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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄧哲明 | |
dc.contributor.author | Shih-Wei Wang | en |
dc.contributor.author | 王士維 | zh_TW |
dc.date.accessioned | 2021-06-12T18:06:55Z | - |
dc.date.available | 2013-02-19 | |
dc.date.copyright | 2008-02-19 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-12-28 | |
dc.identifier.citation | Abiru S, Nakao K, Ichikawa T, Migita K, Shigeno M, Sakamoto M, Ishikawa H, Hamasaki K, Nakata K and Eguchi K (2002) Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells. Hepatology 35:1117-1124.
Adams JM and Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322-1326. Agarwal A, Das K, Lerner N, Sathe S, Cicek M, Casey G and Sizemore N (2005) The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Oncogene 24:1021-1031. Andela VB, Schwarz EM, Puzas JE, O'Keefe RJ and Rosier RN (2000) Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB. Cancer Res 60:6557-6562. Andreasen PA, Kjoller L, Christensen L and Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1-22. Arsura M and Cavin LG (2005) Nuclear factor-kappaB and liver carcinogenesis. Cancer Lett 229:157-169. Avila MA, Berasain C, Sangro B and Prieto J (2006) New therapies for hepatocellular carcinoma. Oncogene 25:3866-3884. Bardelli A, Longati P, Gramaglia D, Stella MC and Comoglio PM (1997) Gab1 coupling to the HGF/Met receptor multifunctional docking site requires binding of Grb2 and correlates with the transforming potential. Oncogene 15:3103-3111. Befeler AS and Di Bisceglie AM (2002) Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 122:1609-1619. Behrendt N, Ronne E and Dano K (1993) Binding of the urokinase-type plasminogen activator to its cell surface receptor is inhibited by low doses of suramin. J Biol Chem 268:5985-5989. Beraud C, Henzel WJ and Baeuerle PA (1999) Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-kappaB activation. Proc Natl Acad Sci U S A 96:429-434. Bhalla KN (2003) Microtubule-targeted anticancer agents and apoptosis. Oncogene 22:9075-9086. Bidere N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C and Senik A (2003) Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. J Biol Chem 278:31401-31411. Birchmeier C, Birchmeier W, Gherardi E and Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915-925. Blagosklonny MV, Giannakakou P, el-Deiry WS, Kingston DG, Higgs PI, Neckers L and Fojo T (1997) Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death. Cancer Res 57:130-135. Blain SW and Massague J (2002) Breast cancer banishes p27 from nucleus. Nat Med 8:1076-1078. Blasi F and Carmeliet P (2002) uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 3:932-943. Breuhahn K, Longerich T and Schirmacher P (2006) Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25:3787-3800. Broker LE, Kruyt FA and Giaccone G (2005) Cell death independent of caspases: a review. Clin Cancer Res 11:3155-3162. Brown K, Gerstberger S, Carlson L, Franzoso G and Siebenlist U (1995) Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485-1488. Bruix J, Sala M and Llovet JM (2004) Chemoembolization for hepatocellular carcinoma. Gastroenterology 127:S179-188. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M and Rodes J (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35:421-430. Burroughs A, Hochhauser D and Meyer T (2004) Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum. Lancet Oncol 5:409-418. Castedo M, Perfettini JL, Roumier T and Kroemer G (2002) Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ 9:1287-1293. Castellino FJ and Ploplis VA (2005) Structure and function of the plasminogen/plasmin system. Thromb Haemost 93:647-654. Chambers AF, Groom AC and MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563-572. Chan CF, Yau TO, Jin DY, Wong CM, Fan ST and Ng IO (2004) Evaluation of nuclear factor-kappaB, urokinase-type plasminogen activator, and HBx and their clinicopathological significance in hepatocellular carcinoma. Clin Cancer Res 10:4140-4149. Checchi PM, Nettles JH, Zhou J, Snyder JP and Joshi HC (2003) Microtubule-interacting drugs for cancer treatment. Trends Pharmacol Sci 24:361-365. Chen CC, Wu LG, Ko FN and Teng CM (1994) Antiplatelet aggregation principles of Dendrobium loddigesii. J Nat Prod 57:1271-1274. Chen YC, Lu PH, Pan SL, Teng CM, Kuo SC, Lin TP, Ho YF, Huang YC and Guh JH (2007) Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways. Biochem Pharmacol 74:10-19. Chetty R (2003) p27 Protein and cancers of the gastrointestinal tract and liver: an overview. J Clin Gastroenterol 37:23-27. Christensen JG, Burrows J and Salgia R (2005) c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett 225:1-26. Chung TW, Lee YC and Kim CH (2004a) Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. Faseb J 18:1123-1125. Chung TW, Moon SK, Chang YC, Ko JH, Lee YC, Cho G, Kim SH, Kim JG and Kim CH (2004b) Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism. Faseb J 18:1670-1681. Coleman TR and Dunphy WG (1994) Cdc2 regulatory factors. Curr Opin Cell Biol 6:877-882. Cory S and Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647-656. Coussens LM, Fingleton B and Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295:2387-2392. Cregan SP, Dawson VL and Slack RS (2004) Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 23:2785-2796. Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N and Kroemer G (2000) Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett 476:118-123. Duffy MJ (2004) The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 10:39-49. El-Serag HB (2004) Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 127:S27-34. El-Serag HB and Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745-750. Elledge SJ (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274:1664-1672. Engelhard HH, Homer RJ, Duncan HA and Rozental J (1998) Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells. J Neurooncol 37:97-108. Farazi PA and DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674-687. Farias EF, Aguirre Ghiso JA, Ladeda V and Bal de Kier Joffe E (1998) Verapamil inhibits tumor protease production, local invasion and metastasis development in murine carcinoma cells. Int J Cancer 78:727-734. Ferlin MG, Chiarelotto G, Gasparotto V, Dalla Via L, Pezzi V, Barzon L, Palu G and Castagliuolo I (2005) Synthesis and in vitro and in vivo antitumor activity of 2-phenylpyrroloquinolin-4-ones. J Med Chem 48:3417-3427. Ferrero R and Torres M (2001) Prolonged exposure to YC-1 induces apoptosis in adrenomedullary endothelial and chromaffin cells through a cGMP-independent mechanism. Neuropharmacology 41:895-906. Fidler IJ (2003) The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3:453-458. Galle J, Zabel U, Hubner U, Hatzelmann A, Wagner B, Wanner C and Schmidt HH (1999) Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity. Br J Pharmacol 127:195-203. Garber K (2005) Divide and conquer: new generation of drugs targets mitosis. J Natl Cancer Inst 97:874-876. Gibbs JB (2000) Mechanism-based target identification and drug discovery in cancer research. Science 287:1969-1973. Gondi CS, Lakka SS, Yanamandra N, Siddique K, Dinh DH, Olivero WC, Gujrati M and Rao JS (2003) Expression of antisense uPAR and antisense uPA from a bicistronic adenoviral construct inhibits glioma cell invasion, tumor growth, and angiogenesis. Oncogene 22:5967-5975. Greten FR and Karin M (2004) The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 206:193-199. Gupta GP and Massague J (2006) Cancer metastasis: building a framework. Cell 127:679-695. Harper JW and Elledge SJ (1996) Cdk inhibitors in development and cancer. Curr Opin Genet Dev 6:56-64. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, Dobrowolski S, Bai C, Connell-Crowley L, Swindell E and et al. (1995) Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 6:387-400. Hartmann G, Weidner KM, Schwarz H and Birchmeier W (1994) The motility signal of scatter factor/hepatocyte growth factor mediated through the receptor tyrosine kinase met requires intracellular action of Ras. J Biol Chem 269:21936-21939. Hayasaka A, Suzuki N, Fujimoto N, Iwama S, Fukuyama E, Kanda Y and Saisho H (1996) Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma. Hepatology 24:1058-1062. Hidalgo M and Eckhardt SG (2001) Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 93:178-193. Ho CK and Chen CC (2003) Moscatilin from the orchid Dendrobrium loddigesii is a potential anticancer agent. Cancer Invest 21:729-736. Hobbs AJ (1997) Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci 18:484-491. Hooper DC (1999) Mode of action of fluoroquinolones. Drugs 58 Suppl 2:6-10. Hsu HK, Juan SH, Ho PY, Liang YC, Lin CH, Teng CM and Lee WS (2003) YC-1 inhibits proliferation of human vascular endothelial cells through a cyclic GMP-independent pathway. Biochem Pharmacol 66:263-271. Huang CC, Wu MC, Xu GW, Li DZ, Cheng H, Tu ZX, Jiang HQ and Gu JR (1992) Overexpression of the MDR1 gene and P-glycoprotein in human hepatocellular carcinoma. J Natl Cancer Inst 84:262-264. Huang LJ, Hsieh MC, Teng CM, Lee KH and Kuo SC (1998) Synthesis and antiplatelet activity of phenyl quinolones. Bioorg Med Chem 6:1657-1662. Huang S, Pettaway CA, Uehara H, Bucana CD and Fidler IJ (2001) Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20:4188-4197. Hwang TL, Hung HW, Kao SH, Teng CM, Wu CC and Cheng SJ (2003) Soluble guanylyl cyclase activator YC-1 inhibits human neutrophil functions through a cGMP-independent but cAMP-dependent pathway. Mol Pharmacol 64:1419-1427. Imai K and Takaoka A (2006) Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6:714-727. Ishitsuka K, Hideshima T, Hamasaki M, Raje N, Kumar S, Podar K, Le Gouill S, Shiraishi N, Yasui H, Roccaro AM, Tai YZ, Chauhan D, Fram R, Tamura K, Jain J and Anderson KC (2005) Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway. Oncogene 24:5888-5896. Itoh T, Hayashi Y, Kanamaru T, Morita Y, Suzuki S, Wang W, Zhou L, Rui JA, Yamamoto M, Kuroda Y and Itoh H (2000) Clinical significance of urokinase-type plasminogen activator activity in hepatocellular carcinoma. J Gastroenterol Hepatol 15:422-430. Jackson JR, Patrick DR, Dar MM and Huang PS (2007) Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer 7:107-117. Johnstone RW, Ruefli AA and Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153-164. Jordan A, Hadfield JA, Lawrence NJ and McGown AT (1998) Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle. Med Res Rev 18:259-296. Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H and Wilson L (1996) Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res 56:816-825. Jordan MA and Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253-265. Kang YH, Yi MJ, Kim MJ, Park MT, Bae S, Kang CM, Cho CK, Park IC, Park MJ, Rhee CH, Hong SI, Chung HY, Lee YS and Lee SJ (2004) Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: reactive oxygen species-mediated poly(ADP-ribose) polymerase-1 activation signals apoptosis-inducing factor release from mitochondria. Cancer Res 64:8960-8967. Kerr JF (1971) Shrinkage necrosis: a distinct mode of cellular death. J Pathol 105:13-20. Kerr JF, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239-257. Kimura H and Murad F (1975) Increased particulate and decreased soluble guanylate cyclase activity in regenerating liver, fetal liver, and hepatoma. Proc Natl Acad Sci U S A 72:1965-1969. Kuo SC, Lee HZ, Juang JP, Lin YT, Wu TS, Chang JJ, Lednicer D, Paull KD, Lin CM, Hamel E and et al. (1993) Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin. J Med Chem 36:1146-1156. Lee MH, Reynisdottir I and Massague J (1995) Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 9:639-649. Li L, Wang HK, Kuo SC, Wu TS, Lednicer D, Lin CM, Hamel E and Lee KH (1994) Antitumor agents. 150. 2',3',4',5',5,6,7-substituted 2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J Med Chem 37:1126-1135. Li LY, Luo X and Wang X (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412:95-99. Liotta LA and Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375-379. Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O'Higgins N, Eppenberger U, Janicke F, Schmitt M and Foekens JA (2002) Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94:116-128. Lopez-Otin C and Matrisian LM (2007) Emerging roles of proteases in tumour suppression. Nat Rev Cancer 7:800-808. Lundberg AS and Weinberg RA (1999) Control of the cell cycle and apoptosis. Eur J Cancer 35:1886-1894. Malumbres M and Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1:222-231. Massague J (2004) G1 cell-cycle control and cancer. Nature 432:298-306. Meyer R, Hatada EN, Hohmann HP, Haiker M, Bartsch C, Rothlisberger U, Lahm HW, Schlaeger EJ, van Loon AP and Scheidereit C (1991) Cloning of the DNA-binding subunit of human nuclear factor kappa B: the level of its mRNA is strongly regulated by phorbol ester or tumor necrosis factor alpha. Proc Natl Acad Sci U S A 88:966-970. Millar AW and Lynch KP (2003) Rethinking clinical trials for cytostatic drugs. Nat Rev Cancer 3:540-545. Mitsunobu M, Toyosaka A, Oriyama T, Okamoto E and Nakao N (1996) Intrahepatic metastases in hepatocellular carcinoma: the role of the portal vein as an efferent vessel. Clin Exp Metastasis 14:520-529. Morgan DO (1995) Principles of CDK regulation. Nature 374:131-134. Mueller MM and Fusenig NE (2004) Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839-849. Mulsch A, Bauersachs J, Schafer A, Stasch JP, Kast R and Busse R (1997) Effect of YC-1, an NO-independent, superoxide-sensitive stimulator of soluble guanylyl cyclase, on smooth muscle responsiveness to nitrovasodilators. Br J Pharmacol 120:681-689. Nguyen HL, Chari S, Gruber D, Lue CM, Chapin SJ and Bulinski JC (1997) Overexpression of full- or partial-length MAP4 stabilizes microtubules and alters cell growth. J Cell Sci 110 ( Pt 2):281-294. Nogales E (2000) Structural insights into microtubule function. Annu Rev Biochem 69:277-302. Okada H and Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4:592-603. Ossowski L, Russo-Payne H and Wilson EL (1991) Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse. Cancer Res 51:274-281. Overall CM and Lopez-Otin C (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2:657-672. Owa T, Yoshino H, Yoshimatsu K and Nagasu T (2001) Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents. Curr Med Chem 8:1487-1503. Pan SL, Guh JH, Chang YL, Kuo SC, Lee FY and Teng CM (2004) YC-1 prevents sodium nitroprusside-mediated apoptosis in vascular smooth muscle cells. Cardiovasc Res 61:152-158. Parkin DM, Pisani P and Ferlay J (1999) Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 80:827-841. Peruzzi B and Bottaro DP (2006) Targeting the c-Met signaling pathway in cancer. Clin Cancer Res 12:3657-3660. Pines J (1991) Cyclins: wheels within wheels. Cell Growth Differ 2:305-310. Ploug M, Ostergaard S, Gardsvoll H, Kovalski K, Holst-Hansen C, Holm A, Ossowski L and Dano K (2001) Peptide-derived antagonists of the urokinase receptor. affinity maturation by combinatorial chemistry, identification of functional epitopes, and inhibitory effect on cancer cell intravasation. Biochemistry 40:12157-12168. Polster BM, Basanez G, Etxebarria A, Hardwick JM and Nicholls DG (2005) Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem 280:6447-6454. Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P and Massague J (1994) Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:59-66. Riedl SJ and Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897-907. Romer J, Nielsen BS and Ploug M (2004) The urokinase receptor as a potential target in cancer therapy. Curr Pharm Des 10:2359-2376. Russell P and Nurse P (1986) cdc25+ functions as an inducer in the mitotic control of fission yeast. Cell 45:145-153. Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7:737-749. Salvi A, Arici B, De Petro G and Barlati S (2004) Small interfering RNA urokinase silencing inhibits invasion and migration of human hepatocellular carcinoma cells. Mol Cancer Ther 3:671-678. Sawyers C (2004) Targeted cancer therapy. Nature 432:294-297. Schmit TL and Ahmad N (2007) Regulation of mitosis via mitotic kinases: new opportunities for cancer management. Mol Cancer Ther 6:1920-1931. Scholzen T and Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182:311-322. Setyono-Han B, Sturzebecher J, Schmalix WA, Muehlenweg B, Sieuwerts AM, Timmermans M, Magdolen V, Schmitt M, Klijn JG and Foekens JA (2005) Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1. Thromb Haemost 93:779-786. Sherr CJ (2000) The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 60:3689-3695. Sherr CJ and Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149-1163. Shiota G, Okano J, Kawasaki H, Kawamoto T and Nakamura T (1995) Serum hepatocyte growth factor levels in liver diseases: clinical implications. Hepatology 21:106-112. Sidenius N and Blasi F (2003) The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 22:205-222. Sliva D (2004) Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. Curr Cancer Drug Targets 4:327-336. Sordat B, Reiter L and Cajot JF (1990) Modulation of the malignant phenotype with the urokinase-type plasminogen activator and the type I plasminogen activator inhibitor. Cell Differ Dev 32:277-285. Sperl S, Jacob U, Arroyo de Prada N, Sturzebecher J, Wilhelm OG, Bode W, Magdolen V, Huber R and Moroder L (2000) (4-aminomethyl)phenylguanidine derivatives as nonpeptidic highly selective inhibitors of human urokinase. Proc Natl Acad Sci U S A 97:5113-5118. Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS and Longo DL (1998) Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol Cell Biol 18:3509-3517. Stewart ZA, Westfall MD and Pietenpol JA (2003) Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci 24:139-145. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM and Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441-446. Turk B (2006) Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov 5:785-799. Ueki T, Fujimoto J, Suzuki T, Yamamoto H and Okamoto E (1997) Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinoma. Hepatology 25:862-866. Ushiro S, Ono M, Nakayama J, Fujiwara T, Komatsu Y, Sugimachi K and Kuwano M (1997) New nortriterpenoid isolated from anti-rheumatoid arthritic plant, Tripterygium wilfordii, modulates tumor growth and neovascularization. Int J Cancer 72:657-663. Vermeulen K, Van Bockstaele DR and Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131-149. Vidal A and Koff A (2000) Cell-cycle inhibitors: three families united by a common cause. Gene 247:1-15. Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A and Santoro M (2002) Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8:1136-1144. Wallon G, Rappsilber J, Mann M and Serrano L (2000) Model for stathmin/OP18 binding to tubulin. Embo J 19:213-222. Wu CC, Ko FN, Kuo SC, Lee FY and Teng CM (1995) YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase. Br J Pharmacol 116:1973-1978. Wu CH, Chang WC, Chang GY, Kuo SC and Teng CM (2004) The inhibitory mechanism of YC-1, a benzyl indazole, on smooth muscle cell proliferation: an in vitro and in vivo study. J Pharmacol Sci 94:252-260. Wyllie AH, Kerr JF and Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251-306. Xia Y, Yang ZY, Xia P, Hackl T, Hamel E, Mauger A, Wu JH and Lee KH (2001) Antitumor Agents. 211. Fluorinated 2-phenyl-4-quinolone derivatives as antimitotic antitumor agents. J Med Chem 44:3932-3936. Xing RH, Mazar A, Henkin J and Rabbani SA (1997) Prevention of breast cancer growth, invasion, and metastasis by antiestrogen tamoxifen alone or in combination with urokinase inhibitor B-428. Cancer Res 57:3585-3593. Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, Chen DS and Chen CJ (2002) Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 347:168-174. Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS and Park JW (2003) YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 95:516-525. Yu C, Rahmani M, Dai Y, Conrad D, Krystal G, Dent P and Grant S (2003) The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process. Cancer Res 63:1822-1833. Zhu M, Gokhale VM, Szabo L, Munoz RM, Baek H, Bashyam S, Hurley LH, Von Hoff DD and Han H (2007) Identification of a novel inhibitor of urokinase-type plasminogen activator. Mol Cancer Ther 6:1348-1356. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27488 | - |
dc.description.abstract | 肝細胞癌是對現有化學治療藥物具有高度抗藥性的癌症,肝癌細胞周圍有許多間質細胞,這些間質細胞會釋放許多生長因子與蛋白溶解酵素協同肝癌細胞破壞細胞外基質,導致肝細胞癌具有高度侵襲的能力,造成肝細胞癌惡化時對於肝臟內部血管的侵潤及後續致命的轉移。在本論文中,將探索具有研發潛力抑制肝細胞癌生長及侵襲的抗癌藥物,並對其作用機轉進行探討。
第一部分主要討論2-phenyl-4-quinolone類化合物CHM-1在動物體內及體外模式抑制人類肝癌細胞生長的作用機轉。我們發現CHM-1具有強效且選擇性的抗癌活性,可經由對微小管聚合作用的抑制及Cdc2/cyclinB1 complex的活化而造成細胞週期之mitotic arrest,導致肝癌細胞的凋亡作用。此外,CHM-1可透過與caspase不相關的機制協同誘發細胞凋亡。在動物實驗中,CHM-1可以有效抑制動物腫瘤的生長,並延長實驗動物的生命週期,而且CHM-1與doxorubicin比較時具有較強的抗癌效果及較少的副作用。以上實驗證明CHM-1是個具有潛力的先導藥物,值得後續的研發與應用於肝細胞癌的治療。 第二部分主要討論CHM-1抑制肝細胞生長因子誘發人類肝癌細胞侵襲的作用與機轉。肝細胞生長因子可以活化c-Met受體誘發人類肝癌細胞SK-Hep-1的侵襲作用,我們發現CHM-1可以抑制c-Met受體tyrosine kinase的磷酸化,使Akt蛋白及NF-kB轉錄因子的活化被抑制,進而阻斷下游MMP-9的表現與活性,最後抑制肝癌細胞的侵襲作用。因此,CHM-1對肝細胞癌具有多方面的功能抑制,在未來的應用相當廣泛。 第三部分主要討論石斛萃取物moscatilin抑制人類肝癌細胞侵襲作用的機轉。我們發現moscatilin可以在細胞正常培養條件下抑制高侵襲性人類肝癌細胞SK-Hep-1的侵襲作用,moscatilin不影響細胞中MMP-2及MMP-9的活性,乃是透過破壞蛋白溶解酵素uPA的表現與活性來抑制肝癌細胞的侵襲,而此作用可能是阻斷PI3K/Akt訊息傳遞路徑所致。 Moscatilin是天然的萃取成分,可經由後續的結構修飾來加強抗癌活性及選擇性。我們認為moscatilin是相當值得未來開發及應用的成分。 第四部分主要討論benzyl-indazole類化合物YC-1抑制人類肝癌細胞增生的作用及機轉。實驗結果顯示,YC-1可以抑制肝癌細胞的生長,此作用乃是透過對於增生的抑制、而非對細胞的毒殺作用。研究發現,YC-1抑制增生的作用與cGMP訊息傳遞機制無關,乃是透過增加 p21蛋白的表現,促使細胞週期停留在G0/G1 期來調控對肝癌細胞增生的抑制作用。此外,YC-1可呈劑量相關性地抑制動物腫瘤的生長,顯示YC-1具有相當不錯的抗癌活性,有機會發展成為臨床肝細胞癌治療的藥物。 | zh_TW |
dc.description.abstract | Hepatocellular carcinoma (HCC) is highly chemoresistant to currently available chemotherapeutic agents. HCC cells are surrounded by stroma cells in liver, the tumor-stroma interactions can produce a lot of growth factors and proteases to degrade extracellular matrix in tumor microenvironment. Thus, invasion is a characteristic of HCC cells, which frequently show early invasion into blood vessels as well as intrahepatic metastasis and extrahepatic metastasis occurs subsequently. The present study is focused on the discovery of novel small-molecule agents to inhibit cell growth and invasion of human HCC cells.
The first part is to investigate the antitumor activity and mechanism of CHM-1, a 2-phenyl-4-quinolone derivative, in human HCC cells. CHM-1 induces mitotic arrest and apoptosis by binding to tubulin and inhibiting tubulin polymerization. CHM-1 causes mitotic arrest, at least partly, by modulating Cdc2/cyclin B1 complex activity and then apoptosis executed by a caspase-independent pathway. Importantly, CHM-1 inhibited tumor growth and prolonged the life span in mice inoculated with HA22T cells. CHM-1 is a promising chemotherapeutic lead compound worthy of further development into a drug candidate for treating cancer, especially HCC. The second part is to evaluate the anti-invasive effects and mechanism of CHM-1 in hepatocyte growth factor (HGF)-induced invasion of SK-Hep-1 human HCC cells. We found that HGF stimulated invasion of SK-Hep-1 cells, together with increased expression of matrix metalloproteinase (MMP)-9. CHM-1 significantly inhibited tyrosine autophosphorylation of c-Met induced by HGF. CHM-1 also suppressed HGF-induced Akt phosphorylation, and NF-kB activation, the downstream regulators of HGF/c-Met signaling, resulting in the inhibition of MMP-9. Based on the findings herein, we suggest that CHM-1 could be effective candidate for prevention of HCC cell invasion associated with the HGF/c-Met system. The third part is to study the anti-invasive mechanism of moscatilin in highly invasive human HCC cells SK-Hep-1. Moscatilin is a bibenzyl derivative extracted from the stems of a traditional Chinese medicine, Orchid Dendrobrium loddigesii. We found moscatilin significantly inhibited cell invasion in a concentration-dependent manner. Moscatilin did not affect the proteolytic activity of MMP-2 and MMP-9 in SK-Hep-1 cells. However, Moscatilin inhibited the enzyme activity and protein expression of urokinase-type plasminogen activator (uPA). We further demonstrated that anti-invasive activity of moscatilin may be through the selective suppression of uPA regulated PI3K/Akt signal transduction. Thus, we suggest that moscatilin is a potential therapeutic agent against tumor invasion. The fourth part is to investigate the antiproliferative mechanism of YC-1 in human HCC cells. This study is the first to delineate that YC-1 directly inhibits proliferation of cancer cells. YC-1 inhibited the growth of human HCC cells in a concentration-dependent manner without significant cytotoxicity. We demonstrated that YC-1-induced antiproliferative effect is a cGMP-independent pathway. YC-1 induced Go/G1 arrest and inhibited tumor growth both in vitro and in vivo via the up-regulation of p21 expression. As a cytostatic agent, YC-1 slows the proliferation of cancer cells, while causing low toxicity to normal cells and allowing patients to “live with their cancer”. Used alone or in combination with other chemotherapeutic agents, YC-1 deserves further investigation in preclinical studies or clinical trial as a potential antitumor agent. | en |
dc.description.provenance | Made available in DSpace on 2021-06-12T18:06:55Z (GMT). No. of bitstreams: 1 ntu-96-D91443006-1.pdf: 5729916 bytes, checksum: 7dd31f494501bc6cc51d4f5dc68c4ed5 (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 縮寫表-1
中文摘要-3 英文摘要-5 第一章 緒論-9 研究動機與目的-11 文獻回顧-13 實驗材料與方法-32 第二章 CHM-1於體內及體外抑制人類肝癌細胞生長之作用機轉探討-43 緒言-45 材料與方法-47 結果-48 討論-53 第三章 CHM-1抑制肝細胞生長因子誘發人類肝癌細胞侵襲之作用與機轉-73 緒言-75 材料與方法-77 結果-78 討論-80 第四章 石斛成分moscatilin抑制人類肝癌細胞侵襲之作用機轉探討-93 緒言-95 材料與方法-97 結果-98 討論-100 第五章 YC-1抑制人類肝癌細胞增生之作用機轉探討-111 緒言-113 材料與方法-115 結果-116 討論-119 第六章 結論與展望-135 參考文獻-141 著作-152 | |
dc.language.iso | zh-TW | |
dc.title | CHM-1, Moscatilin及YC-1對人類肝癌細胞之抗癌作用及機轉研究 | zh_TW |
dc.title | The Anti-Cancer Mechanisms of CHM-1, Moscatilin and YC-1 in Human Hepatocellular Carcinoma Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 黃德富,顧記華,楊春茂,顏茂雄 | |
dc.subject.keyword | 肝細胞癌,微小管標的藥物,細胞凋亡,侵襲作用, | zh_TW |
dc.subject.keyword | HCC, microtubule-targeted agent,apoptosis,invasion, | en |
dc.relation.page | 151 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-12-28 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
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