Non-substituted N-heteroaromatic selenosemicarbazone metal complexes induce apoptosis in cancer cells via activation of mitochondrial pathway
Abstract
We previously published the synthesis, characterization and cytotoxic effect of the novel Zn(II), Ni(II), and Cd(II) complexes with 2-formylpyridine selenosemicarbazone. Here we further investigate the mechanism of their antiproliferative activity against several cancer and vascular endothelial cell lines and compared it to the activity of the ligand itself, corresponding salts and, as a referent compound, cisplatin. Investigated complexes induced apoptosis in a time- and dose-dependent manner as well as changes in a cell cycle distribution. Caspase-3 activation in HeLa cells, MDA-MB-361 and vascular endothelial cells EA.hy 926 cells by ligand alone, as well as Zn(II), Ni(II), and Cd(II) complexes was preceded by the activation of the p53 tumor-suppressor gene family protein p73. In addition to activation of p73, these compounds also trigger cytochrome C release by upregulation of Bax expression. The release of cytochrome C has been linked to loss of mitochondrial membrane potential. H...owever, our data indicated that the increased phosphorylation of ERK could be also one of the mechanism involved in the Zn(II), and Cd(II) complexes- induction of apoptosis. Selenosemicarbazone complexes with Cd(II) and Ni(II), possess dual ability to induce apoptosis as well as necrosis, and might present an added advantage for inducing cell death in a diverse array of malignant cells. Taken together, our findings could indicate potential role of these complexes as activator of cross-talk between different signaling pathways that leads to cell death, and thus making the complex intriguing field for further scientific, and maybe clinical investigations.
Keywords:
Zn(II), Ni(II), and Cd(II) complexes / Selenosemicarbazone / Antiproliferative activity / ApoptosisSource:
European Journal of Medicinal Chemistry, 2011, 46, 9, 3734-3747Publisher:
- Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
Funding / projects:
- Pharmacodynamic and pharmacogenomic research of new drugs in the treatment of solid tumors (RS-41026)
- Interactions of natural products, their derivatives and coordination compounds with proteins and nucleic acids (RS-172055)
DOI: 10.1016/j.ejmech.2011.05.039
ISSN: 0223-5234
PubMed: 21641698
WoS: 000295237400021
Scopus: 2-s2.0-80052960393
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Institution/Community
Institut za medicinska istraživanjaTY - JOUR AU - Srdić-Rajić, Tatjana AU - Zec, Manja M. AU - Todorović, Tamara AU - Anđelković, Katarina AU - Radulović, Siniša PY - 2011 UR - http://rimi.imi.bg.ac.rs/handle/123456789/334 AB - We previously published the synthesis, characterization and cytotoxic effect of the novel Zn(II), Ni(II), and Cd(II) complexes with 2-formylpyridine selenosemicarbazone. Here we further investigate the mechanism of their antiproliferative activity against several cancer and vascular endothelial cell lines and compared it to the activity of the ligand itself, corresponding salts and, as a referent compound, cisplatin. Investigated complexes induced apoptosis in a time- and dose-dependent manner as well as changes in a cell cycle distribution. Caspase-3 activation in HeLa cells, MDA-MB-361 and vascular endothelial cells EA.hy 926 cells by ligand alone, as well as Zn(II), Ni(II), and Cd(II) complexes was preceded by the activation of the p53 tumor-suppressor gene family protein p73. In addition to activation of p73, these compounds also trigger cytochrome C release by upregulation of Bax expression. The release of cytochrome C has been linked to loss of mitochondrial membrane potential. However, our data indicated that the increased phosphorylation of ERK could be also one of the mechanism involved in the Zn(II), and Cd(II) complexes- induction of apoptosis. Selenosemicarbazone complexes with Cd(II) and Ni(II), possess dual ability to induce apoptosis as well as necrosis, and might present an added advantage for inducing cell death in a diverse array of malignant cells. Taken together, our findings could indicate potential role of these complexes as activator of cross-talk between different signaling pathways that leads to cell death, and thus making the complex intriguing field for further scientific, and maybe clinical investigations. PB - Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux T2 - European Journal of Medicinal Chemistry T1 - Non-substituted N-heteroaromatic selenosemicarbazone metal complexes induce apoptosis in cancer cells via activation of mitochondrial pathway EP - 3747 IS - 9 SP - 3734 VL - 46 DO - 10.1016/j.ejmech.2011.05.039 ER -
@article{ author = "Srdić-Rajić, Tatjana and Zec, Manja M. and Todorović, Tamara and Anđelković, Katarina and Radulović, Siniša", year = "2011", abstract = "We previously published the synthesis, characterization and cytotoxic effect of the novel Zn(II), Ni(II), and Cd(II) complexes with 2-formylpyridine selenosemicarbazone. Here we further investigate the mechanism of their antiproliferative activity against several cancer and vascular endothelial cell lines and compared it to the activity of the ligand itself, corresponding salts and, as a referent compound, cisplatin. Investigated complexes induced apoptosis in a time- and dose-dependent manner as well as changes in a cell cycle distribution. Caspase-3 activation in HeLa cells, MDA-MB-361 and vascular endothelial cells EA.hy 926 cells by ligand alone, as well as Zn(II), Ni(II), and Cd(II) complexes was preceded by the activation of the p53 tumor-suppressor gene family protein p73. In addition to activation of p73, these compounds also trigger cytochrome C release by upregulation of Bax expression. The release of cytochrome C has been linked to loss of mitochondrial membrane potential. However, our data indicated that the increased phosphorylation of ERK could be also one of the mechanism involved in the Zn(II), and Cd(II) complexes- induction of apoptosis. Selenosemicarbazone complexes with Cd(II) and Ni(II), possess dual ability to induce apoptosis as well as necrosis, and might present an added advantage for inducing cell death in a diverse array of malignant cells. Taken together, our findings could indicate potential role of these complexes as activator of cross-talk between different signaling pathways that leads to cell death, and thus making the complex intriguing field for further scientific, and maybe clinical investigations.", publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux", journal = "European Journal of Medicinal Chemistry", title = "Non-substituted N-heteroaromatic selenosemicarbazone metal complexes induce apoptosis in cancer cells via activation of mitochondrial pathway", pages = "3747-3734", number = "9", volume = "46", doi = "10.1016/j.ejmech.2011.05.039" }
Srdić-Rajić, T., Zec, M. M., Todorović, T., Anđelković, K.,& Radulović, S.. (2011). Non-substituted N-heteroaromatic selenosemicarbazone metal complexes induce apoptosis in cancer cells via activation of mitochondrial pathway. in European Journal of Medicinal Chemistry Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux., 46(9), 3734-3747. https://doi.org/10.1016/j.ejmech.2011.05.039
Srdić-Rajić T, Zec MM, Todorović T, Anđelković K, Radulović S. Non-substituted N-heteroaromatic selenosemicarbazone metal complexes induce apoptosis in cancer cells via activation of mitochondrial pathway. in European Journal of Medicinal Chemistry. 2011;46(9):3734-3747. doi:10.1016/j.ejmech.2011.05.039 .
Srdić-Rajić, Tatjana, Zec, Manja M., Todorović, Tamara, Anđelković, Katarina, Radulović, Siniša, "Non-substituted N-heteroaromatic selenosemicarbazone metal complexes induce apoptosis in cancer cells via activation of mitochondrial pathway" in European Journal of Medicinal Chemistry, 46, no. 9 (2011):3734-3747, https://doi.org/10.1016/j.ejmech.2011.05.039 . .