Effect of Schiff base Cu(II) complexes on signaling pathways in HT-29 cells.

Schiff base copper (II) complexes are known for their anticancer, antifungal, antiviral and anti-inflammatory activities. The aim of the current study was to investigate biological effects of Schiff base Cu (II) complexes (0.001-100 mu mol/l)-[Cu-2(sal-D, L-glu)(2)(isoquinoline) (2)]center dot 2C(2)H(5)OH (1), [Cu(sal-5-met-L-glu)(H2O)]center dot H2O (2), [Cu(ethanol)(2)(imidazole)(4)][Cu-2(sal-D, L-glu)(2)(imidazole)(2)] (3), [Cu(sal-D, L-glu)(2-methylimidazole)] (4) on the human colon carcinoma cells HT-29, the mouse noncancerous cell line NIH-3T3 and the human noncancerous fibroblast cell line VH10. The results suggested that Cu (II) complexes exhibit cytotoxic effects against the HT-29 cell line, while complexes 3 and 4 were the most effective. Subsequent to 72 h of incubation, apoptosis was observed in the HT-29 cells induced by Cu (II) complexes 1 (0.1, 1, 10 and 50 mu mol/l), 2 (1, 10, 50 and 100 mu mol/l), 3 (0.01, 1, 10 and 50 mu mol/l) and 4 (0.01, 0.1, 1 and 10 mu mol/l). The apoptotic pathways activated by the Cu (II) complexes were identified. The results indicated that complexes 2, 3 and 4 were able to induce the mitochondria-dependent pathway of apoptosis in HT-29 cells, while complex 1 was obsered to activate the extrinsic pathway of apoptosis. The levels of the anti-apoptotic protein Bcl-2 were reduced and those of the pro-apoptotic protein Bax increased following treatment with complexes 2, 3 and 4. Complex 1 had no effect on Bax protein expression. Complexes 2 and 3 induced elevation of cytochrome c (cyt c), while complex 4 induced a time-dependent elevation of cyt c levels. No cyt c was detected in HT-29 cells exposed to complex 1, suggesting that Cu (II) complexes activated the extrinsic pathway of apoptosis. The results from the current study in addition to previous studies suggest that Schiff base Cu(II) complexes have potential as novel anticancer drugs.