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Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance

SIMPLE SUMMARY: Besides zinc, also iron and copper need to be considered to play a role in the mode of action and resistance development of the anticancer thiosemicarbazone COTI-2 and its derivatives. One of these derivatives (COTI-NMe(2)) was discovered as an interesting new drug candidate with imp...

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Autores principales: Pósa, Vivien, Stefanelli, Alessia, Nunes, Julia H. Bormio, Hager, Sonja, Mathuber, Marlene, May, Nóra V., Berger, Walter, Keppler, Bernhard K., Kowol, Christian R., Enyedy, Éva A., Heffeter, Petra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9497102/
https://www.ncbi.nlm.nih.gov/pubmed/36139615
http://dx.doi.org/10.3390/cancers14184455
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author Pósa, Vivien
Stefanelli, Alessia
Nunes, Julia H. Bormio
Hager, Sonja
Mathuber, Marlene
May, Nóra V.
Berger, Walter
Keppler, Bernhard K.
Kowol, Christian R.
Enyedy, Éva A.
Heffeter, Petra
author_facet Pósa, Vivien
Stefanelli, Alessia
Nunes, Julia H. Bormio
Hager, Sonja
Mathuber, Marlene
May, Nóra V.
Berger, Walter
Keppler, Bernhard K.
Kowol, Christian R.
Enyedy, Éva A.
Heffeter, Petra
author_sort Pósa, Vivien
collection PubMed
description SIMPLE SUMMARY: Besides zinc, also iron and copper need to be considered to play a role in the mode of action and resistance development of the anticancer thiosemicarbazone COTI-2 and its derivatives. One of these derivatives (COTI-NMe(2)) was discovered as an interesting new drug candidate with improved anticancer activity and resistance profile. ABSTRACT: COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe(2) and COTI-NMeCy), and the non-substituted analogue (COTI-NH(2)) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe(2) as an interesting new drug candidate with improved anticancer activity and resistance profile.
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spelling pubmed-94971022022-09-23 Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance Pósa, Vivien Stefanelli, Alessia Nunes, Julia H. Bormio Hager, Sonja Mathuber, Marlene May, Nóra V. Berger, Walter Keppler, Bernhard K. Kowol, Christian R. Enyedy, Éva A. Heffeter, Petra Cancers (Basel) Article SIMPLE SUMMARY: Besides zinc, also iron and copper need to be considered to play a role in the mode of action and resistance development of the anticancer thiosemicarbazone COTI-2 and its derivatives. One of these derivatives (COTI-NMe(2)) was discovered as an interesting new drug candidate with improved anticancer activity and resistance profile. ABSTRACT: COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe(2) and COTI-NMeCy), and the non-substituted analogue (COTI-NH(2)) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe(2) as an interesting new drug candidate with improved anticancer activity and resistance profile. MDPI 2022-09-14 /pmc/articles/PMC9497102/ /pubmed/36139615 http://dx.doi.org/10.3390/cancers14184455 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pósa, Vivien
Stefanelli, Alessia
Nunes, Julia H. Bormio
Hager, Sonja
Mathuber, Marlene
May, Nóra V.
Berger, Walter
Keppler, Bernhard K.
Kowol, Christian R.
Enyedy, Éva A.
Heffeter, Petra
Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance
title Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance
title_full Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance
title_fullStr Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance
title_full_unstemmed Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance
title_short Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance
title_sort thiosemicarbazone derivatives developed to overcome coti-2 resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9497102/
https://www.ncbi.nlm.nih.gov/pubmed/36139615
http://dx.doi.org/10.3390/cancers14184455
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