Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion

Tumor hypoxia and hypoxic adaptation of cancer cells represent major barriers to successful cancer treatment. We revealed that improved antioxidant capacity contributes to increased radioresistance of cancer cells with tolerance to chronic-cycling severe hypoxia/reoxygenation stress. We hypothesized...

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Autores principales:	Christine Hansel, Julian Hlouschek, Kexu Xiang, Margarita Melnikova, Juergen Thomale, Thomas Helleday, Verena Jendrossek, Johann Matschke
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chronic cycling hypoxia radiation resistance metabolic reprogramming antioxidant capacity redox homeostasis ionizing radiation Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/07f7324524244c37ac7f0b3d2d3fe5b2
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spelling	oai:doaj.org-article:07f7324524244c37ac7f0b3d2d3fe5b22021-11-25T17:10:43ZAdaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion10.3390/cells101130402073-4409https://doaj.org/article/07f7324524244c37ac7f0b3d2d3fe5b22021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3040https://doaj.org/toc/2073-4409Tumor hypoxia and hypoxic adaptation of cancer cells represent major barriers to successful cancer treatment. We revealed that improved antioxidant capacity contributes to increased radioresistance of cancer cells with tolerance to chronic-cycling severe hypoxia/reoxygenation stress. We hypothesized, that the improved tolerance to oxidative stress will increase the ability of cancer cells to cope with ROS-induced damage to free deoxy-nucleotides (dNTPs) required for DNA replication and may thus contribute to acquired resistance of cancer cells in advanced tumors to antineoplastic agents inhibiting the nucleotide-sanitizing enzyme MutT Homologue-1 (MTH1), ionizing radiation (IR) or both. Therefore, we aimed to explore potential differences in the sensitivity of cancer cells exposed to acute and chronic-cycling hypoxia/reoxygenation stress to the clinically relevant MTH1-inhibitor TH1579 (Karonudib) and to test whether a multi-targeting approach combining the glutathione withdrawer piperlongumine (PLN) and TH1579 may be suited to increase cancer cell sensitivity to TH1579 alone and in combination with IR. Combination of TH1579 treatment with radiotherapy (RT) led to radiosensitization but was not able to counteract increased radioresistance induced by adaptation to chronic-cycling hypoxia/reoxygenation stress. Disruption of redox homeostasis using PLN sensitized anoxia-tolerant cancer cells to MTH1 inhibition by TH1579 under both normoxic and acute hypoxic treatment conditions. Thus, we uncover a glutathione-driven compensatory resistance mechanism towards MTH1-inhibition in form of increased antioxidant capacity as a consequence of microenvironmental or therapeutic stress.Christine HanselJulian HlouschekKexu XiangMargarita MelnikovaJuergen ThomaleThomas HelledayVerena JendrossekJohann MatschkeMDPI AGarticlechronic cycling hypoxiaradiation resistancemetabolic reprogrammingantioxidant capacityredox homeostasisionizing radiationBiology (General)QH301-705.5ENCells, Vol 10, Iss 3040, p 3040 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chronic cycling hypoxia radiation resistance metabolic reprogramming antioxidant capacity redox homeostasis ionizing radiation Biology (General) QH301-705.5
spellingShingle	chronic cycling hypoxia radiation resistance metabolic reprogramming antioxidant capacity redox homeostasis ionizing radiation Biology (General) QH301-705.5 Christine Hansel Julian Hlouschek Kexu Xiang Margarita Melnikova Juergen Thomale Thomas Helleday Verena Jendrossek Johann Matschke Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion
description	Tumor hypoxia and hypoxic adaptation of cancer cells represent major barriers to successful cancer treatment. We revealed that improved antioxidant capacity contributes to increased radioresistance of cancer cells with tolerance to chronic-cycling severe hypoxia/reoxygenation stress. We hypothesized, that the improved tolerance to oxidative stress will increase the ability of cancer cells to cope with ROS-induced damage to free deoxy-nucleotides (dNTPs) required for DNA replication and may thus contribute to acquired resistance of cancer cells in advanced tumors to antineoplastic agents inhibiting the nucleotide-sanitizing enzyme MutT Homologue-1 (MTH1), ionizing radiation (IR) or both. Therefore, we aimed to explore potential differences in the sensitivity of cancer cells exposed to acute and chronic-cycling hypoxia/reoxygenation stress to the clinically relevant MTH1-inhibitor TH1579 (Karonudib) and to test whether a multi-targeting approach combining the glutathione withdrawer piperlongumine (PLN) and TH1579 may be suited to increase cancer cell sensitivity to TH1579 alone and in combination with IR. Combination of TH1579 treatment with radiotherapy (RT) led to radiosensitization but was not able to counteract increased radioresistance induced by adaptation to chronic-cycling hypoxia/reoxygenation stress. Disruption of redox homeostasis using PLN sensitized anoxia-tolerant cancer cells to MTH1 inhibition by TH1579 under both normoxic and acute hypoxic treatment conditions. Thus, we uncover a glutathione-driven compensatory resistance mechanism towards MTH1-inhibition in form of increased antioxidant capacity as a consequence of microenvironmental or therapeutic stress.
format	article
author	Christine Hansel Julian Hlouschek Kexu Xiang Margarita Melnikova Juergen Thomale Thomas Helleday Verena Jendrossek Johann Matschke
author_facet	Christine Hansel Julian Hlouschek Kexu Xiang Margarita Melnikova Juergen Thomale Thomas Helleday Verena Jendrossek Johann Matschke
author_sort	Christine Hansel
title	Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion
title_short	Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion
title_full	Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion
title_fullStr	Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion
title_full_unstemmed	Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion
title_sort	adaptation to chronic-cycling hypoxia renders cancer cells resistant to mth1-inhibitor treatment which can be counteracted by glutathione depletion
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/07f7324524244c37ac7f0b3d2d3fe5b2
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Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion

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