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Cyclohexyl analogues of ethylenediamine dipropanoic acid induce caspase-independent mitochondrial apoptosis in human leukaemic cells.
MedLine Citation:
PMID:  22401584     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
We investigated the cytotoxicity of recently synthesized (S,S)-ethylendiamine-N,N'-di-2-(3-cyclohexyl)propanoic acid esters towards 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 non-esterified parental compound and n-butyl ester were devoid of cytotoxic action. The ethyl ester exhibited the highest cytotoxic activity (IC50 10.7 µM - 45.4 µM), 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. Keywords: leukemia; ethylenediamine-diacetate; apoptosis; differentiation; caspase.
Authors:
Sonja Misirlic Dencic; Jelena Poljarevic; Urosh Vilimanovich; Andrija Bogdanovic; Aleksandra Isakovic; Tamara Kravic Stevovic; Marija Dulovic; Nevena Zogovic; Andjelka Isakovic; Sanja Grguric-Sipka; Vladimir Bumbasirevic; Tibor J Sabo; Vladimir Trajkovic; Ivanka Markovic
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-8
Journal Detail:
Title:  Chemical research in toxicology     Volume:  -     ISSN:  1520-5010     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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