TY  - JOUR
AU  - Misirlić-Dencić, Sonja T
AU  - Poljarević, Jelena M
AU  - Vilimanović, Uros
AU  - Bogdanović, Andrija D
AU  - Isaković, Aleksandra J
AU  - Kravić-Stevović, Tamara K
AU  - Dulović, Marija
AU  - Zogović, Nevena
AU  - Isaković, Anđelka M
AU  - Grgurić-Sipka, Sanja R
AU  - Bumbaširević, Vladimir Z
AU  - Sabo, Tibor J
AU  - Trajković, Vladimir S
AU  - Marković, Ivanka D
PY  - 2012
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1196
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.
T2  - Chemical Research in Toxicology
T1  - Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells
IS  - 4
VL  - 25
EP  - 939
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_1196
ER  - 

@article{
author = "Misirlić-Dencić, Sonja T and Poljarević, Jelena M and Vilimanović, Uros and Bogdanović, Andrija D and Isaković, Aleksandra J and Kravić-Stevović, Tamara K and Dulović, Marija and Zogović, Nevena and Isaković, Anđelka M and Grgurić-Sipka, Sanja R and Bumbaširević, Vladimir Z and Sabo, Tibor J and Trajković, Vladimir S and Marković, Ivanka D",
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.",
journal = "Chemical Research in Toxicology",
title = "Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells",
number = "4",
volume = "25",
pages = "939",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_1196"
}

Misirlić-Dencić, S. T., Poljarević, J. M., Vilimanović, U., Bogdanović, A. D., Isaković, A. J., Kravić-Stevović, T. K., Dulović, M., Zogović, N., Isaković, A. M., Grgurić-Sipka, S. R., Bumbaširević, V. Z., Sabo, T. J., Trajković, V. S.,& Marković, I. D.. (2012). Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells. in Chemical Research in Toxicology, 25(4).
https://hdl.handle.net/21.15107/rcub_ibiss_1196

Misirlić-Dencić ST, Poljarević JM, Vilimanović U, Bogdanović AD, Isaković AJ, Kravić-Stevović TK, Dulović M, Zogović N, Isaković AM, Grgurić-Sipka SR, Bumbaširević VZ, Sabo TJ, Trajković VS, Marković ID. Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells. in Chemical Research in Toxicology. 2012;25(4):null-939.
https://hdl.handle.net/21.15107/rcub_ibiss_1196 .

Misirlić-Dencić, Sonja T, Poljarević, Jelena M, Vilimanović, Uros, Bogdanović, Andrija D, Isaković, Aleksandra J, Kravić-Stevović, Tamara K, Dulović, Marija, Zogović, Nevena, Isaković, Anđelka M, Grgurić-Sipka, Sanja R, Bumbaširević, Vladimir Z, Sabo, Tibor J, Trajković, Vladimir S, Marković, Ivanka D, "Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells" in Chemical Research in Toxicology, 25, no. 4 (2012),
https://hdl.handle.net/21.15107/rcub_ibiss_1196 .