title: New achievements on biological aspects of copper complexes Casiopeínas®: interaction with DNA and proteins and anti-Trypanosoma cruzi activity.
abstract: The mixed-chelate copper(II) complexes Casiopeínas® 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 Casiopeínas 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 Casiopeínas' action on DNA. On the other hand, the tested Casiopeínas 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 Trypanosoma 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.
authors.affiliation: Laboratorio de Interacciones Moleculares, Facultad de Ciencias, UDELAR, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Lorena
authors.initials: L
authors.lastname: Becco
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rodríguez
authors.forename: María Elena
authors.initials: ME
authors.lastname: Bravo
authors.forename: María José
authors.initials: MJ
authors.lastname: Prieto
authors.forename: Lena
authors.initials: L
authors.lastname: Ruiz-Azuara
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garat
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D002942:Circular Dichroism; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D018625:Microscopy, Atomic Force; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D056831:Coordination Complexes; D003598:Cytoskeletal Proteins; D003300:Copper; D004247:DNA