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dc.creatorDencic, Sonja Misirlic
dc.creatorPoljarević, Jelena
dc.creatorVilimanovich, Urosh
dc.creatorBogdanovic, Andrija
dc.creatorIsaković, Aleksandra J.
dc.creatorStevovic, Tamara Kravic
dc.creatorDulovic, Marija
dc.creatorZogovic, Nevena
dc.creatorIsaković, Anđelka M.
dc.creatorGrgurić-Šipka, Sanja
dc.creatorBumbasirevic, Vladimir
dc.creatorSabo, Tibor
dc.creatorTrajković, Vladimir S.
dc.creatorMarković, Ivanka
dc.date.accessioned2018-11-22T00:20:59Z
dc.date.available2018-11-22T00:20:59Z
dc.date.issued2012
dc.identifier.issn0893-228X
dc.identifier.urihttp://cherry.chem.bg.ac.rs/handle/123456789/1279
dc.description.abstractWe investigated the cytotoxicity of recently synthesized (S,S)-ethyleridiamine-N,N'-di-2-(3-cyclohexyl)propanoic acid esters toward human leukemic cell lines and healthy blood mononuclear cells. Cell viability was assessed by acid phosphatase assay, apoptosis, and differentiation were analyzed by flow cytometry and electron microscopy, while intracellular localization of apoptosis-inducing factor (AIF) was determined by immunoblotting. It was demonstrated that methyl, ethyl, and n-propyl esters were toxic to HL-60, REH, MOLT-4, KG-1, JVM-2, and K-562 leukemic cell lines, while the nonesterified parental compound and n-butyl ester were devoid of cytotoxic action. The ethyl ester exhibited the highest cytotoxic activity (IC50 10.7 mu M-45.4 mu M), which was comparable to that of the prototypical anticancer drug cisplatin. The observed cytotoxic effect in HL-60 cells was associated with an increase in superoxide production and mitochondrial membrane depolarization, leading to apoptotic cell death characterized by phosphatidylserine externalization and DNA fragmentation in the absence of autophagic response. DNA fragmentation preceded caspase activation and followed AIF translocation from mitochondria to nucleus, which was indicative of caspase-independent apoptotic cell death. HL-60 cells treated with subtoxic concentration of the compound displayed morphological signs of granulocytic differentiation (nuclear indentations and presence of cytoplasmic primary granules), as well as an increased expression of differentiation markers CD11b and CD15. The cyclohexyl analogues of ethylenediamine dipropanoic acid were also toxic to peripheral blood mononuclear cells of both healthy controls and leukemic patients, the latter being more sensitive. Our data demonstrate that the toxicity of the investigated cyclohexyl compounds against leukemic cell lines is mediated by caspase-independent apoptosis associated with oxidative stress, mitochondrial dysfunction, and AIF translocation.en
dc.publisherAmer Chemical Soc, Washington
dc.relationinfo:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41025/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172035/RS//
dc.rightsrestrictedAccess
dc.sourceChemical Research in Toxicology
dc.titleCyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cellsen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractБогдановиц, Aндрија; Дуловиц, Марија; Трајковиц, Владимир; Денциц, Соња Мисирлиц; Марковиц, Иванка; Вилимановицх, Уросх; Исаковиц, Aлександра Ј.; Бумбасиревиц, Владимир; Пољаревић, Јелена; Стевовиц, Тамара Кравиц; Зоговиц, Невена; Исаковиц, Aндјелка М.; Гргурић-Шипка, Сања; Сабо, Тибор;
dc.citation.volume25
dc.citation.issue4
dc.citation.spage931
dc.citation.epage939
dc.identifier.wos000302826000014
dc.identifier.doi10.1021/tx3000329
dc.citation.other25(4): 931-939
dc.citation.rankM21
dc.identifier.pmid22401584
dc.type.versionpublishedVersionen
dc.identifier.scopus2-s2.0-84859816298
dc.identifier.rcubKon_2302


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