Aim: 

Metal-based drugs have emerged as pharmaceutical chemotherapic agents. DNA is the primary target of many anti-tumour compounds. The aims of this communication are to report the DNA binding and nuclease activity of several copper complexes and to show the potential of these chemical agents to start cellular responses related with p53 overexpression and bcl-2 inhibition, leading the cells to apoptosis.

Methods: 

DNA-copper complex interactions are studied by spectrophotometric, fluorometric and viscosimetry mesasures. The ability of the complexes to cleave DNA has been studied with the aid of gel electrophoresis of supercoiled pUC18 DNA. Cytotoxicity of compounds has been assayed on Jurkat T and caco-2 cells. Protein levels of bcl-2 and p53 have been assessed by western blotting.

Results: 

The copper complexes bind and then break the DNA by means of ROS production. The DNA damage is mediated by attack of hydroxyl radical, superoxide anion, oxygen singlet species and hydrogen peroxide. Cell culture studies indicate antiproliferative effects produced by copper compounds. We have shown that these complexes induce apoptosis on Jurkat and Caco-2 cells via p53 activation pathway and anti-apoptotic bcl-2 inhibition, as well as microtubules degradation.

Conclusion: 

The results reported here demonstrate that copper complexes in the presence of reducing agents are very efficient in promoting in vitro cleavage of DNA by ROS formation. Signalling pathways triggered by these DNA-damaging agents or many other forms of cellular stress ultimately regulate p53 and bcl-2 expression, providing to these compounds an antiproliferative activity.