-724. Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980, 284(5751):67-68. Hidalgo M, Eckhardt SG: Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001, 93(3):178-193. Roomi MW, Monterrey JC, Kalinovsky T, Rath M, Niedzwiecki A: Patterns of MMP-2 and MMP-9 expression in human cancer cell lines. Oncol Rep 2009, 21(5):1323-1333. Baker AH, Edwards DR, Murphy G: Metalloproteinase inhibitors: biological actions and therapeutic opportunities. Journal of cell science 2002, 115(Pt 19):3719-3727. McIntush EW, Smith MF: Matrix metalloproteinases and tissue inhibitors of metalloproteinases in ovarian function. Reviews of reproduction 1998, 3(1):23-30. Bourboulia D, Stetler-Stevenson WG: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Seminars in cancer biology 2010, 20(3):161-168. Lambert E, Dasse E, Haye B, Petitfrere E: TIMPs as multifacial proteins. Critical reviews in oncology/hematology 2004, 49(3):187-198. Ulisse S, Baldini E, Mottolese M, Sentinelli S, Gargiulo P, Valentina B, Sorrenti S, Di Benedetto A, De Antoni E, D''Armiento M: Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas. Bmc Cancer 2010, 10:151. Choong PF, Nadesapillai AP: Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clinical orthopaedics and related research 2003(415 Suppl):S46-58. Duffy MJ: The urokinase plasminogen activator system: role in malignancy. Current pharmaceutical design 2004, 10(1):39-49. Andreasen PA, Kjoller L, Christensen L, Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: a review. International journal of cancer Journal international du cancer 1997, 72(1):1-22. Andreasen PA, Egelund R, Petersen HH: The plasminogen activation system in tumor growth, invasion, and metastasis. Cellular and molecular life sciences : CMLS 2000, 57(1):25-40. Ornstein DL, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Hunt J, Rousseau SM, Stump DC: Coexisting macrophage-associated fibrin formation and tumor cell urokinase in squamous cell and adenocarcinoma of the lung tissues. Cancer 1991, 68(5):1061-1067. Duffy MJ: Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clinical chemistry 2002, 48(8):1194-1197. Duffy MJ, Duggan C: The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer. Clinical biochemistry 2004, 37(7):541-548. Stefansson S, Lawrence DA: Old dogs and new tricks: proteases, inhibitors, and cell migration. Science''s STKE : signal transduction knowledge environment 2003, 2003(189):pe24. Liu G, Shuman MA, Cohen RL: Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. International journal of cancer Journal international du cancer 1995, 60(4):501-506. Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, Sobel ME: Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 1988, 80(3):200-204. Bal A, Joshi K, Logasundaram R, Radotra BD, Singh R: Expression of nm23 in the spectrum of pre-invasive, invasive and metastatic breast lesions. Diagnostic pathology 2008, 3:23. Chow NH, Liu HS, Chan SH: The role of nm23-H1 in the progression of transitional cell bladder cancer. Clin Cancer Res 2000, 6(9):3595-3599. Lim S, Lee HY, Lee H: Inhibition of colonization and cell-matrix adhesion after nm23-H1 transfection of human prostate carcinoma cells. Cancer letters 1998, 133(2):143-149. Dantas da Silveira EJ, Oliveira MC, Silva Arruda de Morais Mde L, Queiroz LM, Lopes Costa Ade L: nm23 protein expression in metastatic and non-metastatic tongue squamous cell carcinoma. Brazilian journal of otorhinolaryngology 2008, 74(3):356-359. Salerno M, Palmieri D, Bouadis A, Halverson D, Steeg PS: Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells. Molecular and cellular biology 2005, 25(4):1379-1388. Baillat G, Gaillard S, Castets F, Monneron A: Interactions of phocein with nucleoside-diphosphate kinase, Eps15, and Dynamin I. The Journal of biological chemistry 2002, 277(21):18961-18966. Fischbach MA, Settleman J: Specific biochemical inactivation of oncogenic Ras proteins by nucleoside diphosphate kinase. Cancer research 2003, 63(14):4089-4094. Cheng S, Alfonso-Jaume MA, Mertens PR, Lovett DH: Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). The Biochemical journal 2002, 366(Pt 3):807-816. Boureux A, Vignal E, Faure S, Fort P: Evolution of the Rho family of ras-like GTPases in eukaryotes. Molecular biology and evolution 2007, 24(1):203-216. Olofsson B: Rho guanine dissociation inhibitors: Pivotal molecules in cellular signalling. Cellular signalling 1999, 11(8):545-554. Chi X, Wang S, Huang Y, Stamnes M, Chen JL: Roles of rho GTPases in intracellular transport and cellular transformation. International journal of molecular sciences 2013, 14(4):7089-7108. Parri M, Chiarugi P: Rac and Rho GTPases in cancer cell motility control. Cell communication and signaling : CCS 2010, 8:23. Jaffe AB, Hall A: Rho GTPases: Biochemistry and biology. Annu Rev Cell Dev Bi 2005, 21:247-269. Vega FM, Ridley AJ: Rho GTPases in cancer cell biology. FEBS letters 2008, 582(14):2093-2101. Campbell ID, Humphries MJ: Integrin structure, activation, and interactions. Cold Spring Harbor perspectives in biology 2011, 3(3). Shen B, Delaney MK, Du XP: Inside-out, outside-in, and inside-outside-in: G protein signaling in integrin-mediated cell adhesion, spreading, and retraction. Curr Opin Cell Biol 2012, 24(5):600-606. Adachi M, Taki T, Higashiyama M, Kohno N, Inufusa H, Miyake M: Significance of integrin alpha 5 gene expression as a prognostic factor in node-negative non-small cell lung cancer. Clin Cancer Res 2000, 6(1):96-101. Schaller MD, Hildebrand JD, Parsons JT: Complex formation with focal adhesion kinase: A mechanism to regulate activity and subcellular localization of Src kinases. Mol Biol Cell 1999, 10(10):3489-3505. Parsons JT: Focal adhesion kinase: the first ten years. Journal of cell science 2003, 116(8):1409-1416. Moissoglu K, Schwartz MA: Integrin signalling in directed cell migration. Biology of the cell / under the auspices of the European Cell Biology Organization 2006, 98(9):547-555. Scheswohl DM, Harrell JR, Rajfur Z, Gao G, Campbell SL, Schaller MD: Multiple paxillin binding sites regulate FAK function. Journal of molecular signaling 2008, 3:1. van Nimwegen MJ, van de Water B: Focal adhesion kinase: a potential target in cancer therapy. Biochemical pharmacology 2007, 73(5):597-609. Schlaepfer DD, Hauck CR, Sieg DJ: Signaling through focal adhesion kinase. Prog Biophys Mol Bio 1999, 71(3-4):435-478. Chuang SM, Wang IC, Yang JL: Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. Carcinogenesis 2000, 21(7):1423-1432. Qi MS, Elion EA: MAP kinase pathways. Journal of cell science 2005, 118(16):3569-3572. Watters JJ, Sommer JA, Pfeiffer ZA, Prabhu U, Guerra AN, Bertics PJ: A differential role for the mitogen-activated protein kinases in lipopolysaccharide signaling: the MEK/ERK pathway is not essential for nitric oxide and interleukin 1beta production. The Journal of biological chemistry 2002, 277(11):9077-9087. Kansra S, Stoll SW, Johnson JL, Elder JT: Autocrine extracellular signal-regulated kinase (ERK) activation in normal human keratinocytes: metalloproteinase-mediated release of amphiregulin triggers signaling from ErbB1 to ERK. Mol Biol Cell 2004, 15(9):4299-4309. Fritz G, Kaina B: Late activation of stress kinases (SAPK/JNK) by genotoxins requires the DNA repair proteins DNA-PKcs and CSB. Mol Biol Cell 2006, 17(2):851-861. Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF: Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Molecular cell 2004, 15(5):713-725. Yoshizuka N, Lai M, Liao R, Cook R, Xiao C, Han J, Sun P: PRAK suppresses oncogenic ras-induced hematopoietic cancer development by antagonizing the JNK pathway. Molecular cancer research : MCR 2012, 10(6):810-820. Staples CJ, Owens DM, Maier JV, Cato ACB, Keyse SM: Cross-talk between the p38 alpha and JNK MAPK Pathways Mediated by MAP Kinase Phosphatase-1 Determines Cellular Sensitivity to UV Radiation. Journal of Biological Chemistry 2010, 285(34):25928-25940. Engel K, Kotlyarov A, Gaestel M: Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation. Embo Journal 1998, 17(12):3363-3371. Aggeli IK, Gaitanaki C, Beis I: Involvement of JNKs and p38-MAPK/MSK1 pathways in H2O2-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells. Cellular signalling 2006, 18(10):1801-1812. Stone MK, Kolling GL, Lindner MH, Obrig TG: p38 mitogen-activated protein kinase mediates lipopolysaccharide and tumor necrosis factor alpha induction of shiga toxin 2 sensitivity in human umbilical vein endothelial cells. Infection and immunity 2008, 76(3):1115-1121. Remy G, Risco AM, Inesta-Vaquera FA, Gonzalez-Teran B, Sabio G, Davis RJ, Cuenda A: Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cellular signalling 2010, 22(4):660-667. Cuadrado A, Nebreda AR: Mechanisms and functions of p38 MAPK signalling. Biochemical Journal 2010, 429:403-417. Rao AV, Rao LG: Carotenoids and human health. Pharmacological research : the official journal of the Italian Pharmacological Society 2007, 55(3):207-216. Pool-Zobel BL, Bub A, Muller H, Wollowski I, Rechkemmer G: Consumption of vegetables reduces genetic damage in humans: first results of a human intervention trial with carotenoid-rich foods. Carcinogenesis 1997, 18(9):1847-1850. Failla ML, Huo T, Thakkar SK: In vitro screening of relative bioaccessibility of carotenoids from foods. Asia Pacific journal of clinical nutrition 2008, 17 Suppl 1:200-203. Bauernfeind JC: Carotenoid vitamin A precursors and analogs in foods and feeds. Journal of agricultural and food chemistry 1972, 20(3):456-473. Nishino H, Murakosh M, Ii T, Takemura M, Kuchide M, Kanazawa M, Mou XY, Wada S, Masuda M, Ohsaka Y et al: Carotenoids in cancer chemoprevention. Cancer metastasis reviews 2002, 21(3-4):257-264. Hu FB: Plant-based foods and prevention of cardiovascular disease: an overview. The American journal of clinical nutrition 2003, 78(3 Suppl):544S-551S. Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ: Plasma carotenoids, retinol, and tocopherols and risk of breast cancer. Am J Epidemiol 2005, 161(2):153-160. 71. Le Marchand L, Hankin JH, Kolonel LN, Beecher GR, Wilkens LR, Zhao LP: Intake of specific carotenoids and lung cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 1993, 2(3):183-187. Jaswir I, Noviendri D, Hasrini RF, Octavianti F: Carotenoids: Sources, medicinal properties and their application in food and nutraceutical industry. J Med Plants Res 2011, 5(33):7119-7131. Sakhi AK, Bohn SK, Smeland S, Thoresen M, Smedshaug GB, Tausjo J, Svilaas A, Karlsen A, Russnes KM, Svilaas T et al: Postradiotherapy plasma lutein, alpha-carotene, and beta-carotene are positively associated with survival in patients with head and neck squamous cell carcinoma. Nutrition and cancer 2010, 62(3):322-328. Trumbo P, Yates AA, Schlicker S, Poos M: Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Journal of the American Dietetic Association 2001, 101(3):294-301. Kotake-Nara E, Kushiro M, Zhang H, Sugawara T, Miyashita K, Nagao A: Carotenoids affect proliferation of human prostate cancer cells. The Journal of nutrition 2001, 131(12):3303-3306. Murakoshi M, Takayasu J, Kimura O, Kohmura E, Nishino H, Iwashima A, Okuzumi J, Sakai T, Sugimoto T, Imanishi J et al: Inhibitory effects of alpha-carotene on proliferation of the human neuroblastoma cell line GOTO. J Natl Cancer Inst 1989, 81(21):1649-1652. Kozuki Y, Miura Y, Yagasaki K: Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture. Cancer Lett 2000, 151(1):111-115. Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M: Connexins regulate calcium signaling by controlling ATP release. Proceedings of the National Academy of Sciences of the United States of America 1998, 95(26):15735-15740. Bedner P, Niessen H, Odermatt B, Kretz M, Willecke K, Harz H: Selective permeability of different connexin channels to the second messenger cyclic AMP. The Journal of biological chemistry 2006, 281(10):6673-6681. Niessen H, Harz H, Bedner P, Kramer K, Willecke K: Selective permeability of different connexin channels to the second messenger inositol 1,4,5-trisphosphate. Journal of cell science 2000, 113 ( Pt 8):1365-1372. Krutovskikh VA, Piccoli C, Yamasaki H: Gap junction intercellular communication propagates cell death in cancerous cells. Oncogene 2002, 21(13):1989-1999. Liu CL, Huang YS, Hosokawa M, Miyashita K, Hu ML: Inhibition of proliferation of a hepatoma cell line by fucoxanthin in relation to cell cycle arrest and enhanced gap junctional intercellular communication. Chemico-biological interactions 2009, 182(2-3):165-172. Liu CL, Huang YS, Hosokawa M, Miyashita K, Hu ML: Inhibition of proliferation of a hepatoma cell line by fucoxanthin in relation to cell cycle arrest and enhanced gap junctional intercellular communication. Chemico-biological interactions 2009, 182(2-3):165-172. Kucuk O, Sarkar FH, Sakr W, Khachik F, Djuric Z, Banerjee M, Pollak MN, Bertram JS, Wood DP: Lycopene in the treatment of prostate cancer. Pure Appl Chem 2002, 74(8):1443-1450. Zhang LX, Cooney RV, Bertram JS: Carotenoids Enhance Gap Junctional Communication and Inhibit Lipid-Peroxidation in C3h/10t1/2 Cells - Relationship to Their Cancer Chemopreventive Action. Carcinogenesis 1991, 12(11):2109-2114. Zhang LX, Cooney RV, Bertram JS: Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 1991, 12(11):2109-2114. Murakoshi M, Nishino H, Satomi Y, Takayasu J, Hasegawa T, Tokuda H, Iwashima A, Okuzumi J, Okabe H, Kitano H et al: Potent preventive action of alpha-carotene against carcinogenesis: spontaneous liver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by beta-carotene. Cancer research 1992, 52(23):6583-6587. Narisawa T, Fukaura Y, Hasebe M, Ito M, Aizawa R, Murakoshi M, Uemura S, Khachik F, Nishino H: Inhibitory effects of natural carotenoids, alpha-carotene, beta-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats. Cancer Lett 1996, 107(1):137-142. Rock CL, Flatt SW, Natarajan L, Thomson CA, Bardwell WA, Newman VA, Hollenbach KA, Jones L, Caan BJ, Pierce JP: Plasma carotenoids and recurrence-free survival in women with a history of breast cancer. J Clin Oncol 2005, 23(27):6631-6638. Butalla AC, Crane TE, Patil B, Wertheim BC, Thompson P, Thomson CA: Effects of a carrot juice intervention on plasma carotenoids, oxidative stress, and inflammation in overweight breast cancer survivors. Nutrition and cancer 2012, 64(2):331-341. Watzl B, Kulling SE, Moseneder J, Barth SW, Bub A: A 4-wk intervention with high intake of carotenoid-rich vegetables and fruit reduces plasma C-reactive protein in healthy, nonsmoking men. The American journal of clinical nutrition 2005, 82(5):1052-1058. Buijsse B, Feskens EJ, Kwape L, Kok FJ, Kromhout D: Both alpha- and beta-carotene, but not tocopherols and vitamin C, are inversely related to 15-year cardiovascular mortality in Dutch elderly men. J Nutr 2008, 138(2):344-350. Michaud DS, Feskanich D, Rimm EB, Colditz GA, Speizer FE, Willett WC, Giovannucci E: Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. The American journal of clinical nutrition 2000, 72(4):990-997. Li C, Ford ES, Zhao G, Balluz LS, Giles WH, Liu S: Serum alpha-carotene concentrations and risk of death among US Adults: the Third National Health and Nutrition Examination Survey Follow-up Study. Arch Intern Med, 171(6):507-515. Nakayama K, Nakayama N, Katagiri H, Miyazaki K: Mechanisms of ovarian cancer metastasis: biochemical pathways. International journal of molecular sciences 2012, 13(9):11705-11717. Failla ML, Huo T, Thakkar SK: In vitro screening of relative bioaccessibility of carotenoids from foods. Asia Pacific journal of clinical nutrition 2008, 17 Suppl 1:200-203. Rao AV, Rao LG: Carotenoids and human health. Pharmacological research : the official journal of the Italian Pharmacological Society 2007, 55(3):207-216. Trumbo P, Yates AA, Schlicker S, Poos M: Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Journal of the American Dietetic Association 2001, 101(3):294-301. Hu FB: Plant-based foods and prevention of cardiovascular disease: an overview. The American journal of clinical nutrition 2003, 78(3 Suppl):544S-551S. Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ: Plasma carotenoids, retinol, and tocopherols and risk of breast cancer. Am J Epidemiol 2005, 161(2):153-160. Le Marchand L, Hankin JH, Kolonel LN, Beecher GR, Wilkens LR, Zhao LP: Intake of specific carotenoids and lung cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 1993, 2(3):183-187. Zhang LX, Cooney RV, Bertram JS: Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 1991, 12(11):2109-2114. Murakoshi M, Takayasu J, Kimura O, Kohmura E, Nishino H, Iwashima A, Okuzumi J, Sakai T, Sugimoto T, Imanishi J et al: Inhibitory effects of alpha-carotene on proliferation of the human neuroblastoma cell line GOTO. J Natl Cancer Inst 1989, 81(21):1649-1652. Murakoshi M, Nishino H, Satomi Y, Takayasu J, Hasegawa T, Tokuda H, Iwashima A, Okuzumi J, Okabe H, Kitano H et al: Potent preventive action of alpha-carotene against carcinogenesis: spontaneous liver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by beta-carotene. Cancer research 1992, 52(23):6583-6587. Kozuki Y, Miura Y, Yagasaki K: Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture. Cancer letters 2000, 151(1):111-115. Lim YP, Kuo SC, Lai ML, Huang JD: Inhibition of CYP3A4 expression by ketoconazole is mediated by the disruption of pregnane X receptor, steroid receptor coactivator-1, and hepatocyte nuclear factor 4 alpha interaction. Pharmacogenetics and genomics 2009, 19(1):11-24. Yang TT, Sinai P, Kain SR: An acid phosphatase assay for quantifying the growth of adherent and nonadherent cells. Analytical biochemistry 1996, 241(1):103-108. Yang CM, Liu YZ, Liao JW, Hu ML: The in vitro and in vivo anti-metastatic efficacy of oxythiamine and the possible mechanisms of action. Clin Exp Metastasis 2010, 27(5):341-349. Repesh LA: A new in vitro assay for quantitating tumor cell invasion. Invasion & metastasis 1989, 9(3):192-208. Kleiner DE, Stetler-Stevenson WG: Quantitative zymography: detection of picogram quantities of gelatinases. Analytical biochemistry 1994, 218(2):325-329. Bourboulia D, Stetler-Stevenson WG: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Seminars in cancer biology 2010, 20(3):161-168. Lambert E, Dasse E, Haye B, Petitfrere E: TIMPs as multifacial proteins. Critical reviews in oncology/hematology 2004, 49(3):187-198. Duffy MJ: Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clinical chemistry 2002, 48(8):1194-1197. Ornstein DL, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Hunt J, Rousseau SM, Stump DC: Coexisting macrophage-associated fibrin formation and tumor cell urokinase in squamous cell and adenocarcinoma of the lung tissues. Cancer 1991, 68(5):1061-1067. Stefansson S, Lawrence DA: Old dogs and new tricks: proteases, inhibitors, and cell migration. Science''s STKE : signal transduction knowledge environment 2003, 2003(189):pe24. Duffy MJ: The urokinase plasminogen activator system: role in malignancy. Current pharmaceutical design 2004, 10(1):39-49. Andreasen PA, Kjoller L, Christensen L, Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: a review. International journal of cancer Journal international du cancer 1997, 72(1):1-22. Hsu NY, Chen CY, Hsu CP, Lin TY, Chou MC, Chiou SH, Chow KC: Prognostic significance of expression of nm23-H1 and focal adhesion kinase in non-small cell lung cancer. Oncol Rep 2007, 18(1):81-85. Baillat G, Gaillard S, Castets F, Monneron A: Interactions of phocein with nucleoside-diphosphate kinase, Eps15, and Dynamin I. The Journal of biological chemistry 2002, 277(21):18961-18966. Fischbach MA, Settleman J: Specific biochemical inactivation of oncogenic Ras proteins by nucleoside diphosphate kinase. Cancer research 2003, 63(14):4089-4094. Cheng S, Alfonso-Jaume MA, Mertens PR, Lovett DH: Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). The Biochemical journal 2002, 366(Pt 3):807-816. Schoenwaelder SM, Burridge K: Bidirectional signaling between the cytoskeleton and integrins. Curr Opin Cell Biol 1999, 11(2):274-286. Mitra SK, Schlaepfer DD: Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 2006, 18(5):516-523. Westermarck J, Kahari VM: Regulation of matrix metalloproteinase expression in tumor invasion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999, 13(8):781-792. Adjei AA: The role of mitogen-activated ERK-kinase inhibitors in lung cancer therapy. Clin Lung Cancer 2005, 7(3):221-223. Altucci L, Gronemeyer H: The promise of retinoids to fight against cancer. Nature reviews Cancer 2001, 1(3):181-193. Kim MS, Lee EJ, Kim HRC, Moon A: p38 kinase is a key signaling molecule for H-ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer research 2003, 63(17):5454-5461. Talmadge JE, Fidler IJ: AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer research 2010, 70(14):5649-5669. Parri M, Chiarugi P: Rac and Rho GTPases in cancer cell motility control. Cell communication and signaling : CCS 2010, 8:23. Schwartz J, Shklar G: Regression of experimental oral carcinomas by local injection of beta-carotene and canthaxanthin. Nutrition and cancer 1988, 11(1):35-40. Ziegler RG: Vegetables, fruits, and carotenoids and the risk of cancer. The American journal of clinical nutrition 1991, 53(1 Suppl):251S-259S. Sakhi AK, Bohn SK, Smeland S, Thoresen M, Smedshaug GB, Tausjo J, Svilaas A, Karlsen A, Russnes KM, Svilaas T et al: Postradiotherapy plasma lutein, alpha-carotene, and beta-carotene are positively associated with survival in patients with head and neck squamous cell carcinoma. Nutrition and cancer 2010, 62(3):322-328. Micozzi MS, Brown ED, Edwards BK, Bieri JG, Taylor PR, Khachik F, Beecher GR, Smith JC, Jr.: Plasma carotenoid response to chronic intake of selected foods and beta-carotene supplements in men. The American journal of clinical nutrition 1992, 55(6):1120-1125. McInerney JK, Seccafien CA, Stewart CM, Bird AR: Effects of high pressure processing on antioxidant activity, and total carotenoid content and availability, in vegetables. Innov Food Sci Emerg 2007, 8(4):543-548. Young AJ, Lowe GM: Antioxidant and prooxidant properties of carotenoids. Archives of biochemistry and biophysics 2001, 385(1):20-27. Palozza P: Prooxidant actions of carotenoids in biologic systems. Nutr Rev 1998, 56(9):257-265. Huang CS, Shih MK, Chuang CH, Hu ML: Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. The Journal of nutrition 2005, 135(9):2119-2123. Young AJ, Lowe GM: Antioxidant and prooxidant properties of carotenoids. Archives of biochemistry and biophysics 2001, 385(1):20-27. Yeh SL, Yang TH, Huang CH, Hu ML: Exposure of calf thymus DNA to autoxidized beta-carotene results in the formation of 8-oxo-deoxyguanosine. Food Chem 2003, 81(3):439-445. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA: a cancer journal for clinicians 2012, 62(1):10-29. Talmadge JE, Fidler IJ: AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer research 2010, 70(14):5649-5669. Failla ML, Huo T, Thakkar SK: In vitro screening of relative bioaccessibility of carotenoids from foods. Asia Pacific journal of clinical nutrition 2008, 17 Suppl 1:200-203. Trumbo P, Yates AA, Schlicker S, Poos M: Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Journal of the American Dietetic Association 2001, 101(3):294-301. Li C, Ford ES, Zhao G, Balluz LS, Giles WH, Liu S: Serum alpha-carotene concentrations and risk of death among US Adults: the Third National Health and Nutrition Examination Survey Follow-up Study. Arch Intern Med, 171(6):507-515. Murakoshi M, Nishino H, Satomi Y, Takayasu J, Hasegawa T, Tokuda H, Iwashima A, Okuzumi J, Okabe H, Kitano H et al: Potent preventive action of alpha-carotene against carcinogenesis: spontaneous liver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by beta-carotene. Cancer research 1992, 52(23):6583-6587. 7. Narisawa T, Fukaura Y, Hasebe M, Ito M, Aizawa R, Murakoshi M, Uemura S, Khachik F, Nishino H: Inhibitory effects of natural carotenoids, alpha-carotene, beta-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats. Cancer letters 1996, 107(1):137-142. Wessely R, Schomig A, Kastrati A: Sirolimus and Paclitaxel on polymer-based drug-eluting stents: similar but different. Journal of the American College of Cardiology 2006, 47(4):708-714. Fitzpatrick FA, Wheeler R: The immunopharmacology of paclitaxel (Taxol), docetaxel (Taxotere), and related agents. International immunopharmacology 2003, 3(13-14):1699-1714. Socinski MA: Single-agent paclitaxel in the treatment of advanced non-small cell lung cancer. Oncologist 1999, 4(5):408-416. Ma Y, Zhao N, Liu G: Conjugate (MTC-220) of Muramyl Dipeptide Analogue and Paclitaxel Prevents Both Tumor Growth and Metastasis in Mice. Journal of medicinal chemistry 2011, 54(8):2767-2777. Jia WW, Bu X, Philips D, Yan H, Liu G, Chen X, Bush JA, Li G: Rh2, a compound extracted from ginseng, hypersensitizes multidrug-resistant tumor cells to chemotherapy. Canadian journal of physiology and pharmacology 2004, 82(7):431-437. Chen MF, Yang CM, Su CM, Liao JW, Hu ML: Inhibitory effect of vitamin C in combination with vitamin K3 on tumor growth and metastasis of Lewis lung carcinoma xenografted in C57BL/6 mice. Nutrition and cancer 2011, 63(7):1036-1043. Kleiner DE, Stetler-Stevenson WG: Quantitative zymography: detection of picogram quantities of gelatinases. Analytical biochemistry 1994, 218(2):325-329. Chuang CH, Huang CS, Hu ML: Vitamin E and rutin synergistically inhibit expression of vascular endothelial growth factor through down-regulation of binding activity of activator protein-1 in human promyelocytic leukemia (HL-60) cells. Chemico-biological interactions 2010, 183(3):434-441. Stahl W, Junghans A, de Boer B, Driomina ES, Briviba K, Sies H: Carotenoid mixtures protect multilamellar liposomes against oxidative damage: synergistic effects of lycopene and lutein. FEBS letters 1998, 427(2):305-308. Chuang CH, Huang CS, Hu ML: Vitamin E and rutin synergistically inhibit expression of vascular endothelial growth factor through down-regulation of binding activity of activator protein-1 in human promyelocytic leukemia (HL-60) cells. Chemico-biological interactions 2010, 183(3):434-441. Duarte VM, Han E, Veena MS, Salvado A, Suh JD, Liang LJ, Faull KF, Srivatsan ES, Wang MB: Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKbeta protein of the NFkappaB pathway. Mol Cancer Ther 2010, 9(10):2665-2675. Yunos NM, Beale P, Yu JQ, Huq F: Synergism from the Combination of Oxaliplatin with Selected Phytochemicals in Human Ovarian Cancer Cell Lines. Anticancer Res 2011, 31(12):4283-4289. Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer 2002, 2(3):161-174. Deryugina EI, Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer metastasis reviews 2006, 25(1):9-34. Duffy MJ: Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clinical chemistry 2002, 48(8):1194-1197. Ornstein DL, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Hunt J, Rousseau SM, Stump DC: Coexisting macrophage-associated fibrin formation and tumor cell urokinase in squamous cell and adenocarcinoma of the lung tissues. Cancer 1991, 68(5):1061-1067. Schmitt M, Wilhelm OG, Reuning U, Kruger A, Harbeck N, Lengyel E, Graeff H, Gansbacher B, Kessler H, Burgle M et al: The urokinase plasminogen activator system as a novel target for tumour therapy. Fibrinolysis Proteol 2000, 14(2-3):114-132. Muehlenweg B, Sperl S, Magdolen V, Schmitt M, Harbeck N: Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours. Expert Opin Biol Th 2001, 1(4):683-691. McIntush EW, Smith MF: Matrix metalloproteinases and tissue inhibitors of metalloproteinases in ovarian function. Reviews of reproduction 1998, 3(1):23-30. Bourboulia D, Stetler-Stevenson WG: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Seminars in cancer biology 2010, 20(3):161-168. Stefansson S, Lawrence DA: Old dogs and new tricks: proteases, inhibitors, and cell migration. Science''s STKE : signal transduction knowledge environment 2003, 2003(189):pe24. Cheng SF, Alfonso-Jaume MA, Mertens PR, Lovett DH: Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by
摘要: 
α-胡蘿蔔素為人類血漿中主要類胡蘿蔔素之一,富含於深綠色水果和蔬菜中,例如:胡蘿蔔、菠菜、南瓜和番茄。流行病學研究指出在血漿中含有較高的α-胡蘿蔔素濃度,可以降低慢性疾病發生的風險,如:癌症。在我們過去的研究發現,α-胡蘿蔔素具有抑制人類肝癌細胞株SK-Hep-1轉移的效果。然而,α-胡蘿蔔素對於肺癌是否也具有同樣效果仍不清楚,而肺癌為台灣因癌症死亡的主要原因之一。因此本論文第一部分的研究目的在於利用具有高度轉移能力的小鼠肺癌細胞株(Lewis lung carcinoma, LLC1)作為細胞模式,探討α-胡蘿蔔素抑制癌轉移的作用及其可能機制,並與β-胡蘿蔔素比較。結果發現α-胡蘿蔔素可以顯著抑制LLC1的侵襲、移動及黏附作用,而在相同濃度下(2.5 μM)其抑制效果也較β-胡蘿蔔素好。我們也發現α-胡蘿蔔素可降低細胞膜上整合素β1 (Integrin β1)所調控的黏著斑激酶(Focal Adhesion Kinase, FAK)表現,並進一步調節有絲分裂活化蛋白質激酶(Mitogen-activated protein kinase, MAPKs)的磷酸化作用,而影響到下游Rho small GTPase蛋白的表現。此外,α-胡蘿蔔素會顯著減少尿素激酶型胞漿素原活化子(Urokinase plasminogen activator, uPA)和基質金屬蛋白酶(Matrix metalloproteinases, MMPs)-2和-9的酵素活性,並提升胞漿素原活化子抑制物(Plasminogen activator inhibitor-1, PAI-1)、基質金屬蛋白酶內生性抑制劑(Tissue inhibitor of matrix etalloproteinase, TIMP)-1及-2和抗轉移蛋白23(Non-metastatic protein 23 H1, Nm23-H1)的蛋白質表現。
在本論文的第二部份,我們更進一步利用異體移植LLC1的B57CL/6小鼠模式探討α-胡蘿蔔素合併太平洋紫杉醇在活體內抑制癌轉移的作用。以皮下注射方式將LLC1接種至C57BL/6小鼠的背部,九天後依小鼠腫瘤大小和體重分成五組:(1)腫瘤控制組;(2) α-胡蘿蔔素(5 mg/kg);(3)太平洋紫杉醇(6 mg/kg);(4) α-胡蘿蔔素(1 mg/kg)+太平洋紫杉醇(6 mg/kg);(5) α-胡蘿蔔素(5 mg/kg)+太平洋紫杉醇(6 mg/kg)。以一週三次的頻率經由管餵給予α-胡蘿蔔素並由腹腔注射給予太平洋紫杉醇,持續二十一天。結果發現單獨給予α-胡蘿蔔素(5 mg/kg)和太平洋紫杉醇(6 mg/kg)可顯著:(1)抑制肺臟轉移的作用;(2)降低肺臟組織中整合素β1、p-FAK和Rho small GTPase的蛋白質表現;(3)增加肺臟組織中TIMP-1、TIMP-2、PAI-1和nm23-H1的蛋白質表現;(4)抑制血漿中uPA、MMP-2和-9的酵素活性。此外單獨給予太平洋紫杉醇可顯著抑制腫瘤的生長。合併給予α-胡蘿蔔素(5 mg/kg)及太平洋紫杉醇(6 mg/kg)對於腫瘤生長及肺臟轉移具有相加性抑制作用;在機制方面,合併給予α-胡蘿蔔素(5 mg/kg)及太平洋紫杉醇(6 mg/kg)對於肺臟組織中Rho和Rac的蛋白質表現具有相加性抑制作用,但對於TIMP-2蛋白質表現則具有加乘性促進作用。這些活體外和活體內試驗的結果顯示:α-胡蘿蔔素本身除了具有癌症化學預防的能力之外,亦具有作為抗癌藥物佐劑之潛力。

α-Carotene, one of the major carotenoids in human plasma, can be found in yellow-orange and dark-green fruits and vegetables, such as carrots, spinach, pumpkin and tomatoes. Epidemiological studies have indicated that higher serum levels of α-carotene are associated with lower risk of chronic diseases, including cancer. Our previous studies have demonstrated that α-carotene exhibits anti-metastatic activity in human hepatocarcinoma SK-Hep-1 cells. However, it is unclear whether α-carotene has similar effects in lung cancer, the major leading cause of death in cancer patients in Taiwan. Therefore, the aim of the first part of this thesis was to determine the anti-metastatic effects and possible mechanisms of α-carotene in comparison with β-carotene in highly invasive Lewis lung carcinoma (LLC1). Results reveal that α-carotene significantly inhibited cell invasion, migration and adhesion in LLC, and that these inhibitory effects of α-carotene are similar to β-carotene at the same concentration (2.5 μM). We also found that α-carotene significantly inhibited the phosphorylation of integrin β1 receptor-mediated focal adhesion kinase (FAK), which in turn reduced the phosphorylation of mitogen-activated protein kinase (MAPKs). Such an inhibition was concomitant to reduction of Rho small GTPase expression, including Rho and Rac. In addition, α-carotene significantly decreased activities of urokinase plasminogen activator (uPA) and matrix metalloproteinase (MMP-2 and -9), but increased protein expression of plasminogen activator inhibitor (PAI)-1 and tissue inhibitor of MMP (TIMP)-1 and -2 as well as nm23H1.
In the second part of this thesis, we further examined the anti-metastatic effects of α-carotene in combination with taxol in C57BL/6 mice xenografted with LLC model. After implantation (s.c.) with LLC for 9 d, mice were divided into five groups: group 1, tumor control; group 2, α-carotene (5 mg/kg); group 3, taxol (6 mg/kg); group 4, α-carotene (1 mg/kg) + taxol (6 mg/kg); group 5, α-carotene (5 mg/kg) + taxol (6 mg/kg). Mice were orally supplied with α-carotene and administrated (i.p.) with taxol three times a week for an additional 21 d. Results reveal that α-carotene (5 mg/kg) and Taxol (6 mg/kg) treatment alone resulted in: 1) significant inhibition of lung metastasis; 2) significantly decreased protein expression of integrin β1, p-FAK and Rho small GTPase in lung tissues; 3) significantly increased protein expression of TIMP-1、TIMP-2、PAI-1 and nm23-H1 in lung tissues; and 4) significantly decreased activities of uPA, MMP-2 and MMP-9 in plasma. Taxol (6 mg/kg) treatment alone also significantly inhibited tumor growth, as evidence by inhibition of tumor volume and tumor weight. α-Carotene (5 mg/kg) in combination with Taxol (6 mg/kg) exhibited additive inhibition on tumor growth and lung metastasis. Mechanistically, α-carotene (5 mg/kg) in combination with Taxol (6 mg/kg) additively inhibited Rho and Rac protein expression but synergistically increased TIMP-2 protein expression in lung tissues. Overall, the present results suggest that α-carotene could be used as an adjuvant for anti-cancer drugs or as a chemopreventive agent.
URI: http://hdl.handle.net/11455/52133
其他識別: U0005-1508201318024900
Appears in Collections:食品暨應用生物科技學系

Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.