TY  - JOUR
AU  - Isaković, Anđelka M
AU  - Petričević, Sasa M.
AU  - Ristić, Slavica M.
AU  - Popadić, Dušan M.
AU  - Kravić-Stevović, Tamara K
AU  - Zogović, Nevena
AU  - Poljarević, Jelena M.
AU  - Živanović Radnić, Tatjana V
AU  - Sabo, Tibor J.
AU  - Isaković, Aleksandra J.
AU  - Marković, Ivanka D.
AU  - Trajković, Vladimir S.
AU  - Misirlić-Denčić, Sonja T
PY  - 2018
UR  - https://insights.ovid.com/crossref?an=00008390-201802000-00002
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3004
AB  - Melanoma, an aggressive skin tumor with high metastatic potential, is associated with high mortality and increasing morbidity. Multiple available chemotherapeutic and immunotherapeutic modalities failed to improve survival in advanced disease, and the search for new agents is ongoing. The aim of this study was to investigate antimelanoma effects of O,O-diethyl-(S,S)-ethylenediamine-N,N'di-2-(3-cyclohexyl) propanoate dihydrochloride (EE), a previously synthesized and characterized organic compound. Mouse melanoma B16 cell viability was assessed using acid phosphatase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, sulforhodamine B, and lactate dehydrogenase assays. Apoptosis and autophagy were investigated using flow cytometry, fluorescence and electron microscopy, and western blotting. In vivo antitumor potential was assessed in subcutaneous mouse melanoma model after 14 days of treatment with EE. Tumor mass and volume were measured, and RT-PCR was used for investigating the expression of autophagy-related, proapoptotic, and antiapoptotic molecules in tumor tissue. Investigated organic compound exerts significant cytotoxic effect against B16 cells. EE induced apoptosis, as confirmed by phosphatidyl serine externalisation, caspase activation, and ultrastructural features typical for apoptosis seen on fluorescence and electron microscopes. The apoptotic mechanism included prompt disruption of mitochondrial membrane potential and oxidative stress. No autophagy was observed. Antimelanoma action and apoptosis induction were confirmed in vivo, as EE decreased mass and volume of tumors, and increased expression of several proapoptotic genes. EE possesses significant antimelanoma action and causes caspase-dependent apoptosis mediated by mitochondrial damage and reactive oxygen species production. Decrease in tumor growth and increase in expression of proapoptotic genes in tumor tissue suggest that EE warrants further investigation as a candidate agent in treating melanoma.
PB  - Melanoma Research
T2  - Melanoma Research
T2  - Melanoma Research
T1  - In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid.
IS  - 1
VL  - 28
DO  - 10.1097/CMR.0000000000000409
SP  - 8
EP  - 20
ER  - 

@article{
author = "Isaković, Anđelka M and Petričević, Sasa M. and Ristić, Slavica M. and Popadić, Dušan M. and Kravić-Stevović, Tamara K and Zogović, Nevena and Poljarević, Jelena M. and Živanović Radnić, Tatjana V and Sabo, Tibor J. and Isaković, Aleksandra J. and Marković, Ivanka D. and Trajković, Vladimir S. and Misirlić-Denčić, Sonja T",
year = "2018",
abstract = "Melanoma, an aggressive skin tumor with high metastatic potential, is associated with high mortality and increasing morbidity. Multiple available chemotherapeutic and immunotherapeutic modalities failed to improve survival in advanced disease, and the search for new agents is ongoing. The aim of this study was to investigate antimelanoma effects of O,O-diethyl-(S,S)-ethylenediamine-N,N'di-2-(3-cyclohexyl) propanoate dihydrochloride (EE), a previously synthesized and characterized organic compound. Mouse melanoma B16 cell viability was assessed using acid phosphatase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, sulforhodamine B, and lactate dehydrogenase assays. Apoptosis and autophagy were investigated using flow cytometry, fluorescence and electron microscopy, and western blotting. In vivo antitumor potential was assessed in subcutaneous mouse melanoma model after 14 days of treatment with EE. Tumor mass and volume were measured, and RT-PCR was used for investigating the expression of autophagy-related, proapoptotic, and antiapoptotic molecules in tumor tissue. Investigated organic compound exerts significant cytotoxic effect against B16 cells. EE induced apoptosis, as confirmed by phosphatidyl serine externalisation, caspase activation, and ultrastructural features typical for apoptosis seen on fluorescence and electron microscopes. The apoptotic mechanism included prompt disruption of mitochondrial membrane potential and oxidative stress. No autophagy was observed. Antimelanoma action and apoptosis induction were confirmed in vivo, as EE decreased mass and volume of tumors, and increased expression of several proapoptotic genes. EE possesses significant antimelanoma action and causes caspase-dependent apoptosis mediated by mitochondrial damage and reactive oxygen species production. Decrease in tumor growth and increase in expression of proapoptotic genes in tumor tissue suggest that EE warrants further investigation as a candidate agent in treating melanoma.",
publisher = "Melanoma Research",
journal = "Melanoma Research, Melanoma Research",
title = "In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid.",
number = "1",
volume = "28",
doi = "10.1097/CMR.0000000000000409",
pages = "8-20"
}

Isaković, A. M., Petričević, S. M., Ristić, S. M., Popadić, D. M., Kravić-Stevović, T. K., Zogović, N., Poljarević, J. M., Živanović Radnić, T. V., Sabo, T. J., Isaković, A. J., Marković, I. D., Trajković, V. S.,& Misirlić-Denčić, S. T.. (2018). In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid.. in Melanoma Research
Melanoma Research., 28(1), 8-20.
https://doi.org/10.1097/CMR.0000000000000409

Isaković AM, Petričević SM, Ristić SM, Popadić DM, Kravić-Stevović TK, Zogović N, Poljarević JM, Živanović Radnić TV, Sabo TJ, Isaković AJ, Marković ID, Trajković VS, Misirlić-Denčić ST. In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid.. in Melanoma Research. 2018;28(1):8-20.
doi:10.1097/CMR.0000000000000409 .

Isaković, Anđelka M, Petričević, Sasa M., Ristić, Slavica M., Popadić, Dušan M., Kravić-Stevović, Tamara K, Zogović, Nevena, Poljarević, Jelena M., Živanović Radnić, Tatjana V, Sabo, Tibor J., Isaković, Aleksandra J., Marković, Ivanka D., Trajković, Vladimir S., Misirlić-Denčić, Sonja T, "In vitro and in vivo antimelanoma effect of ethyl ester cyclohexyl analog of ethylenediamine dipropanoic acid." in Melanoma Research, 28, no. 1 (2018):8-20,
https://doi.org/10.1097/CMR.0000000000000409 . .

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 .

TY  - JOUR
AU  - Isaković, Aleksandra J
AU  - Janković, Teodora
AU  - Harhaji-Trajković, Ljubica
AU  - Kostić-Rajačić, Slađana V.
AU  - Nikolić, Zoran M
AU  - Vajs, Vlatka E
AU  - Trajković, Vladimir S
PY  - 2008
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/1530
AB  - The present study identifies xanthones gentiakochianin and gentiacaulein as the active principles responsible for the in vitro antiglioma action of ether and methanolic extracts of the plant Gentiana kochiana. Gentiakochianin and gentiacaulein induced cell cycle arrest in G(2)/M and G(0)/G(1) phases, respectively, in both C6 rat glioma and U251 human glioma cell lines. The more efficient antiproliferative action of gentiakochianin was associated with its ability to induce microtubule stabilization in a cell-free assay. Both the xanthones reduced mitochondrial membrane potential and increased the production of reactive oxygen species in glioma cells, but only the effects of gentiakochianin were pronounced enough to cause caspase activation and subsequent apoptotic cell death. The assessment of structure-activity relationship in a series of structurally related xanthones from G. kochiana and Gentianella austriaca revealed dihydroxylation at positions 7, 8 of the xanthonic nucleus as the key structural feature responsible for the ability of gentiakochianin to induce microtubule-associated G(2)/M cell block and apoptotic cell death in glioma cells. (C) 2008 Elsevier Ltd. All rights reserved.
T2  - Bioorganic & Medicinal Chemistry
T1  - Antiglioma action of xanthones from Gentiana kochiana: Mechanistic and structure-activity requirements
IS  - 10
VL  - 16
EP  - 5694
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_1530
ER  - 

@article{
author = "Isaković, Aleksandra J and Janković, Teodora and Harhaji-Trajković, Ljubica and Kostić-Rajačić, Slađana V. and Nikolić, Zoran M and Vajs, Vlatka E and Trajković, Vladimir S",
year = "2008",
abstract = "The present study identifies xanthones gentiakochianin and gentiacaulein as the active principles responsible for the in vitro antiglioma action of ether and methanolic extracts of the plant Gentiana kochiana. Gentiakochianin and gentiacaulein induced cell cycle arrest in G(2)/M and G(0)/G(1) phases, respectively, in both C6 rat glioma and U251 human glioma cell lines. The more efficient antiproliferative action of gentiakochianin was associated with its ability to induce microtubule stabilization in a cell-free assay. Both the xanthones reduced mitochondrial membrane potential and increased the production of reactive oxygen species in glioma cells, but only the effects of gentiakochianin were pronounced enough to cause caspase activation and subsequent apoptotic cell death. The assessment of structure-activity relationship in a series of structurally related xanthones from G. kochiana and Gentianella austriaca revealed dihydroxylation at positions 7, 8 of the xanthonic nucleus as the key structural feature responsible for the ability of gentiakochianin to induce microtubule-associated G(2)/M cell block and apoptotic cell death in glioma cells. (C) 2008 Elsevier Ltd. All rights reserved.",
journal = "Bioorganic & Medicinal Chemistry",
title = "Antiglioma action of xanthones from Gentiana kochiana: Mechanistic and structure-activity requirements",
number = "10",
volume = "16",
pages = "5694",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_1530"
}

Isaković, A. J., Janković, T., Harhaji-Trajković, L., Kostić-Rajačić, S. V., Nikolić, Z. M., Vajs, V. E.,& Trajković, V. S.. (2008). Antiglioma action of xanthones from Gentiana kochiana: Mechanistic and structure-activity requirements. in Bioorganic & Medicinal Chemistry, 16(10).
https://hdl.handle.net/21.15107/rcub_ibiss_1530

Isaković AJ, Janković T, Harhaji-Trajković L, Kostić-Rajačić SV, Nikolić ZM, Vajs VE, Trajković VS. Antiglioma action of xanthones from Gentiana kochiana: Mechanistic and structure-activity requirements. in Bioorganic & Medicinal Chemistry. 2008;16(10):null-5694.
https://hdl.handle.net/21.15107/rcub_ibiss_1530 .

Isaković, Aleksandra J, Janković, Teodora, Harhaji-Trajković, Ljubica, Kostić-Rajačić, Slađana V., Nikolić, Zoran M, Vajs, Vlatka E, Trajković, Vladimir S, "Antiglioma action of xanthones from Gentiana kochiana: Mechanistic and structure-activity requirements" in Bioorganic & Medicinal Chemistry, 16, no. 10 (2008),
https://hdl.handle.net/21.15107/rcub_ibiss_1530 .