Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines
The chemotherapeutic agent cisplatin typically induces apoptosis by inhibiting the cell cycle. Cancer Stem Cells (CSCs), which are a proliferative quiescent and slowly-cycling cell population, are less sensitive and therefore frequently spared from toxic effects. Thus, it remains a priority to incre...
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doaj-a1a36eeedf7b4b789ae161979d2d33482021-05-20T07:36:59ZengElsevierBiomedicine & Pharmacotherapy0753-33222019-05-01113Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell linesZhi Yang0Fang Guo1Andreas E. Albers2Jalid Sehouli3Andreas M. Kaufmann4Clinic for Gynecology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyClinic for Gynecology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyDepartment of Otolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyClinic for Gynecology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyClinic for Gynecology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Corresponding author at: Clinic for Gynecology, Hindenburgdamm 30, 12203 Berlin, Germany.The chemotherapeutic agent cisplatin typically induces apoptosis by inhibiting the cell cycle. Cancer Stem Cells (CSCs), which are a proliferative quiescent and slowly-cycling cell population, are less sensitive and therefore frequently spared from toxic effects. Thus, it remains a priority to increase the sensitivity of CSCs to cisplatin-based chemotherapy, or to specifically target CSCs to improve the therapeutic outcome in breast cancer. Disulfiram (DSF) is a drug used clinically for alcoholism treatment that has displayed promising anti-cancer activity in vitro and in cancer xenografts in breast cancer. Our study provides evidence that DSF inhibits Aldehyde dehydrogenase (ALDH) enzyme activity, inhibits the expression of stemness-related transcription factors (Sox, Nanog, Oct) in CSC derived from breast cancer cell lines, and modulates intracellular reactive oxygen species (ROS) generation. Importantly, our research proved that ALDH + stem-like cells play important roles in the resistance to the conventional chemotherapeutic agent cisplatin. DSF enhances the cytotoxic effect of cisplatin through inhibiting the stemness and by overcoming cisplatin resistance of ALDH + stem-like cells. A quantitative measurement showed the synergistic effect of DSF and cisplatin. Further, we show that ALDH + cancer stem-like cells and ALDH- bulk cancer cells have different intrinsic ROS levels, what may explain differences in susceptibility to cisplatin treatment. Importantly, this difference is eliminated by DSF treatment making both cell types similarly susceptible for cytotoxic effects by cisplatin. These findings may influence chemotherapeutic treatment approaches in the future.http://www.sciencedirect.com/science/article/pii/S0753332218379137ALDH enzyme activityROSChemotherapy resistanceCancer stem cellsNovel adjuvant treatment |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhi Yang Fang Guo Andreas E. Albers Jalid Sehouli Andreas M. Kaufmann |
spellingShingle |
Zhi Yang Fang Guo Andreas E. Albers Jalid Sehouli Andreas M. Kaufmann Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines Biomedicine & Pharmacotherapy ALDH enzyme activity ROS Chemotherapy resistance Cancer stem cells Novel adjuvant treatment |
author_facet |
Zhi Yang Fang Guo Andreas E. Albers Jalid Sehouli Andreas M. Kaufmann |
author_sort |
Zhi Yang |
title |
Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines |
title_short |
Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines |
title_full |
Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines |
title_fullStr |
Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines |
title_full_unstemmed |
Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines |
title_sort |
disulfiram modulates ros accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines |
publisher |
Elsevier |
series |
Biomedicine & Pharmacotherapy |
issn |
0753-3322 |
publishDate |
2019-05-01 |
description |
The chemotherapeutic agent cisplatin typically induces apoptosis by inhibiting the cell cycle. Cancer Stem Cells (CSCs), which are a proliferative quiescent and slowly-cycling cell population, are less sensitive and therefore frequently spared from toxic effects. Thus, it remains a priority to increase the sensitivity of CSCs to cisplatin-based chemotherapy, or to specifically target CSCs to improve the therapeutic outcome in breast cancer. Disulfiram (DSF) is a drug used clinically for alcoholism treatment that has displayed promising anti-cancer activity in vitro and in cancer xenografts in breast cancer. Our study provides evidence that DSF inhibits Aldehyde dehydrogenase (ALDH) enzyme activity, inhibits the expression of stemness-related transcription factors (Sox, Nanog, Oct) in CSC derived from breast cancer cell lines, and modulates intracellular reactive oxygen species (ROS) generation. Importantly, our research proved that ALDH + stem-like cells play important roles in the resistance to the conventional chemotherapeutic agent cisplatin. DSF enhances the cytotoxic effect of cisplatin through inhibiting the stemness and by overcoming cisplatin resistance of ALDH + stem-like cells. A quantitative measurement showed the synergistic effect of DSF and cisplatin. Further, we show that ALDH + cancer stem-like cells and ALDH- bulk cancer cells have different intrinsic ROS levels, what may explain differences in susceptibility to cisplatin treatment. Importantly, this difference is eliminated by DSF treatment making both cell types similarly susceptible for cytotoxic effects by cisplatin. These findings may influence chemotherapeutic treatment approaches in the future. |
topic |
ALDH enzyme activity ROS Chemotherapy resistance Cancer stem cells Novel adjuvant treatment |
url |
http://www.sciencedirect.com/science/article/pii/S0753332218379137 |
work_keys_str_mv |
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