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 . .