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The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells

The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity. For...

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Autores principales: Behnisch-Cornwell, Steven, Wolff, Lisa, Bednarski, Patrick J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766971/
https://www.ncbi.nlm.nih.gov/pubmed/33353055
http://dx.doi.org/10.3390/antiox9121300
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author Behnisch-Cornwell, Steven
Wolff, Lisa
Bednarski, Patrick J.
author_facet Behnisch-Cornwell, Steven
Wolff, Lisa
Bednarski, Patrick J.
author_sort Behnisch-Cornwell, Steven
collection PubMed
description The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity. For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generated and compared to the native cell line with regards to morphology, growth and metabolic rates, and oxidative stress defenses. Furthermore, the IC(50) values of two peroxides and 16 widely used anticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1 cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increases in the cytotoxic potency of hydrogen peroxide and tert-butylhydroperoxide, the anticancer drugs cisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found. While a concentration dependent increases in intracellular reactive oxygen species (ROS) levels were observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide, no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the native cell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decrease in glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting that factors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in the GPx1 knockout cells.
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spelling pubmed-77669712020-12-28 The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells Behnisch-Cornwell, Steven Wolff, Lisa Bednarski, Patrick J. Antioxidants (Basel) Article The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity. For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generated and compared to the native cell line with regards to morphology, growth and metabolic rates, and oxidative stress defenses. Furthermore, the IC(50) values of two peroxides and 16 widely used anticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1 cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increases in the cytotoxic potency of hydrogen peroxide and tert-butylhydroperoxide, the anticancer drugs cisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found. While a concentration dependent increases in intracellular reactive oxygen species (ROS) levels were observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide, no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the native cell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decrease in glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting that factors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in the GPx1 knockout cells. MDPI 2020-12-18 /pmc/articles/PMC7766971/ /pubmed/33353055 http://dx.doi.org/10.3390/antiox9121300 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Behnisch-Cornwell, Steven
Wolff, Lisa
Bednarski, Patrick J.
The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
title The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
title_full The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
title_fullStr The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
title_full_unstemmed The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
title_short The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells
title_sort effect of glutathione peroxidase-1 knockout on anticancer drug sensitivities and reactive oxygen species in haploid hap-1 cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766971/
https://www.ncbi.nlm.nih.gov/pubmed/33353055
http://dx.doi.org/10.3390/antiox9121300
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