Copper-Catalyzed Glutathione Oxidation is Accelerated by the Anticancer Thiosemicarbazone Dp44mT and Further Boosted at Lower pH
- Author(s)
- Enrico Falcone, Alessandra G. Ritacca, Sonja Hager, Hemma Schueffl, Bertrand Vileno, Youssef El Khoury, Petra Hellwig, Christian R. Kowol, Petra Heffeter, Emilia Sicilia, Peter Faller
- Abstract
Glutathione (GSH) is the most abundant thiol in mammalian cells and plays a crucial role in maintaining redox cellular homeostasis. The thiols of two GSH molecules can be oxidized to the disulfide GSSG. The cytosolic GSH/GSSG ratio is very high (>100), and its reduction can lead to apoptosis or necrosis, which are of interest in cancer research. CuII ions are very efficient oxidants of thiols, but with an excess of GSH, CuIn(GS)m clusters are formed, in which CuI is very slowly reoxidized by O2 at pH 7.4 and even more slowly at lower pH. Here, the aerobic oxidation of GSH by CuII was investigated at different pH values in the presence of the anticancer thiosemicarbazone Dp44mT, which accumulates in lysosomes and induces lysosomal membrane permeabilization in a Cu-dependent manner. The results showed that CuII-Dp44mT catalyzes GSH oxidation faster than CuII alone at pH 7.4 and hence accelerates the production of very reactive hydroxyl radicals. Moreover, GSH oxidation and hydroxyl radical production by CuII-Dp44mT were accelerated at the acidic pH found in lysosomes. To decipher this unusually faster thiol oxidation at lower pH, density functional theory (DFT) calculations, electrochemical and spectroscopic studies were performed. The results suggest that the acceleration is due to the protonation of CuII-Dp44mT on the hydrazinic nitrogen, which favors the rate-limiting reduction step without subsequent dissociation of the CuI intermediate. Furthermore, preliminary biological studies in cell culture using the proton pump inhibitor bafilomycin A1 indicated that the lysosomal pH plays a role in the activity of CuII-Dp44mT.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Université de Strasbourg, Università della Calabria, Medizinische Universität Wien, Institut Universitaire de France, Paris 75005, France.
- Journal
- Journal of the American Chemical Society
- Volume
- 144
- Pages
- 14758-14768
- No. of pages
- 11
- ISSN
- 0002-7863
- DOI
- https://doi.org/10.1021/jacs.2c05355
- Publication date
- 08-2022
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- General Chemistry, Biochemistry, Catalysis, Colloid and Surface Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/a532e5c5-94b1-45ce-a432-4859b07c7f10