title: Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with antiproliferative activity.
abstract: Thiosemicarbazones are versatile organic compounds that present considerable pharmaceutical interest because of a wide range of properties. In our laboratory we synthesised some new metal-complexes with thiosemicarbazones derived from natural aldehydes which showed peculiar biological activities. In particular, a nickel complex [Ni(S-tcitr)(2)] (S-tcitr=S-citronellalthiosemicarbazonate) was observed to induce an antiproliferative effect on U937, a human histiocytic lymphoma cell line, at low concentrations (IC(50)=14.4microM). Therefore, we decided to study the interactions of this molecule with various cellular components and to characterise the induced apoptotic pathway. Results showed that [Ni(S-tcitr)(2)] causes programmed cell death via down-regulation of Bcl-2, alteration of mitochondrial membrane potential and caspase-3 activity, regardless of p53 function. The metal complex is not active on G(0) cells (i.e. fresh leukocytes) but is able to induce perturbation of the cell cycle on stimulated lymphocytes and U937 cells, in which a G(2)/M block was detected. It reaches the nucleus where it induces, at low concentrations (2.5-5.0microM), DNA damage, which could be partially ascribed to oxidative stress. [Ni(S-tcitr)(2)] is moreover able to strongly reduce the telomerase activity. Although the biological target of this metal complex is still unknown, the reported data suggest that [Ni(S-tcitr)(2)] could be a good model for the synthesis of new metal thiosemicarbazones with specific biological activity.
authors.affiliation: Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione, Università di Parma, Italy. annamaria.buschini@unipr.it
authors.forename: Annamaria
authors.initials: A
authors.lastname: Buschini
authors.forename: Silvana
authors.initials: S
authors.lastname: Pinelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Pellacani
authors.forename: Federica
authors.initials: F
authors.lastname: Giordani
authors.forename: Marisa Belicchi
authors.initials: MB
authors.lastname: Ferrari
authors.forename: Franco
authors.initials: F
authors.lastname: Bisceglie
authors.forename: Marco
authors.initials: M
authors.lastname: Giannetto
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pelosi
authors.forename: Pieralberto
authors.initials: P
authors.lastname: Tarasconi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020552:Comet Assay; D018360:Crystallography, X-Ray; D005434:Flow Cytometry; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008958:Models, Molecular; D009532:Nickel / Q000737:chemistry*; D009930:Organic Chemicals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D013882:Thiosemicarbazones / Q000737:chemistry*; D020298:U937 Cells
chemical_list: D009930:Organic Chemicals; D019253:Proto-Oncogene Proteins c-bcl-2; D013882:Thiosemicarbazones; D009532:Nickel; D019098:Telomerase; D020169:Caspases