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Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with antiproliferative activity
Authors:Annamaria Buschini  Silvana Pinelli  Federica Giordani  Franco Bisceglie  Giorgio Pelosi
Institution:a Dipartimento di Genetica, Biologia dei Microrganismi, Antropologia, Evoluzione, Università di Parma, Viale G.P. Usberti 11/A, 43100 Parma, Italy
b Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università di Parma, Via Gramsci 14, 43100 Parma, Italy
c Dipartimento di Chimica Generale e Inorganica, Chimica Analitica, Chimica Fisica, Università di Parma, Viale G.P. Usberti 17/A, 43100 Parma, Italy
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 (IC50 = 14.4 μM). 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 G0 cells (i.e. fresh leukocytes) but is able to induce perturbation of the cell cycle on stimulated lymphocytes and U937 cells, in which a G2/M block was detected. It reaches the nucleus where it induces, at low concentrations (2.5-5.0 μM), 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.
Keywords:Thiosemicarbazones  Nickel complexes  Apoptosis  Telomerase activity  DNA damage
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