Show simple item record

In vitro and in vivo evaluation of antitumor activity of NO-modified compounds, Saquinavir-NO and GIT-27NO in colon cancer

dc.contributor.advisorMijatović, Sanja
dc.contributor.otherMijatović, Sanja
dc.contributor.otherMatić, Gordana
dc.contributor.otherStošić-Grujičić, Stanislava
dc.contributor.otherMaksimović-Ivanić, Danijela
dc.creatorMojić, Marija S.
dc.date.accessioned2016-01-05T11:46:41Z
dc.date.available2016-01-05T11:46:41Z
dc.date.issued2013-03-07
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=169
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:5402/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1024570546
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/2082
dc.descriptionIz poznate uzročno-posledične veze infekcije i inflamacije, s jedne strane i karcinogeneze i progresije tumora, s druge strane, proistekla je ideja o upotrebi anti-inflamatornih i anti-infektivnih agenasa u terapiji kancera. Međutim, problem gastrotoksičnosti anti-inflamatornih, kao i generalne toksičnosti anti-viralnih lekova uz činjenicu da je reč o agensima niske biološke iskoristljivosti, ozbiljne su barijere u razmatranju njihove primene u terapiji bolesti za koje inicijalno nisu namenjeni. Kako bi se prevazišla farmakološka ograničenja pomenutih jedinjenja, a imajući u vidu poznato svojstvo azot-monoksida (NO) da neutrališe toksičnost supstanci na različitim nivoima, anti-inflamatornom agensu VGX-1027 i anti-retroviralnom agensu sakvinaviru (Saq) adekvatnom hemijskom intervencijom je dodata grupa dizajnirana da donira NO. Prednost novodobijenih jedinjenja GIT-27NO i Saq-NO nad poznatim nesteroidnim anti-inflamatornim agensima modifikovanim kovalentnim vezivanjem NO (NO-NSAID) je odsustvo molekula “nosača”, koji je inače odgovoran za genotoksičnost NO-NSAID. Strukturna promena ova dva jedinjenja doprinela je njihovom snažnom antitumorskom svojstvu, što je potvđeno brojnim in vitro i in vivo studijama, uz umanjenu toksičnost u slučaju GIT-27NO ili potpunom gubitku toksičnosti Saq-NO tretmana.U ovoj studiji je po prvi put ispitano antitumorsko delovanje GIT-27NO i Saq-NO in vitro i in vivo na modelu kancera kolona, jednog od najtežih formi maligniteta. Kako su oba agensa NO-derivati, definisana je uloga NO u njihovom antitumorskom delovanju. Na molekularnom nivou, determinisani su glavni unutarćelijski događaji pokrenuti u odgovoru na tretman pomenutim jedinjenjima. Na kraju, imajući u vidu značaj mikrosredine za rast i progresiju tumora, ispitana je sposobnost GIT-27NO i Saq-NO da povrate osetljivost ćelija kancera kolona na antitumorski imunski odgovor posredovan TRAIL molekulom.sr
dc.descriptionConcept of using anti-inflammatory and anti-infectious agents in cancer therapy is based on a known relationship between inflammation and infection on one side and carcinogenesis and tumor progression on the other side. However, the problem of gastrotoxicity of anti-inflammatory and general toxicity of antiviral drugs, along with their low bioavailability, marks a strong barrier when considering them in therapies for which they were not initially intended for. In order to overcome the pharmacological limits of these compounds, nitric-oxide (NO) with its documented feature to neutralize toxicity of drugs on various levels was added to anti-inflammatory agent VGX-1027 and antiretroviral agent saquinavir (Saq). The advantage of new compounds, GIT-27NO and Saq-NO, over known non-steroid anti-inflammatory agents modified by covalent binding NO moiety (NO-NSAID) is the absence of “carrier” molecule, which is responsible for genotoxicity of NO-NSAID. Structural change in these compounds resulted in potentiation of antitumor action, confirmed by numerous in vitro and in vivo studies, along with reduced toxicity of GIT-27NO or complete loss of toxicity of Saq-NO treatment. In this study, antitumor potential of GIT-27NO and Saq-NO was tested in vitro and in vivo for the first time in colon cancer model, one of the most severe forms of malignancy. As both agents are NO-derivates, the role of NO in their antitumor action was defined. On molecular level, main intercellular events triggered by the treatment were determined. Finally, considering the importance of microenvironment for tumor growth and progression, the ability of GIT-27NO and Saq-NO to re-establish colon cancer cell sensitivity to TRAIL-mediated antitumor immune response was tested. GIT-27NO and Saq-NO reduced the viability of mouse CT26CL25 and human HCT116 colon cancer cell lines, both in vitro and in vivo. The importance of NO release for antitumor action was quite different. While cell viability reduction under GIT-27NO treatment was due to accumulation of high intracellular concentration of NO and consecutively generated oxidative and nitrosative stress, antitumor action of Saq-NO was not mediated by a release of quantitatively relevant amount of this free radical. GIT-27NO induced the accumulation of p53 tumor suppressor, changed pro- and antiapoptotic molecule ratio and triggered mitochondrial membrane depolarization which resulted in cell death via caspase-dependent apoptosis.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.rightsAutorstvo-Nekomercijalno-Deliti pod istim uslovima 3.0 Srbija (CC BY-NC-SA 3.0)
dc.sourceУниверзитет у Београдуsr
dc.subjectKancer kolonasr
dc.subjectColon canceren
dc.subjecthemioterapijasr
dc.subjectGIT-27NOsr
dc.subjectSaq-NOsr
dc.subjectapoptozasr
dc.subjectmetastazesr
dc.subjectS6 proteinsr
dc.subjectTRAILsr
dc.subjectchemotherapyen
dc.subjectGIT-27NOen
dc.subjectSaq-NOen
dc.subjectapoptosisen
dc.subjectmetastasisen
dc.subjectS6 proteinen
dc.subjectTRAILen
dc.titleAnaliza antitumorskog delovanja agenasa modifikovanih azot-monoksidom, Sakvinavir-NO i GIT-27NO na kanceru kolona in vitro i in vivosr
dc.titleIn vitro and in vivo evaluation of antitumor activity of NO-modified compounds, Saquinavir-NO and GIT-27NO in colon canceren
dc.typePhD thesis
dcterms.abstractМијатовић, Сања; Максимовић-Иванић, Данијела; Стошић-Грујичић, Станислава; Мијатовић, Сања; Матић, Гордана; Мојић, Марија С.; Aнализа антитуморског деловања агенаса модификованих азот-моноксидом, Саквинавир-НО и ГИТ-27НО на канцеру колона ин витро и ин виво; Aнализа антитуморског деловања агенаса модификованих азот-моноксидом, Саквинавир-НО и ГИТ-27НО на канцеру колона ин витро и ин виво;


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record