New achievements on biological aspects of copper complexes Casiopeinas®: Interaction with DNA and proteins and anti-Trypanosoma cruzi activity

The mixed-chelate copper(II) complexes Casiopeinas (R) have been tested in several models in vitro and in vivo, showing promising antitumoral results. However, their mechanism of action remains to be defined. Trying to get a deeper insight into their molecular mode of action, further analyses, including gel electrophoresis, atomic force microscopy and circular dichroism were carried out to study their interaction with DNA and some cytoskeleton proteins. Our results revealed that the interaction of Casiopeinas triggers DNA cleavage by a free radical mechanism. The tested complexes showed a differential response to reducing and scavenger agents. Differences on target preference were also evident using double stranded oligonucleotides as sequence competitors. Surprisingly, distamycin A, a minor groove binder, enhanced the Casiopeinas' action on DNA. On the other hand, the tested Casiopeinas produce strong changes in protein structure of tubulin, integrin and fibronectin. All together these results suggest a multiple mode of action for these metal-based drugs. In addition, since it has been proposed that antitumor drugs efficiently interacting with DNA could also show activity against Trypanosome cruzi, etiologic agent of Chagas disease, we evaluated the activity of these compounds on this protozoan parasite. The tested complexes showed in vitro anti-T. cruzi activity similar to the anti-trypanosomal reference drug Nifurtimox. (C) 2012 Elsevier Inc. All rights reserved.