Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione
Despite continuous advancement in skin cancer therapy, the disease is still fatal in many patients, demonstrating the need to improve existing therapies, such as electrochemotherapy (ECT). ECT can be applied in the palliative or curative setting and is based on the application of pulsed electric fie...
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MDPI AG
2022-11-01
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Online Access: | https://www.mdpi.com/1422-0067/23/23/14772 |
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author | Christina M. Wolff Sander Bekeschus |
author_facet | Christina M. Wolff Sander Bekeschus |
author_sort | Christina M. Wolff |
collection | DOAJ |
description | Despite continuous advancement in skin cancer therapy, the disease is still fatal in many patients, demonstrating the need to improve existing therapies, such as electrochemotherapy (ECT). ECT can be applied in the palliative or curative setting and is based on the application of pulsed electric fields (PEF), which by themselves exerts none to low cancer toxicity but become potently toxic when combined with low-dosed chemotherapeutics such as bleomycin and cisplatin. Albeit their favorable side-effect profiles, not all patients respond to standard ECT, and some responders experience tumor recurrence. To identify potential adjuvant or alternative agents to standard electrochemotherapy, we explored the possibility of combining PEF with a physiological compound, glutathione (GSH), to amplify anticancer toxicity. GSH is an endogenous antioxidant and is available as a dietary supplement. Surprisingly, neither GSH nor PEF mono treatment but GSH + PEF combination treatment exerted strong cytotoxic effects and declined metabolic activity in four skin cancer cell lines in vitro. The potential applicability to other tumor cells was verified by corroborating results in two leukemia cell lines. Strikingly, GSH + PEF treatment did not immediately increase intracellular GSH levels, while levels 24 h following treatment were enhanced. Similar tendencies were made for intracellular reactive oxygen species (ROS) levels, while extracellular ROS increased following combination treatment. ROS levels and the degree of cytotoxicity could be partially reversed by pre-incubating cells with the NADPH-oxidase (NOX) inhibitor diphenyleneiodonium (DPI) and the H<sub>2</sub>O<sub>2</sub>-degrading enzyme catalase. Collectively, our findings suggest a promising new “endogenous” drug to be combined with PEF for future anticancer research approaches. |
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issn | 1661-6596 1422-0067 |
language | English |
last_indexed | 2024-03-09T17:46:23Z |
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series | International Journal of Molecular Sciences |
spelling | doaj.art-4ea3f3f1ebcf4a6c981468ce59119cdf2023-11-24T11:07:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231477210.3390/ijms232314772Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and GlutathioneChristina M. Wolff0Sander Bekeschus1ZIK Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, GermanyZIK Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, GermanyDespite continuous advancement in skin cancer therapy, the disease is still fatal in many patients, demonstrating the need to improve existing therapies, such as electrochemotherapy (ECT). ECT can be applied in the palliative or curative setting and is based on the application of pulsed electric fields (PEF), which by themselves exerts none to low cancer toxicity but become potently toxic when combined with low-dosed chemotherapeutics such as bleomycin and cisplatin. Albeit their favorable side-effect profiles, not all patients respond to standard ECT, and some responders experience tumor recurrence. To identify potential adjuvant or alternative agents to standard electrochemotherapy, we explored the possibility of combining PEF with a physiological compound, glutathione (GSH), to amplify anticancer toxicity. GSH is an endogenous antioxidant and is available as a dietary supplement. Surprisingly, neither GSH nor PEF mono treatment but GSH + PEF combination treatment exerted strong cytotoxic effects and declined metabolic activity in four skin cancer cell lines in vitro. The potential applicability to other tumor cells was verified by corroborating results in two leukemia cell lines. Strikingly, GSH + PEF treatment did not immediately increase intracellular GSH levels, while levels 24 h following treatment were enhanced. Similar tendencies were made for intracellular reactive oxygen species (ROS) levels, while extracellular ROS increased following combination treatment. ROS levels and the degree of cytotoxicity could be partially reversed by pre-incubating cells with the NADPH-oxidase (NOX) inhibitor diphenyleneiodonium (DPI) and the H<sub>2</sub>O<sub>2</sub>-degrading enzyme catalase. Collectively, our findings suggest a promising new “endogenous” drug to be combined with PEF for future anticancer research approaches.https://www.mdpi.com/1422-0067/23/23/14772apoptosiselectrochemotherapyECTGSHleukemiamelanoma |
spellingShingle | Christina M. Wolff Sander Bekeschus Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione International Journal of Molecular Sciences apoptosis electrochemotherapy ECT GSH leukemia melanoma |
title | Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione |
title_full | Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione |
title_fullStr | Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione |
title_full_unstemmed | Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione |
title_short | Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione |
title_sort | synergistic in vitro anticancer toxicity of pulsed electric fields and glutathione |
topic | apoptosis electrochemotherapy ECT GSH leukemia melanoma |
url | https://www.mdpi.com/1422-0067/23/23/14772 |
work_keys_str_mv | AT christinamwolff synergisticinvitroanticancertoxicityofpulsedelectricfieldsandglutathione AT sanderbekeschus synergisticinvitroanticancertoxicityofpulsedelectricfieldsandglutathione |