Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres

Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo....

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Autores principales: Maciejewska, Natalia, Olszewski, Mateusz, Jurasz, Jakub, Baginski, Maciej, Stasevych, Maryna, Zvarych, Viktor, Folini, Marco, Zaffaroni, Nadia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9701690/
https://www.ncbi.nlm.nih.gov/pubmed/36437244
http://dx.doi.org/10.1038/s41419-022-05443-y
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author Maciejewska, Natalia
Olszewski, Mateusz
Jurasz, Jakub
Baginski, Maciej
Stasevych, Maryna
Zvarych, Viktor
Folini, Marco
Zaffaroni, Nadia
author_facet Maciejewska, Natalia
Olszewski, Mateusz
Jurasz, Jakub
Baginski, Maciej
Stasevych, Maryna
Zvarych, Viktor
Folini, Marco
Zaffaroni, Nadia
author_sort Maciejewska, Natalia
collection PubMed
description Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.
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spelling pubmed-97016902022-11-29 Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres Maciejewska, Natalia Olszewski, Mateusz Jurasz, Jakub Baginski, Maciej Stasevych, Maryna Zvarych, Viktor Folini, Marco Zaffaroni, Nadia Cell Death Dis Article Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents. Nature Publishing Group UK 2022-11-28 /pmc/articles/PMC9701690/ /pubmed/36437244 http://dx.doi.org/10.1038/s41419-022-05443-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Maciejewska, Natalia
Olszewski, Mateusz
Jurasz, Jakub
Baginski, Maciej
Stasevych, Maryna
Zvarych, Viktor
Folini, Marco
Zaffaroni, Nadia
Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres
title Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres
title_full Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres
title_fullStr Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres
title_full_unstemmed Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres
title_short Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres
title_sort teloxantron inhibits the processivity of telomerase with preferential dna damage on telomeres
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9701690/
https://www.ncbi.nlm.nih.gov/pubmed/36437244
http://dx.doi.org/10.1038/s41419-022-05443-y
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