Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds
- Author(s)
- Christian Kowol, Petra Heffeter, Walter Miklos, Lars Gille, Robert Trondl, Loredana Cappellacci, Walter Berger, Bernhard Keppler
- Abstract
Intracellular generation of reactive oxygen species (ROS) via thiol-mediated reduction of copper(II) to copper(I) has been assumed as the major mechanism underlying the anticancer activity of copper(II) complexes. The aim of this study was to compare the anticancer potential of copper(II) complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; currently in phase II clinical trials) and its terminally dimethylated derivative with that of 2-formylpyridine thiosemicarbazone and that of 2,2'-bipyridyl-6-carbothioamide. Experiments on generation of oxidative stress and the influence of biologically relevant reductants (glutathione, ascorbic acid) on the anticancer activity of the copper complexes revealed that reductant-dependent redox cycling occurred mainly outside the cells, leading to generation and dismutation of superoxide radicals resulting in cytotoxic amounts of H2O2. However, without extracellular reductants only weak intracellular ROS generation was observed at IC50 levels, suggesting that cellular thiols are not involved in copper-complex-induced oxidative stress. Taken together, thiol-induced intracellular ROS generation might contribute to the anticancer activity of copper thiosemicarbazone complexes but is not the determining factor.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Medizinische Universität Wien, Veterinärmedizinische Universität Wien
- Journal
- Journal of Biological Inorganic Chemistry
- Volume
- 17
- Pages
- 409-423
- No. of pages
- 15
- ISSN
- 0949-8257
- DOI
- https://doi.org/10.1007/s00775-011-0864-x
- Publication date
- 2012
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301303 Medical biochemistry
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/968b2f76-b5c6-4339-87d2-6166a604cd3a