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Unveiling the Potential of Innovative Gold(I) and Silver(I) Selenourea Complexes as Anticancer Agents Targeting TrxR and Cellular Redox Homeostasis |
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| Authors: | Dr. Michele De Franco Dr. Marina Saab Dr. Marina Porchia Prof. Cristina Marzano Prof. Steven P. Nolan Prof. Fady Nahra Prof. Kristof Van Hecke Prof. Valentina Gandin |
| Affiliation: | 1. Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, I-35131 Padova, Italy These authors contributed equally to this work.;2. Department of Chemistry, Center for Sustainable Chemistry Ghent University, Krigsman 281, Building S3, 9000 Ghent Belgium These authors contributed equally to this work.;3. ICMATE-CNR, Corso Stati Uniti 4, I-35131 Padova, Italy;4. Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, I-35131 Padova, Italy;5. Department of Chemistry, Center for Sustainable Chemistry Ghent University, Krigsman 281, Building S3, 9000 Ghent Belgium |
| Abstract: | A series of NHC-based selenourea Ag(I) and Au(I) complexes were evaluated for their anticancer potential in vitro, on 2D and 3D human cancer cell systems. All NHC-based selenourea complexes possess an outstanding cytotoxic potency, which was comparable or even better than that of the reference metallodrug auranofin, and were also able to overcome both platinum-based and multi-drug resistances. Intriguingly, their cytotoxic potency did not correlate with solution stability, partition coefficient or cellular uptake. On the other hand, mechanistic studies in cancer cells revealed their ability to strongly and selectively inhibit the redox-regulating enzyme Thioredoxin Reductase (TrxR), being even more effective than auranofin, a well-known TrxR inhibitor, without affecting other redox enzymes such as Glutathione Reductase (GR). The inhibition of TrxR in H157 human cancer cells caused, in turn, the disruption of cellular thiol-redox homeostasis and of mitochondria pathophysiology, ultimately leading to cancer cell death through apoptosis. |
| Keywords: | cytotoxicity gold(I) complexes silver(I) complexes TrxR inhibition |