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Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines

BACKGROUND: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism...

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Autores principales: Parczyk, Jonas, Ruhnau, Jérôme, Pelz, Carsten, Schilling, Max, Wu, Hao, Piaskowski, Nicole Nadine, Eickholt, Britta, Kühn, Hartmut, Danker, Kerstin, Klein, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086110/
https://www.ncbi.nlm.nih.gov/pubmed/33931028
http://dx.doi.org/10.1186/s12885-021-08186-9
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author Parczyk, Jonas
Ruhnau, Jérôme
Pelz, Carsten
Schilling, Max
Wu, Hao
Piaskowski, Nicole Nadine
Eickholt, Britta
Kühn, Hartmut
Danker, Kerstin
Klein, Andreas
author_facet Parczyk, Jonas
Ruhnau, Jérôme
Pelz, Carsten
Schilling, Max
Wu, Hao
Piaskowski, Nicole Nadine
Eickholt, Britta
Kühn, Hartmut
Danker, Kerstin
Klein, Andreas
author_sort Parczyk, Jonas
collection PubMed
description BACKGROUND: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and the HIF-1α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms. METHODS: The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells. RESULTS: The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment. CONCLUSIONS: Here, we found that these tumor metabolism-targeting compounds exhibited a potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-08186-9.
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spelling pubmed-80861102021-04-30 Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines Parczyk, Jonas Ruhnau, Jérôme Pelz, Carsten Schilling, Max Wu, Hao Piaskowski, Nicole Nadine Eickholt, Britta Kühn, Hartmut Danker, Kerstin Klein, Andreas BMC Cancer Research Article BACKGROUND: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and the HIF-1α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms. METHODS: The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells. RESULTS: The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment. CONCLUSIONS: Here, we found that these tumor metabolism-targeting compounds exhibited a potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-08186-9. BioMed Central 2021-04-30 /pmc/articles/PMC8086110/ /pubmed/33931028 http://dx.doi.org/10.1186/s12885-021-08186-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Parczyk, Jonas
Ruhnau, Jérôme
Pelz, Carsten
Schilling, Max
Wu, Hao
Piaskowski, Nicole Nadine
Eickholt, Britta
Kühn, Hartmut
Danker, Kerstin
Klein, Andreas
Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines
title Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines
title_full Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines
title_fullStr Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines
title_full_unstemmed Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines
title_short Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines
title_sort dichloroacetate and px-478 exhibit strong synergistic effects in a various number of cancer cell lines
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086110/
https://www.ncbi.nlm.nih.gov/pubmed/33931028
http://dx.doi.org/10.1186/s12885-021-08186-9
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