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Evaluation of aloe emodin effect on B16 and A375 melanoma cells and their sensitivity to anticancer drugs and immune response

dc.contributor.advisorMaksimović-Ivanić, Danijela
dc.contributor.otherKataranovski, Milena
dc.contributor.otherMijatović, Sanja
dc.contributor.otherStošić-Grujičić, Stanislava
dc.contributor.otherBožić, Biljana
dc.creatorRadović, Julijana M.
dc.date.accessioned2016-01-05T11:46:16Z
dc.date.available2016-01-05T11:46:16Z
dc.date.available2020-07-03T08:08:57Z
dc.date.issued2012-09-28
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=46
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/2058
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:2765/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1024530098
dc.description.abstractAloe emodin (AE) spada u biljne molekule antraciklinskog tipa koji zahvaljujući reaktivnim grupama na atomima ugljenika benzenovih prstenova pokazuje izrazitu reaktivnost i posledično široki spektar biološke aktivnosti poput baktericidnog, fungicidnog, viricidnog, imunosupresivnog, antiinflamatornog, hepatoprotektivnog, laksativnog i vazorelaksirajućeg delovanja. Istraživanja novijeg datuma stavljaju u žižu interesovanja njegova antitumorska dejstva. Ciljevi koji su postavljeni u ovoj tezi podrazumevali su utvrđivanje tumoricidnog delovanja AE-a na ćelije mišjeg, B16 i humanog, A375 melanoma koje se inicijalno razlikuju u redoks statusu i aktivnosti signalnih puteva uključenih u kancerogenezu. Uz uporednu analizu unutarćelijskog odgovora pomenutih linija na tretman AE-om, ispitivan je i uticaja AE-a na osetljivost melanoma na imunski odgovor usmeren protiv transformisane ćelije kao i na efikasnost konvencionalne citostatske terapije. AE je snažno inhibirao rast obe ćelijske linije posredstvom različitih mehanizama. U slučaju A375 ćelija, AE je doveo do indukcije apoptoze zavisne od aktivnosti kaspaza uz smanjenje nivoa antiapoptotskih proteina XIAP i Bcl-2. Suprotno, tretman AE-om je indukovao ireverzibilnu diferencijaciju B16 ćelija u smeru primarnog fenotipa manifestovanog povećanom ekspresijom enzima tirozinaze i naknadnom produkcijom melanina. Opisana promena B16 ćelija bila je praćena brzom akumulacijom p53, ciklina D1 i D3. Ključni događaj u diferencijaciji B16 ćelija je, najverovatnije, povećana produkcija H2O2 indukovana AE-om. U osnovi heterogenih ishoda tretmana istovetnim agensom je recipročna regulacija aktivnosti ERK1/2 i Akt. Poseban značaj ima podatak da se apoptoza pokrenuta AE-om u A375 ćelijama odvija u uslovima prekomerne aktivnosti Akt. Analiza paralelnog tretmana ćelija melanoma AE-om i konvencionalnim citostaticima (doksorubicin i paklitaksel) pokazala je da pomenuta supstanca umanjuje efikasnost hemioterapije. Nekonzistentnost ishoda ko-tretmana AE-a i medijatora imunskog odgovora iz familije TNF molekula ukazala je na kompleksnost uticaja mikrosredine na učinak AE-a. U celini, rezultati ove doktorske disertacije pokazuju kako specifičnost ćelija melanoma definiše mehanizam delovanja AE-a iako ne ugrožava njegov antitumorski potencijal. S druge strane, opisani rezultati upozoravaju na opasnost kombinovanja biljnih preparata sa konvencionalnim terapeuticima usled mogućeg neutrališućeg efekta.sr
dc.description.abstractAloe emodin is an herbal antraquinone that, due to reactive groups on the carbon atoms of benzene rings, posseses a strong reactivity and consequently shows a wide range of biological activities such as antibacterial, antifungal, antiviral, diuretic, immunosuppressive, anti-inflammatory, hepatoprotective, laxative and vasorelaxant. Recent studies put the focus on its antitumor effects. The aim of this thesis was to determine and evaluate antitumor activity of AE on two melanoma cell lines that initially differs in redox status and activities of signaling pathways involved in carcinogenesis: mouse melanoma B16, and human melanoma A375 cells. Together with comparative analysis of the intracellular responses of two lines to the AE treatment, the impact of AE on the sensitivity of melanoma to antitumor immune response as well as the efficiency of conventional cytostatic therapy, were examined. AE decreased the growth of both cell lines through different mechanisms. In the case of A375 cells, AE inducted caspase dependent apoptosis by reducing protein levels of antiapoptotic molecules XIAP and Bcl-2. In contrast, treatment with AE promoted irreversible differentiation of B16 cells towords its primary phenotype manifested through increased expression of the tyrosinase and the subsequent production of melanin. Described change in B16 cells was accompanied by a rapid accumulation of p53, cyclin D1 and D3. Increased production of H2O2 triggered by AE is probably first in a line of events responsible for induction of differentiation of B16 cells. Opposite regulation of two main signaling pathways involved in cell proliferation, differentiation and death- MEK-ERK1/2 and PI3K-Akt in tested cell lines could be essential for different outcome of the treatment with single agent. Furthermore, analysis of the parallel treatment of melanoma cells with the AE and conventional cytostatics (doxorubicin and paclitaxel) showed that introduced substance decreases the effectiveness of chemotherapy. Incoherent outcome of co-treatment of AE and TNF, FasL or TRAIL, the most relevant mediators of nonspecific immune response aginst tumor cells, points to the complexity of the influence of microenvironmental factors to the effect of AE. In general, the results of this PhD thesis show that cell specificity of melanomas defines the mechanism of AE action, while it does not jeopardize its anticancer potential. On the other hand, presented results point to a danger of combining herbal medicines with conventional therapeutics due to their possible neutralizing effects.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Биолошки факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173013/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectAloe emodinsr
dc.subjectAloe emodinen
dc.subjectmelanomsr
dc.subjectERK1/2sr
dc.subjectAktsr
dc.subjectapoptozasr
dc.subjectdiferencijacijasr
dc.subjectmelanomaen
dc.subjectERK1/2en
dc.subjectAkten
dc.subjectapoptosisen
dc.subjectdifferentiationen
dc.titleIspitivanje uticaja aloe emodina na ćelije melanoma B16 i A375 i njihovu osetljivost na citostatike i imunski odgovorsr
dc.titleEvaluation of aloe emodin effect on B16 and A375 melanoma cells and their sensitivity to anticancer drugs and immune responseen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dcterms.abstractМаксимовић-Иванић, Данијела; Божић, Биљана; Катарановски, Милена; Мијатовић, Сања; Стошић-Грујичић, Станислава; Радовић, Јулијана М.; Испитивање утицаја алое емодина на ћелије меланома Б16 и A375 и њихову осетљивост на цитостатике и имунски одговор; Испитивање утицаја алое емодина на ћелије меланома Б16 и A375 и њихову осетљивост на цитостатике и имунски одговор;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/1980/Disertacija.pdf


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