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Mixed copper(ii)-phenanthroline complexes induce cell death of ovarian cancer cells by evoking the unfolded protein response

L. Moráň, T. Pivetta, S. Masuri, K. Vašíčková, F. Walter, J. Prehn, M. Elkalaf, J. Trnka, J. Havel, P. Vaňhara,

. 2019 ; 11 (9) : 1481-1489. [pub] 20190726

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc20025702

There is an ongoing need for the development of new cancer therapeutics that combine high cytotoxic efficiency with low side effects, and also override resistance to the first-line chemotherapeutics. Copper(ii)-phenanthroline complexes are promising compounds that were shown previously to induce an immediate cytotoxic response over a panel of tumor cell lines in vitro. The molecular mechanism, however, remained unresolved. In this work we performed a thorough study of the copper(ii)-phenanthroline complexes containing different imidazolidine-2-thione ligands in ovarian cancer cells, and revealed that these complexes induce endoplasmic reticulum (ER) stress and subsequently cell death mediated by the unfolded protein response. Alleviation of the ER-stress by tauroursodeoxycholic acid (TUDCA) attenuated the cytotoxic effects. In summary, we have identified a novel, ER-dependent, molecular mechanism mediating cytotoxic effects of copper(ii)-phenanthroline complexes.

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$a There is an ongoing need for the development of new cancer therapeutics that combine high cytotoxic efficiency with low side effects, and also override resistance to the first-line chemotherapeutics. Copper(ii)-phenanthroline complexes are promising compounds that were shown previously to induce an immediate cytotoxic response over a panel of tumor cell lines in vitro. The molecular mechanism, however, remained unresolved. In this work we performed a thorough study of the copper(ii)-phenanthroline complexes containing different imidazolidine-2-thione ligands in ovarian cancer cells, and revealed that these complexes induce endoplasmic reticulum (ER) stress and subsequently cell death mediated by the unfolded protein response. Alleviation of the ER-stress by tauroursodeoxycholic acid (TUDCA) attenuated the cytotoxic effects. In summary, we have identified a novel, ER-dependent, molecular mechanism mediating cytotoxic effects of copper(ii)-phenanthroline complexes.
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$a Pivetta, Tiziana $u Department of Chemical and Geological Sciences, University of Cagliari, Monserrato, CA, Italy.
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$a Masuri, Sebastiano $u Department of Chemical and Geological Sciences, University of Cagliari, Monserrato, CA, Italy.
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$a Vašíčková, Kateřina $u Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 3, CZ-62500, Brno, Czech Republic. pvanhara@med.muni.cz. $7 mub20181010327
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$a Walter, Franziska $u Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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$a Prehn, Jochen $u Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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$a Elkalaf, Moustafa $u Laboratory for Metabolism and Bioenergetics, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic and Centre for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
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$a Trnka, Jan $u Laboratory for Metabolism and Bioenergetics, Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic and Centre for Research on Nutrition, Metabolism and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
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$a Havel, Josef $u Department of Chemistry, Faculty of Science, Masaryk University, Brno, Czech Republic and International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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$a Vaňhara, Petr $u Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Kamenice 3, CZ-62500, Brno, Czech Republic. pvanhara@med.muni.cz and International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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