Tautomerization of 2-nitroso-N-arylanilines by coordination as N,N'-chelate ligands to rhenium(I) complexes and the anticancer activity of newly synthesized oximine rhenium(I) complexes against human melanoma and leukemia cells in vitro.

The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(I) complexes are described. The reaction of the halogenido complexes (CO)(5)ReX (X = Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C(6)H(3)ClNO)NH(C(6)H(4)R)} (R = p-Cl, p-Me, o-Cl, H) (3a-d) in tetrahydrofurane (THF) yields the complexes fac-(CO)(3)XRe{(C(6)H(3)ClNO)NH(C(6)H(4)R)} (6a-d, 7a-d) with the tautomerized ligand acting as a N,N'-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by (1)H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their (1)H and (13)C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N'-chelating ligands for all Re(I) complexes. Biological activity of four oximine rhenium(I) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(I) complexes than leukemia cells. None of the ligands (3a-d) showed any significant anticancer activity.

A non-apoptotic function of caspase-3 in pharmacologically-induced differentiation of K562 cells.

BACKGROUND AND PURPOSE: Several anticancer drugs with diverse chemical structures can induce differentiation of cancer cells. This study was undertaken to explore the potential contribution of caspase-3 to pharmacologically-induced differentiation of K562 cells. EXPERIMENTAL APPROACH: We assessed differentiation by measuring the expression of glycophorin A and haemoglobin synthesis in K562 cells treated with low concentrations of doxorubicin, hydroxyurea, cytosine arabinoside, cisplatin and haemin. Caspase-3 activation, mitochondrial membrane potential dissipation and viability were assessed by FACS. GATA-1-binding activity was evaluated by EMSA. KEY RESULTS: Treatment of K562 cells with low concentrations of the tested drugs activated caspase-3 but did not trigger detectable apoptosis. Instead, elevated levels of haemoglobin-positive and glycophorin A/caspase-3-double-positive cells were observed, suggesting involvement of caspase-3 in drug-induced differentiation. Inhibition of caspase-3 activity significantly reduced the ability of K562 cells to execute the differentiation programme. Mitochondrial membrane potential dissipation was observed, indicating involvement of the mitochondrial pathway. Binding activity of GATA-1, transcription factor responsible for differentiation and cell survival, was not diminished by increased caspase-3 activity during drug-stimulated differentiation. CONCLUSIONS AND IMPLICATIONS: Our results could explain how anticancer drugs, with diverse structures and modes of action, can stimulate erythroid differentiation in leukaemic cells with appropriate genetic backgrounds. Our findings imply that some similarities exist between pharmacologically-induced differentiation of erythroleukaemic cells and normal erythropoiesis, both involving caspase-3 activation at high levels of anti-apoptotic protein Bcl-X(L) and chaperone protein Hsp70 (heat shock protein 70). Therefore, the functions of caspase-3, unrelated to cell death, can be extended to pharmacologically-induced differentiation of some cancer cells.