Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 103, Issue 5, Pages 666-677Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2008.12.016
Keywords
Thiosemicarbazones; Nickel complexes; Apoptosis; Telomerase activity; DNA damage
Funding
- Italian Ministry of University and Research (MIUR, PRIN) [2004059078]
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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 anti proliferative effect on U937, a human histiocytic lymphoma cell line, at low concentrations (IC50 = 14.4 mu M). 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 (2.5-5.0 mu M), 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. (C) 2009 Elsevier Inc. All rights reserved.
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