title: 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. 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.
authors.affiliation: Department of Experimental Oncology, Laboratory for Experimental Pharmacology, Institute for Oncology and Radiology of Serbia, National Cancer Research Center, Pasterova 14, 11 000 Belgrade, Serbia. tsrdic@yahoo.com
authors.forename: Tatjana
authors.initials: T
authors.lastname: Srdić-Rajić
authors.forename: Manja
authors.initials: M
authors.lastname: Zec
authors.forename: Tamara
authors.initials: T
authors.lastname: Todorović
authors.forename: Katarina
authors.initials: K
authors.lastname: Anđelković
authors.forename: Siniša
authors.initials: S
authors.lastname: Radulović
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D008564:Membrane Potentials; D008670:Metals / Q000737:chemistry*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D009369:Neoplasms / Q000473:pathology*; D012643:Selenium / Q000737:chemistry*; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008563:Membrane Lipids; D008670:Metals; D012664:Semicarbazones; D045304:Cytochromes c; D053148:Caspase 3; D012643:Selenium