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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 蘇銘嘉(Ming-Jai Su) | |
dc.contributor.author | Yi-Fan Yang | en |
dc.contributor.author | 楊怡凡 | zh_TW |
dc.date.accessioned | 2021-06-13T17:00:34Z | - |
dc.date.available | 2011-10-07 | |
dc.date.copyright | 2011-10-07 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-07-14 | |
dc.identifier.citation | Adams JM, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol 19:488-96
Akduman B, Crawford ED (2001) Terazosin, doxazosin, and prazosin: current clinical experience. Urology 58:49-54 ALLHAT Collaborative Research Group (2000) Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Jama 283:1967-75 Amann T, Hellerbrand C (2009) GLUT1 as a therapeutic target in hepatocellular carcinoma. Expert Opin Ther Targets 13:1411-27 Anglin IE, Glassman DT, Kyprianou N (2002) Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component. Prostate Cancer Prostatic Dis 5:88-95 Balaburski GM, Hontz RD, Murphy ME (2010) p53 and ARF: unexpected players in autophagy. Trends Cell Biol 20:363-9 Barth S, Glick D, Macleod KF (2010) Autophagy: assays and artifacts. J Pathol 221:117-24 Benning CM, Kyprianou N (2002) Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action. Cancer Res 62:597-602 Bobik A (2006) Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol 26:1712-20 Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T and others (2005) Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 25:1025-40 Brady CA, Attardi LD (2010) p53 at a glance. J Cell Sci 123:2527-32 Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74:184-95 Burman C, Ktistakis NT (2010) Autophagosome formation in mammalian cells. Semin Immunopathol 32:397-413 Bursch W, Ellinger A (2005) Autophagy--a basic mechanism and a potential role for neurodegeneration. Folia Neuropathol 43:297-310 Bursch W, Hochegger K, Torok L, Marian B, Ellinger A, Hermann RS (2000) Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci 113 ( Pt 7):1189-98 Calderone A, Abdelaziz N, Colombo F, Schreiber KL, Rindt H (2000) A farnesyltransferase inhibitor attenuates cardiac myocyte hypertrophy and gene expression. J Mol Cell Cardiol 32:1127-40 Cao Y, Klionsky DJ (2007) Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein. Cell Res 17:839-49 Caporali S, Alvino E, Starace G, Ciomei M, Brasca MG, Levati L, Garbin A, Castiglia D, Covaciu C, Bonmassar E and others (2010) The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound. Pharmacol Res 61:437-48 Chaudhury A, Howe PH (2009) The tale of transforming growth factor-beta (TGFbeta) signaling: a soigne enigma. IUBMB Life 61:929-39 Chen N, Debnath J (2010) Autophagy and tumorigenesis. FEBS Lett 584:1427-35 Chen N, Karantza V (2011) Autophagy as a therapeutic target in cancer. Cancer Biol Ther 11:157-68 Chon JK, Borkowski A, Partin AW, Isaacs JT, Jacobs SC, Kyprianou N (1999) Alpha 1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia. J Urol 161:2002-8 Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH and others (1986) Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 314:1547-52 Corcelle EA, Puustinen P, Jaattela M (2009) Apoptosis and autophagy: Targeting autophagy signalling in cancer cells -'trick or treats'? Febs J 276:6084-96 de Caestecker M (2004) The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev 15:1-11 de la Cruz-Merino L, Henao-Carrasco F, Garcia-Manrique T, Fernandez-Salguero PM, Codes-Manuel de Villena M (2009) Role of transforming growth factor beta in cancer microenvironment. Clin Transl Oncol 11:715-20 De Meyer GR, Martinet W (2009) Autophagy in the cardiovascular system. Biochim Biophys Acta 1793:1485-95 Deretic V (2010) Autophagy in infection. Curr Opin Cell Biol 22:252-62 Derynck R, Akhurst RJ (2007) Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol 9:1000-4 Eiras S, Fernandez P, Pineiro R, Iglesias MJ, Gonzalez-Juanatey JR, Lago F (2006) Doxazosin induces activation of GADD153 and cleavage of focal adhesion kinase in cardiomyocytes en route to apoptosis. Cardiovasc Res 71:118-28 Euler-Taimor G, Heger J (2006) The complex pattern of SMAD signaling in the cardiovascular system. Cardiovasc Res 69:15-25 Feng Z, Levine AJ (2010) The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 20:427-34 Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102:8204-9 Frick MH, Halttunen P, Himanen P, Huttunen M, Porsti P, Pitkajarvi T, Poyhonen L, Pyykonen ML, Reinikainen P, Salmela P and others (1986) A long-term double-blind comparison of doxazosin and atenolol in patients with mild to moderate essential hypertension. Br J Clin Pharmacol 21 Suppl 1:55S-62S Galluzzi L, Morselli E, Vicencio JM, Kepp O, Joza N, Tajeddine N, Kroemer G (2008) Life, death and burial: multifaceted impact of autophagy. Biochem Soc Trans 36:786-90 Garrison JB, Kyprianou N (2006) Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptor-mediated pathway. Cancer Res 66:464-72 Germain M, Slack RS (2010) Dining in with BCL-2: new guests at the autophagy table. Clin Sci (Lond) 118:173-81 Gonzalez-Juanatey JR, Iglesias MJ, Alcaide C, Pineiro R, Lago F (2003) Doxazosin induces apoptosis in cardiomyocytes cultured in vitro by a mechanism that is independent of alpha1-adrenergic blockade. Circulation 107:127-31 Gonzalez-Polo RA, Boya P, Pauleau AL, Jalil A, Larochette N, Souquere S, Eskelinen EL, Pierron G, Saftig P, Kroemer G (2005) The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death. J Cell Sci 118:3091-102 Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891-906 Grainger DJ (2007) TGF-beta and atherosclerosis in man. Cardiovasc Res 74:213-22 Grygielko ET, Martin WM, Tweed C, Thornton P, Harling J, Brooks DP, Laping NJ (2005) Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther 313:943-51 Gump JM, Thorburn A (2011) Autophagy and apoptosis: what is the connection? Trends Cell Biol In Press Gustafsson AB, Gottlieb RA (2009) Autophagy in ischemic heart disease. Circ Res 104:150-8 He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67-93 Hermonat PL, Li D, Yang B, Mehta JL (2007) Mechanism of action and delivery possibilities for TGFbeta1 in the treatment of myocardial ischemia. Cardiovasc Res 74:235-43 Hotchkiss RS, Strasser A, McDunn JE, Swanson PE (2009) Cell death. N Engl J Med 361:1570-83 Hussein AM, Ahmed OM (2010) Regioselective one-pot synthesis and anti-proliferative and apoptotic effects of some novel tetrazolo[1,5-a]pyrimidine derivatives. Bioorg Med Chem 18:2639-44 Ihara T, Yamamoto T, Sugamata M, Okumura H, Ueno Y (1998) The process of ultrastructural changes from nuclei to apoptotic body. Virchows Arch 433:443-7 Ilio KY, Park, II, Pins MR, Kozlowski JM, Lee C (2001) Apoptotic activity of doxazosin on prostate stroma in vitro is mediated through an autocrine expression of TGF-beta1. Prostate 48:131-5 Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB (2007) Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 25:209-26 Javelaud D, Mauviel A (2004) Mammalian transforming growth factor-betas: Smad signaling and physio-pathological roles. Int J Biochem Cell Biol 36:1161-5 Javelaud D, Mauviel A (2005) Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene 24:5742-50 Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283-93 Kang JS, Liu C, Derynck R (2009) New regulatory mechanisms of TGF-beta receptor function. Trends Cell Biol 19:385-94 Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, Fujii T, Komuro A, Kiyono K, Kaminishi M and others (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc Natl Acad Sci U S A 104:3460-5 Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, Kockel L (2010) With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 11:453-65 Kassiotis C, Ballal K, Wellnitz K, Vela D, Gong M, Salazar R, Frazier OH, Taegtmeyer H (2009) Markers of autophagy are downregulated in failing human heart after mechanical unloading. Circulation 120:S191-7 Katsuno M, Adachi H, Banno H, Suzuki K, Tanaka F, Sobue G (2011) Transforming growth factor-beta signaling in motor neuron diseases. Curr Mol Med 11:48-56 Keledjian K, Borkowski A, Kim G, Isaacs JT, Jacobs SC, Kyprianou N (2001) Reduction of human prostate tumor vascularity by the alpha1-adrenoceptor antagonist terazosin. Prostate 48:71-8 Keledjian K, Garrison JB, Kyprianou N (2005) Doxazosin inhibits human vascular endothelial cell adhesion, migration, and invasion. J Cell Biochem 94:374-88 Kelly RJ, Morris JC (2010) Transforming growth factor-beta: a target for cancer therapy. J Immunotoxicol 7:15-26 Khan R, Agrotis A, Bobik A (2007) Understanding the role of transforming growth factor-beta1 in intimal thickening after vascular injury. Cardiovasc Res 74:223-34 Kim R, Emi M, Tanabe K (2005) Caspase-dependent and -independent cell death pathways after DNA damage (Review). Oncol Rep 14:595-9 Kintscher U, Wakino S, Kim S, Jackson SM, Fleck E, Hsueh WA, Law RE (2000) Doxazosin inhibits retinoblastoma protein phosphorylation and G(1)-->S transition in human coronary smooth muscle cells. Arterioscler Thromb Vasc Biol 20:1216-24 Kirby RS, Pool JL (1997) Alpha adrenoceptor blockade in the treatment of benign prostatic hyperplasia: past, present and future. Br J Urol 80:521-32 Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931-7 Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, Baba M, Baehrecke EH, Bahr BA, Ballabio A and others (2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:151-75 Korolchuk VI, Rubinsztein DC (2011) Regulation of autophagy by lysosomal positioning. Autophagy 7 Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR and others (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16:3-11 Kyprianou N, Vaughan TB, Michel MC (2009) Apoptosis induction by doxazosin and other quinazoline alpha1-adrenoceptor antagonists: a new mechanism for cancer treatment? Naunyn Schmiedebergs Arch Pharmacol 380:473-7 Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J and others (2002) Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol 62:58-64 Lee AS, Su MJ (2008) Comparison of the cardiac effects between quinazoline-based alpha1-adrenoceptor antagonists on occlusion-reperfusion injury. J Biomed Sci 15:239-49 Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9:749-58 Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4:600-6 Levy JM, Thorburn A (2011) Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacol Ther 131:130-41 Liao CH, Guh JH, Chueh SC, Yu HJ (2011) Anti-angiogenic effects and mechanism of prazosin. Prostate 71:976-84 Lin SC, Chueh SC, Hsiao CJ, Li TK, Chen TH, Liao CH, Lyu PC, Guh JH (2007) Prazosin displays anticancer activity against human prostate cancers: targeting DNA and cell cycle. Neoplasia 9:830-9 Maddocks OD, Vousden KH (2011) Metabolic regulation by p53. J Mol Med 89:237-45 Maiuri MC, Galluzzi L, Morselli E, Kepp O, Malik SA, Kroemer G (2010) Autophagy regulation by p53. Curr Opin Cell Biol 22:181-5 Marques G (2005) Morphogens and synaptogenesis in Drosophila. J Neurobiol 64:417-34 Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753-91 Massague J (2008) TGFbeta in Cancer. Cell 134:215-30 Massague J, Chen YG (2000) Controlling TGF-beta signaling. Genes Dev 14:627-44 Mehrpour M, Esclatine A, Beau I, Codogno P (2010a) Autophagy in health and disease. 1. Regulation and significance of autophagy: an overview. Am J Physiol Cell Physiol 298:C776-85 Mehrpour M, Esclatine A, Beau I, Codogno P (2010b) Overview of macroautophagy regulation in mammalian cells. Cell Res 20:748-62 Meulmeester E, Ten Dijke P (2011) The dynamic roles of TGF-beta in cancer. J Pathol 223:205-18 Mizushima N, Yoshimori T (2007) How to interpret LC3 immunoblotting. Autophagy 3:542-5 Moretti L, Cha YI, Niermann KJ, Lu B (2007) Switch between apoptosis and autophagy: radiation-induced endoplasmic reticulum stress? Cell Cycle 6:793-8 Moustakas A, Heldin CH (2009) The regulation of TGFbeta signal transduction. Development 136:3699-714 Mulder KM (2000) Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev 11:23-35 Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K (2009) The role of autophagy in the heart. Cell Death Differ 16:31-8 Noda T, Fujita N, Yoshimori T (2009) The late stages of autophagy: how does the end begin? Cell Death Differ 16:984-90 Pardali E, Goumans MJ, ten Dijke P (2010) Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20:556-67 Partin JV, Anglin IE, Kyprianou N (2003) Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction. Br J Cancer 88:1615-21 Patterson GI, Padgett RW (2000) TGF beta-related pathways. Roles in Caenorhabditis elegans development. Trends Genet 16:27-33 Petersen M, Thorikay M, Deckers M, van Dinther M, Grygielko ET, Gellibert F, de Gouville AC, Huet S, ten Dijke P, Laping NJ (2008) Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int 73:705-15 Poels J, Spasic MR, Callaerts P, Norga KK (2009) Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. Bioessays 31:944-52 Rami A, Kogel D (2008) Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin? Autophagy 4:422-6 Reers M, Smiley ST, Mottola-Hartshorn C, Chen A, Lin M, Chen LB (1995) Mitochondrial membrane potential monitored by JC-1 dye. Methods Enzymol 260:406-17 Roberts AB, Tian F, Byfield SD, Stuelten C, Ooshima A, Saika S, Flanders KC (2006) Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev 17:19-27 Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A 100:8621-3 Rodriguez-Feo JA, Fortes J, Aceituno E, Farre J, Ayala R, Castilla C, Rico L, Gonzalez-Fernandez F, Garcia-Duran M, Casado S and others (2000) Doxazosin modifies Bcl-2 and Bax protein expression in the left ventricle of spontaneously hypertensive rats. J Hypertens 18:307-15 Rojas Gomez DM, Schulte JS, Mohr FW, Dhein S (2008) Alpha-1-adrenoceptor subtype selective regulation of connexin 43 expression in rat cardiomyocytes. Naunyn Schmiedebergs Arch Pharmacol 377:77-85 Rosenfeldt MT, Ryan KM (2011) The multiple roles of autophagy in cancer. Carcinogenesis In Press Rothermel BA, Hill JA (2008) Autophagy in load-induced heart disease. Circ Res 103:1363-9 Ruiz-Ortega M, Rodriguez-Vita J, Sanchez-Lopez E, Carvajal G, Egido J (2007) TGF-beta signaling in vascular fibrosis. Cardiovasc Res 74:196-206 Ryan KM (2011) p53 and autophagy in cancer: Guardian of the genome meets guardian of the proteome. Eur J Cancer 47:44-50 Sakamoto S, Schwarze S, Kyprianou N (2011) Anoikis disruption of focal adhesion-akt signaling impairs renal cell carcinoma. Eur Urol 59:734-44 Salminen A, Kaarniranta K (2009) Regulation of the aging process by autophagy. Trends Mol Med 15:217-24 Sanchez-Capelo A (2005) Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev 16:15-34 Sandri M (2010) Autophagy in health and disease. 3. Involvement of autophagy in muscle atrophy. Am J Physiol Cell Physiol 298:C1291-7 Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596-603 Schiller M, Javelaud D, Mauviel A (2004) TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 35:83-92 Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64:2627-33 Sciarretta S, Hariharan N, Monden Y, Zablocki D, Sadoshima J (2011) Is Autophagy in Response to Ischemia and Reperfusion Protective or Detrimental for the Heart? Pediatr Cardiol 32:275-81 Shaw RJ (2009) LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 196:65-80 Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685-700 Sinha S, Levine B (2009) The autophagy effector Beclin 1: a novel BH3-only protein. Oncogene 27 Suppl 1:S137-48 Soderberg SS, Karlsson G, Karlsson S (2009) Complex and context dependent regulation of hematopoiesis by TGF-beta superfamily signaling. Ann N Y Acad Sci 1176:55-69 Sui X, Jin L, Huang X, Geng S, He C, Hu X (2011) p53 signaling and autophagy in cancer: A revolutionary strategy could be developed for cancer treatment. Autophagy 7 Sun HY, Wang NP, Halkos M, Kerendi F, Kin H, Guyton RA, Vinten-Johansen J, Zhao ZQ (2006) Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis 11:1583-93 Tahmatzopoulos A, Kyprianou N (2004) Apoptotic impact of alpha1-blockers on prostate cancer growth: a myth or an inviting reality? Prostate 59:91-100 Tahmatzopoulos A, Rowland RG, Kyprianou N (2004) The role of alpha-blockers in the management of prostate cancer. Expert Opin Pharmacother 5:1279-85 Taimor G, Schluter KD, Frischkopf K, Flesch M, Rosenkranz S, Piper HM (1999) Autocrine regulation of TGF beta expression in adult cardiomyocytes. J Mol Cell Cardiol 31:2127-36 Takemura G, Kanamori H, Goto K, Maruyama R, Tsujimoto A, Fujiwara H, Seishima M, Minatoguchi S (2009) Autophagy maintains cardiac function in the starved adult. Autophagy 5:1034-6 Thomas D, Bloehs R, Koschny R, Ficker E, Sykora J, Kiehn J, Schlomer K, Gierten J, Kathofer S, Zitron E and others (2008) Doxazosin induces apoptosis of cells expressing hERG K(+) channels. Eur J Pharmacol 579:98-103 Thomas D, Wimmer AB, Wu K, Hammerling BC, Ficker EK, Kuryshev YA, Kiehn J, Katus HA, Schoels W, Karle CA (2004) Inhibition of human ether-a-go-go-related gene potassium channels by alpha 1-adrenoceptor antagonists prazosin, doxazosin, and terazosin. Naunyn Schmiedebergs Arch Pharmacol 369:462-72 Traganos F, Darzynkiewicz Z (1994) Lysosomal proton pump activity: supravital cell staining with acridine orange differentiates leukocyte subpopulations. Methods Cell Biol 41:185-94 Tsuchihara K, Fujii S, Esumi H (2009) Autophagy and cancer: dynamism of the metabolism of tumor cells and tissues. Cancer Lett 278:130-8 Tsujimoto Y, Shimizu S (2005) Another way to die: autophagic programmed cell death. Cell Death Differ 12 Suppl 2:1528-34 Varga J, Pasche B (2008) Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis. Curr Opin Rheumatol 20:720-8 Vicencio JM, Galluzzi L, Tajeddine N, Ortiz C, Criollo A, Tasdemir E, Morselli E, Ben Younes A, Maiuri MC, Lavandero S and others (2008) Senescence, apoptosis or autophagy? When a damaged cell must decide its path--a mini-review. Gerontology 54:92-9 Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691-700 Walden PD, Globina Y, Nieder A (2004) Induction of anoikis by doxazosin in prostate cancer cells is associated with activation of caspase-3 and a reduction of focal adhesion kinase. Urol Res 32:261-5 Wang W, Guan KL (2009) AMP-activated protein kinase and cancer. Acta Physiol (Oxf) 196:55-63 Watanabe E, Muenzer JT, Hawkins WG, Davis CG, Dixon DJ, McDunn JE, Brackett DJ, Lerner MR, Swanson PE, Hotchkiss RS (2009) Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study. Lab Invest 89:549-61 Wipff PJ, Hinz B (2008) Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship. Eur J Cell Biol 87:601-15 Worthington JJ, Klementowicz JE, Travis MA (2011) TGFbeta: a sleeping giant awoken by integrins. Trends Biochem Sci 36:47-54 Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9:1102-9 Yan L, Sadoshima J, Vatner DE, Vatner SF (2009) Autophagy in ischemic preconditioning and hibernating myocardium. Autophagy 5:709-12 Yang YF, Wu CC, Chen WP, Su MJ (2009) Transforming growth factor-beta type I receptor/ALK5 contributes to doxazosin-induced apoptosis in H9C2 cells. Naunyn Schmiedebergs Arch Pharmacol 380:561-7 Zhang XD, Qin ZH, Wang J (2010) The role of p53 in cell metabolism. Acta Pharmacol Sin 31:1208-12 Zhao H, Lai F, Nonn L, Brooks JD, Peehl DM (2005) Molecular targets of doxazosin in human prostatic stromal cells. Prostate 62:400-10 Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21-35 Zong WX, Moll U (2008) p53 in autophagy control. Cell Cycle 7:2947 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/39073 | - |
dc.description.abstract | Quinazoline類α1-腎上腺素受體拮抗劑最初是開發用於高血壓治療的藥物,然而許多的臨床試驗結果顯示,這類藥物如Prazosin及Doxazosin,用於心臟衰竭病人時會增加突發性心血管疾病及死亡的風險。因此,Quinazoline類α1-腎上腺素受體拮抗劑目前已不再被視為第一線的心血管疾病用藥,但這類藥物仍被廣泛的運用在良性攝護腺肥大(benign prostate hyperplasia, BPH)的治療上。此外,這類藥物所特有的與α1-腎上腺素受體拮抗無關之細胞毒性作用已有許多相關的研究及報告。
在本研究中,我們以H9C2小鼠心肌母細胞株作為實驗模型並分析Quinazoline類α1-腎上腺素受體拮抗劑之中參與細胞毒性的分子機制。研究結果顯示,在我們所測試的四種Quinazoline類α1-腎上腺素受體拮抗劑(Prazosin, Doxazosin, Terazosin及Bunazosin)中,只有Peazosin及Doxazosin對H9C2具有明顯的細胞毒性。在後續針對Prazosin及Doxazosin的研究,我們發現了兩種全然不同的分子機制分別參與了Prazosin及Doxazosin所引起的細胞死亡過程。 在Doxazosin引起細胞死亡研究中,我們發現transforming growth factor-β(TGF-β)第一型受體(TβRI/ALK5)參與了Doxazosin所引發的H9C2細胞凋亡。經由測定細胞存活率、凋亡之細胞核及caspase-3的活性,我們發現Doxazosin可以引起濃度及時間相關性的H9C2細胞凋亡,且在10 ng/ml的TGF-β1存在下,30 μM Doxazosin所引發的H9C2細胞凋亡現象被明顯的加強。H9C2細胞以Doxazosin處理時,其p38 MAPK的蛋白質磷酸化被顯著的提升,若以TGF-β1處理時,則Smad3的蛋白質磷酸化被顯著的提升。然而,同時以Doxazosin及TGF-β1處理H9C2細胞時,TGF-β1所引起的Smad3的蛋白質磷酸化被顯著的減少,而Doxazosin所引起的p38 MAPK蛋白質磷酸化被顯著的增加。此外,TβRI/ALK5的抑制劑(SB431542)、p38 MAPK的抑制劑(SB202190)及TβRI/ALK5的knockdown都可以明顯的減少Doxazosin在H9C2細胞所引起的細胞凋亡現象。我們於是歸納出TβRI/ALK5-p38 MAPK蛋白質磷酸化的細胞信息傳遞路徑參與了Doxazosin在H9C2細胞所引起的細胞凋亡現象,此路徑可經由TGF-β1相關的Smad3蛋白質磷酸化降低而進一步被加強。 在Prazosin引起細胞死亡的研究中,我們發現Prazosin會在H9C2細胞引發自我吞噬(Autophagy)的現象,包括細胞質中出現空泡(vacuoles)、細胞微小管蛋白質輕鏈(microtubule-associated protein 1 light chain 3, LC3)發生結構改變及細胞內酸性空泡狀胞器(acidic vesicular organelle, AVO)的大量堆積等。經由西方點墨法分析蛋白質磷酸化發現,在prazosin的處理下,p53與AMPK的蛋白質磷酸化程度呈現明顯的增加,相反的mTOR, Akt與p70S6K的蛋白質磷酸化程度則呈現明顯下降的趨勢。此外,雖然在Autophagy抑制劑3-Methyladenine及p53抑制劑Pifithrin-α的前處理下,Prazosin所引發的AVO大量堆積會被明顯抑制,但是Prazosin所引發的細胞死亡作用並無法被阻斷,且Prazosin所引發的caspase-3活化有被加強的現象。基於這些發現,我們推測Prazosin可經由p53的媒介作用引發自我吞噬性細胞死亡(autophagic cell death),而當這個機制被阻斷時,Prazosin仍可轉而加強細胞凋亡路徑中的caspase-3活性,引發細胞死亡。 | zh_TW |
dc.description.abstract | Quinazoline-based α1-adrenoceptor antagonists are drugs initially developed for the treatment of hypertension. However, results from trials reveal that some of them, especially prazosin and doxazosin, are associated with greater mortality and risks of cardiovascular accidents among heart failure patients. Therefore, quinazoline-based α1-adrenoceptor antagonists has no longer been considered as the first-line drug in the treatment of hypertension, but introduced primarily in the treatment of benign prostate hyperplasia (BPH). The α-adrenoceptor blockade-independent cytotoxic effects of these drugs also attract great attentions of researchers.
In present study, we used H9C2 mouse ventricular myoblast cell line as experiment model and attempted to dissect the molecular mechanisms lying in the cytotoxicity of quinazoline-based α1-adrenoceptor antagonists. Our results demonstrated that in the four kinds of quinazoline-based α1-adrenoceptor antagonists we tested (prazosin, doxazosin, treazosin and bunazosin), only prazosin and doxazosin showed significant cytotoxicity to H9C2 cells. In the subsequent analysis focused on prazosin and doxazosin, we identified two distinct molecular mechanisms participated in prazosin- and doxazosin-induced cell death. In doxazosin-induced cell death, we proposed that the transforming growth factor-β type I receptor (TβRI/ALK5) may contribute to the doxazosin-induced apoptosis in H9C2 cardiomyoblasts. Via the detection of cell viability, apoptotic nuclei and caspase-3 activity, we found that doxazosin induced concentration- and time-dependent apoptosis in H9C2 cells. The cell apoptosis induced by 30 μM doxazosin was exacerbated by the addition of 10 ng/ml transforming growth factor-β1 (TGF-β1). Doxazosin or TGF-β1 alone respectively elevated p38 MAPK and Smad3 protein phosphorylation in H9C2 cells. However, the co-treatment of doxazosin and TGF-β1 attenuated the TGF-β1-induced Smad3 protein phosphorylation and increased doxazosin-induced p38 MAPK protein phosphorylation. Furthermore, inhibitors of TβRI/ALK5 (SB431542) and p38 MAPK (SB202190) or TβRI/ALK5 knockdown all dramatically reduced the doxazosin-induced apoptosis in H9C2 cells. We concluded that TβRI/ALK5-p38 MAPK phosphorylation signaling pathway could contribute to doxazosin-induced cell apoptosis, which could be further enhanced by TGF-β1 in association with attenuating Smad3 phosphorylation in H9C2 cells. In prazosin-induced cell death, we found that prazosin could induce patterns of autophagy in H9C2 cells, including formation of intracellular vacuoles, conversion of microtubule-associated protein 1 light chain (LC3) and augmentation of acidic vesicular organelles (AVO). Analysis of phosphorylated proteins by Western blotting revealed that, under the exposure of prazosin, the level of phospho-p53 and phospho-AMPK was increased, where in contrast, phospho-mTOR, phospho-Akt and phospho-p70S6K were dramatically decreased. Furthermore, pretreatment of pharmacological autophagy inhibitor 3-methyladenine and p53 inhibitor pifithrin-α although both suppressed prazosin-induced AVO formation, it did not reverse prazosin-induced decline in cell viability but enhanced prazosin-induced caspase-3 activation. Based on these results we suggest that prazosin induced autophagic cell death via p53-mediated mechanism. When autophagy pathway was blocked, prazosin could still induce programmed cell death, at least in part, through the enhancement of apoptotic caspase-3 cascade. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T17:00:34Z (GMT). No. of bitstreams: 1 ntu-100-D89443005-1.pdf: 2434653 bytes, checksum: c909d40ced512b00d9a963caf880bd46 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 口試委員會審定書 .................................................................................. I
誌謝 ........................................................................................................ II 中文摘要 ............................................................................................... III Abstract ................................................................................................. IV Chapter 1 Introduction ....................................................................... 1 1.1 Quinazoline-based α1-Adrenoceptor Antagonists .............. 2 1.1A Quinazoline-based α1-adrenoceptor antagonists induce α1-adrenoceptor blockade-independent cytotoxicity ...... 2 1.1B Mechanisms involved in the pro-apoptotic effects of quinazoline-based α1-adrenoceptor antagonists .............. 3 1.2 Autophagic Cell Death ....................................................... 6 1.2A Programmed cell death .................................................... 6 1.2B Signaling pathways involved in autophagy ..................... 7 1.2C Multifaceted roles of autophagy in cardiovascular system and cancer ......................................................... 10 1.3 Transforming Growth Factor-β Signaling ........................ 14 1.3A The transforming growth factor-β superfamily ............. 14 1.3B Multifaceted roles of transforming growth factor-β in cardiovascular system and human cancer ..................... 17 1.4 Purpose of Present Study .................................................. 20 Chapter 2 Materials and Methods ................................................... 22 2.1 Chemicals and Reagents ................................................... 23 2.2 Cell Culture ....................................................................... 26 2.2A Culture of cell lines ........................................................ 26 2.2B Preservation of cell lines ................................................ 26 2.2C Primary culture of neonatal rat ventricular cardiomyocytes ............................................................. 27 2.3 GFP-LC3 Transfection ..................................................... 29 2.4 RNA Interference (RNAi) ................................................ 30 2.5 Cell Viability and Apoptosis Assay .................................. 32 2.5A MTT assay ..................................................................... 32 2.5B Apoptosis assay .............................................................. 32 2.6 TGF-β1 Immunoassay ...................................................... 34 2.7 Acridine Orange Staining ................................................. 35 2.8 Transmission Electron Microscopy .................................. 36 2.9 Western Blotting Analysis ................................................ 37 2.10 Analysis of Mitochondrial Membrane Potential by Flow Cytometry ..................................................................... 41 2.11 Data Analysis .................................................................. 42 Chapter 3 Results .............................................................................. 43 3.1 Cytotoxicity of Quinazoline-based α1-Adrenoceptor Antagonists on Cardiomyocytes ...................................... 44 3.2 TGF-β1 and Doxazosin-treated H9C2 Cells ..................... 46 3.2A Effects of TGF-β1 and pharmacological inhibitors on doxazosin-treated H9C2 cells ....................................... 46 3.2B Effects of TβRI/ALK5 Knockdown on Doxazosin-treated Cells ................................................ 48 3.3 Autophagy and Prazosin-treated H9C2 Cells ................... 49 3.3A Prazosin induces autophagic cell death in H9C2 cells ..................................................................... 49 3.3B Effects of prazosin treatment on protein phosphorylation ............................................................ 50 3.3C Effects of pharmacological inhibitors on prazosin-induced autophagy, caspase-3 activity and cell viability ............................................................ 51 3.3D Effects of prazosin on cellular energy status ................. 52 Chapter 4 Discussion ......................................................................... 53 4.1 The Role of TGF-β Signaling in Doxazosin-induced Apoptosis ......................................................................... 54 4.2 The Role of Autophagy in Prazosin-induced Cell Death ........................................................................ 59 4.3 The Perspectives ............................................................... 63 References .............................................................................................. 64 Figures and Tables ............................................................................... 76 Appendix ............................................................................................. 112 | |
dc.language.iso | en | |
dc.title | Quinazoline類α1-腎上腺素受體拮抗劑在培養心肌細胞毒性作用機制之探討 | zh_TW |
dc.title | The Cytotoxic Effects of Quinazoline-based α1-Adrenoceptor Antagonists on Cultured Cardiomyocytes | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 顏茂雄,林正一,吳美環,吳造中 | |
dc.subject.keyword | 自我吞噬,細胞凋亡, | zh_TW |
dc.subject.keyword | quinazoline,prazosin,doxazosin,TGF-β,TβRI,ALK5,p38 MAPK,autophagy,apoptosis,p53, | en |
dc.relation.page | 112 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-07-14 | |
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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