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Caracterització De L'efecte De Compostos Naturals En Models In Caracterització de l’efecte de compostos naturals en models in vitro i in vivo de càncer de còlon Susana Sánchez Tena ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. 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Departament de Bioquímica i Biologia Molecular Facultat de Biologia Caracterització de l’efecte de compostos naturals en models in vitro i in vivo de càncer de còlon Susana Sánchez Tena 2012 Departament de Bioquímica i Biologia Molecular Facultat de Biologia Programa de Doctorat de Biomedicina de la Universitat de Barcelona Caracterització de l’efecte de compostos naturals en models in vitro i in vivo de càncer de còlon Memòria presentada per Susana Sánchez Tena, llicenciada en Biologia per la Universitat de Barcelona, per optar al grau de Doctora per la Universitat de Barcelona. Tesi realitzada sota la direcció de la Dra. Marta Cascante Serratosa, el Dr. Josep Lluís Torres Simón i el Dr. Pedro Vizán Carralcázar. Dra. Marta Cascante Dr. Josep Lluís Torres Dr. Pedro Vizán Susana Sánchez Tena Sólo una cosa convierte en imposible un sueño: el miedo a fracasar Paulo Coelho CONTINGUT Contingut CONTINGUT i INTRODUCCIÓ GENERAL 1 1. EL CÀNCER 3 1.1. Característiques tumorals 4 1.2. Càncer de còlon 8 1.2.1. Genètica de la carcinogènesi colònica 9 1.3. El cicle cel·lular 10 1.3.1. Diferenciació cel·lular 12 1.3.1.1. El butirat com agent diferenciador 12 1.3.1.2. Diferenciació de les cèl·lules intestinals: via de transducció Wnt 13 1.3.1.2.1. Exemple d’errors en la via Wnt: ratolins ApcMin/+ 14 1.4. L’apoptosi 14 1.5. L’angiogènesi tumoral 16 1.6. El metabolisme tumoral 17 1.6.1. Glicòlisi 18 1.6.2. La glutaminòlisi 20 1.6.3. L’activació de rutes biosintètiques 21 2. APLICACIÓ DE PRODUCTES NATURALS COM ANTITUMORALS 22 2.1. Hamamelis virginiana 23 2.2. Té verd 25 2.3. Raïm 26 2.3.1. Fibra dietètica antioxidant de raïm 26 2.4. Àcid maslínic 27 iii Contingut 3. BIOLOGIA DE SISTEMES 28 3.1. La transcriptòmica 29 3.1.1. Tècnica de Microarrays 29 3.1.2. Tecnica de PCR a temps real (RT-PCR o qPCR) 30 3.2. La proteòmica 30 3.3. La citòmica 31 3.4. La metabolòmica 32 OBJECTIUS 35 INFORME DEL DIRECTOR 39 RESUM GLOBAL: RESULTATS, DISCUSSIÓ I CONCLUSIONS 43 RESULTATS 45 DISCUSSIÓ 54 CONCLUSIONS 63 BIBLIOGRAFIA 65 PUBLICACIONS 83 Capítol 1. L’hamamelitanin d’Hamamelis virginiana mostra citotoxicitat específica contra cèl·lules de càncer de còlon. 85 Capítol 2. Els polifenols majoritaris en té verd inhibeixen la diferenciació induïda per butirat mitjançant la interacció amb el Transportador Monocarboxílic 1 (MCT1) 111 Capítol 3. L’epicatequin gal·lat interfereix amb la productivitat metabòlica en cèl·lules de càncer de còlon 135 Capítol 4. La fibra dietètica antioxidant de raïm (GADF) inhibeix la poliposi intestinal en ratolins ApcMin/+ 157 iv Contingut Capítol 5. Efecte quimiopreventiu de l’àcid maslínic contra la tumorigenesis intestinal en ratolins ApcMin/+ 185 Capítol 6. Caracterització dels canvis metabòlics associats a l’activació angiogènica: identificació de potencials dianes terapèutiques 229 ANNEX 255 Annex 1. Sánchez-Tena et al. (2012) J Nat Prod. 75(1):26-33. Annex 2. Vizán et al. (2009) Carcinogenesis 30(6):946-52. Annex 3. Matito et al. (2011) J Agric Food Chem. 59(9):4489-95. Annex 4. Carreras et al. (2012) J Agric Food Chem. 60(7):1659-65. v INTRODUCCIÓ GENERAL Introducció general 1. EL CÀNCER El càncer és un conjunt de malalties que s’origina a partir d’una proliferació accelerada, desordenada i descontrolada de les cèl·lules d’un teixit que envaeixen, desplacen i destrueixen, localment i a distancia, altres teixits sans de l’organisme. El càncer, també denominat neoplàsia o tumor maligne, és un terme molt ampli que engloba més de dos-cents tipus de tumors malignes. Cadascun d’ells posseeix unes característiques particulars, que en alguns casos són completament diferents a la resta de càncers, podent-se considerar malalties independents, amb les seves causes, evolució i tractament específics (www.aecc.es). Segons estimacions de l’Organització Mundial de la Salut (OMS), el càncer és una de les principals causes de mort a escala mundial (http://www.who.int/es/). Concretament, 7,6 milions de defuncions (aproximadament el 13% del total) produïdes en tot el món l’any 2008 es van atribuir a aquesta malaltia. A més, les morts degudes a neoplàsies segueixen augmentant any rere any, ocupant el primer lloc les produïdes com a conseqüència del càncer de pulmó, seguides de prop per les d’estómac, fetge, còlon i mama. El procés pel qual les cèl·lules normals es transformen en canceroses i adquireixen la capacitat de multiplicar-se descontroladament i d’envair teixits i altres òrgans s’anomena carcinogènesi. La carcinogènesi es dóna per un procés anàleg a l'evolució Darwiniana, en el qual es produeixen canvis genètics successius, que confereixen avantatges de proliferació, portant a la conversió progressiva de les cèl·lules normals en cèl·lules tumorals (Foulds, 1954; Nowel et al., 1976). Aquest procés pot produir-se per alteracions genètiques espontànies, heretades o bé per l'acció d'agents carcinògens externs: els carcinògens físics (llum ultraviolada o radiacions ionitzants), els carcinògens químics (components del fum del tabac o contaminants en aliments) i els carcinògens biològics (infeccions víriques, bacterianes o parasitàries). La carcinogènesi pot durar anys i es desenvolupa en tres fases diferents: iniciació, promoció i progressió (Ziech et al., 2011). La iniciació consisteix en una lesió irreversible a l’àcid desoxiribonucleic (ADN) d'una cèl·lula que li confereix la capacitat de proliferar descontroladament respecte a la resta de cèl·lules que l'envolten. La cèl·lula iniciada pot donar lloc a cèl·lules filles portadores de la mateixa alteració al material genètic. En les cèl·lules iniciades, la multiplicació cel·lular comença a ser més ràpida i la probabilitat de que es produeixin noves mutacions augmenta. Aquesta és la fase de promoció. Finalment, les cèl·lules pateixen noves mutacions i cada vegada es fan més anòmales pel que respecta al seu creixement i comportament. Aquestes cèl·lules adquireixen la capacitat d'invasió, tant a nivell local com a distància, originant les metàstasis. Aquesta és la fase de progressió. 3 Introducció general Com a norma general s'ha de tenir en compte que una única mutació no és suficient per provocar la transformació d'una cèl·lula normal (Hahn et al., 2002). Les mutacions s'han d'acumular i afectar diferents gens involucrats directa o indirectament en el control del creixement cel·lular com els protooncogens o els gens supressors de tumors. Els protooncogens es troben en les cèl·lules normals exercint funcions relacionades amb el control de la proliferació cel·lular. Aquests codifiquen per a factors de transcripció, proteïnes de transducció de senyal que estimulen la divisió i factors reguladors del cicle cel·lular i l’apoptosi. Quan un protooncogen sofreix una mutació de guany de funció, és a dir, una alteració que fa que es mantingui actiu en situacions en què no hauria d'estar-ho, es converteix en un oncogen i provoca un increment en la taxa de proliferació cel·lular.
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