title: Novel selenosemicarbazone metal complexes exert anti-tumor effect via alternative, caspase-independent necroptotic cell death.
abstract: The synthesis and chemical characterization of the novel 2,6-diacetylpyridine-bis(selenosemicarbazone) metal complexes of Zn(II), Cd(II) and Ni(II) were published previously. Here we report first evidence on anti-proliferative activity of the complexes and molecular patterns that underlie it. The complexes and the corresponding ligand are shown to be cytotoxic on the panel of nine, malignant and non-malignant cell lines, with the exception of Ni(II) complex that did not achieve IC50 value on any of the cell lines tested. Further experiments on the selected cell lines including A 549, MRC-5, EA.hy 926 and HeLa, have shown that the complexes posses unambiguous property of inducing necrosis in the cells treated for 6 hours, with the ligand and Zn(II) complex being the most active on all cell lines. On the contrary, only small portion of early apoptotic events was detected, under the same experimental condition. This was in complete concordance with the results obtained from Western blot analysis of the treated cells that showed no or slight increase of the protein amounts of two crucial apoptotic mediators: Cytochrome C and Caspase III. We propose the model, under which tested complexes induce necroptosis in treated cells, a recently described type of cell death with necrotic morphological features and acting via caspase independent pathway, and without elevated amounts of intracellular ROS. Endothelial EA.hy 926 cells have proven to be extremely sensitive on the necrosis-inducing effect of the complexes, which could indicate potential anti-angiogenic effect of the novel complexes that is to be investigated.
authors.forename: Manja
authors.initials: M
authors.lastname: Zec
authors.forename: Tatjana
authors.initials: T
authors.lastname: Srdic-Rajic
authors.forename: Ana
authors.initials: A
authors.lastname: Krivokuca
authors.forename: Radmila
authors.initials: R
authors.lastname: Jankovic
authors.forename: Tamara
authors.initials: T
authors.lastname: Todorovic
authors.forename: Katarina
authors.initials: K
authors.lastname: Andelkovic
authors.affiliation: National Cancer Research Center, Department of Experimental Pharmacology, Pasterova 14, 11 000 Belgrade, Serbia. sinisar@ncrc.ac.rs.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Radulovic
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002104:Cadmium / Q000737:chemistry; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002413:Cations, Divalent; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009532:Nickel / Q000737:chemistry; D009928:Organ Specificity; D017382:Reactive Oxygen Species / Q000378:metabolism; D018036:Selenium Compounds / Q000737:chemistry*; D012664:Semicarbazones / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D002413:Cations, Divalent; D056831:Coordination Complexes; D017382:Reactive Oxygen Species; D018036:Selenium Compounds; D012664:Semicarbazones; D002104:Cadmium; D009532:Nickel; D045304:Cytochromes c; D053148:Caspase 3; D015032:Zinc