An Artemisinin-Derivative-(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity
| Autor: | Marie-Lise Maddelein, Olivier Cuvillier, Christian Bijani, Xing Wang, Catherine Hemmert, Xue Qin, Pierre-Yves Fortin, Heinz Gornitzka, Chen Zhang, Álvaro Fernández Álvarez, Guillaume Barnoin |
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| Přispěvatelé: | Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2020 |
| Předmět: |
Sorafenib
Auranofin NF-E2-Related Factor 2 Cell Antineoplastic Agents 010402 general chemistry 01 natural sciences Catalysis chemistry.chemical_compound Cell Line Tumor medicine Cytotoxic T cell Humans [CHIM.COOR]Chemical Sciences/Coordination chemistry Artemisinin Cytotoxicity Transcription factor IC50 010405 organic chemistry Chemistry Cancer Biological activity NF-κB General Chemistry General Medicine Hep G2 Cells medicine.disease Artemisinins 0104 chemical sciences 3. Good health medicine.anatomical_structure Mechanism of action Drug Resistance Neoplasm Cancer research Gold medicine.symptom Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Angewandte Chemie International Edition Angewandte Chemie International Edition, Wiley-VCH Verlag, 2020, 59 (29), pp.12062-12068. ⟨10.1002/anie.202002992⟩ |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.202002992⟩ |
| Popis: | A family of original bis(artemisinin-NHC)gold(I) complexes have been synthesized. These hybrid molecules combine two biological active motifs, an artemisinin derivative (DHA) and a cationic bis(NHC)gold(I) unit. One of these complexes, complex 2a, has been analyzed by single-crystal X-ray diffraction and tested in depth for its anticancer properties. Complex 2a shows strong anticancer activities on a representative panel of human cancer cell models from 8 different localizations (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias). Complex 2a shows anticancer activity to a much better degree than Auranofin and DHA standards with GI50 values in nM range, together with a superior selectivity in regard to non-cancer cell models. Next to expected ROS formation and TrxR inhibition, an original and distinctive mechanism of action through inhibition of NRF2 - a transcription factor strongly associated with aggressiveness and resistance to cancer therapies - with an IC50 value at nM range has been evidenced. Importantly, the NRF2 inhibitory effect of complex 2a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is known to be associated with primary and acquired drug resistance. Moreover, complex 2a also inhibited NF-κB and HIF transcriptional activities, which are also linked to progression and resistance in cancer. Our findings provide experimental evidence that hybrid (NHC)gold(I) molecules - such as complex 2a - represent a new class of organometallic hybrid molecules that may yield new therapeutic agents. |
| Databáze: | OpenAIRE |
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