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

Abstract

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 (0.001‑100µmol/l)‑[Cu2(sal‑D, L‑glu)2(isoquinoline)2]·2C2H5OH(1), [Cu(sal‑5‑met‑L‑glu)(H2O)].H2O(2), [Cu(ethanol)2(imidazole)4][Cu2(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 3and4 were the most effective. Subsequent to 72h of incubation, apoptosis was observed in the HT‑29 cells induced by Cu(II) complexes1 (0.1, 1, 10and50µmol/l), 2(1, 10, 50and100µmol/l), 3(0.01, 1, 10and50µmol/l) and 4(0.01, 0.1, 1and10µmol/l). The apoptotic pathways activated by the Cu(II) complexes were identified. The results indicated that complexes2, 3 and4 were able to induce the mitochondria‑dependent pathway of apoptosis in HT‑29 cells, while complex1 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 complexes2, 3and4. Complex1 had no effect on Bax protein expression. Complexes2 and3induced elevation of cytochromec (cytc), while complex4 induced a time‑dependent elevation of cytc levels. No cytc was detected in HT‑29 cells exposed to complex1, 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.