TY  - JOUR
AU  - Misirlić-Denčić, Sonja
AU  - Poljarević, Jelena
AU  - Vilimanovich, Urosh
AU  - Bogdanović, Andrija
AU  - Isaković, Aleksandra J.
AU  - Kravić-Stevović, Tamara
AU  - Dulović, Marija
AU  - Zogović, Nevena
AU  - Isaković, Anđelka M.
AU  - Grgurić-Šipka, Sanja
AU  - Bumbasirevic, Vladimir
AU  - Sabo, Tibor
AU  - Trajković, Vladimir S.
AU  - Marković, Ivanka
PY  - 2012
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/1279
AB  - We 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.
PB  - Amer Chemical Soc, Washington
T2  - Chemical Research in Toxicology
T1  - Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells
VL  - 25
IS  - 4
SP  - 931
EP  - 939
DO  - 10.1021/tx3000329
ER  - 

@article{
author = "Misirlić-Denčić, Sonja and Poljarević, Jelena and Vilimanovich, Urosh and Bogdanović, Andrija and Isaković, Aleksandra J. and Kravić-Stevović, Tamara and Dulović, Marija and Zogović, Nevena and Isaković, Anđelka M. and Grgurić-Šipka, Sanja and Bumbasirevic, Vladimir and Sabo, Tibor and Trajković, Vladimir S. and Marković, Ivanka",
year = "2012",
abstract = "We 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.",
publisher = "Amer Chemical Soc, Washington",
journal = "Chemical Research in Toxicology",
title = "Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells",
volume = "25",
number = "4",
pages = "931-939",
doi = "10.1021/tx3000329"
}

Misirlić-Denčić, S., Poljarević, J., Vilimanovich, U., Bogdanović, A., Isaković, A. J., Kravić-Stevović, T., Dulović, M., Zogović, N., Isaković, A. M., Grgurić-Šipka, S., Bumbasirevic, V., Sabo, T., Trajković, V. S.,& Marković, I.. (2012). Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells. in Chemical Research in Toxicology
Amer Chemical Soc, Washington., 25(4), 931-939.
https://doi.org/10.1021/tx3000329

Misirlić-Denčić S, Poljarević J, Vilimanovich U, Bogdanović A, Isaković AJ, Kravić-Stevović T, Dulović M, Zogović N, Isaković AM, Grgurić-Šipka S, Bumbasirevic V, Sabo T, Trajković VS, Marković I. Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells. in Chemical Research in Toxicology. 2012;25(4):931-939.
doi:10.1021/tx3000329 .

Misirlić-Denčić, Sonja, Poljarević, Jelena, Vilimanovich, Urosh, Bogdanović, Andrija, Isaković, Aleksandra J., Kravić-Stevović, Tamara, Dulović, Marija, Zogović, Nevena, Isaković, Anđelka M., Grgurić-Šipka, Sanja, Bumbasirevic, Vladimir, Sabo, Tibor, Trajković, Vladimir S., Marković, Ivanka, "Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells" in Chemical Research in Toxicology, 25, no. 4 (2012):931-939,
https://doi.org/10.1021/tx3000329 . .