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

Abstract 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 met...

Full description

Bibliographic Details
Main Authors:	Jonas Parczyk, Jérôme Ruhnau, Carsten Pelz, Max Schilling, Hao Wu, Nicole Nadine Piaskowski, Britta Eickholt, Hartmut Kühn, Kerstin Danker, Andreas Klein
Format:	Article
Language:	English
Published:	BMC 2021-04-01
Series:	BMC Cancer
Subjects:	PX-478 HIF-1α inhibition Dichloroacetate Synergism Cancer therapy Drug combination
Online Access:	https://doi.org/10.1186/s12885-021-08186-9

id	doaj-d088ebf1f5634ab2825caf74af90cb4a
record_format	Article
spelling	doaj-d088ebf1f5634ab2825caf74af90cb4a2021-05-02T11:47:13ZengBMCBMC Cancer1471-24072021-04-0121111410.1186/s12885-021-08186-9Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell linesJonas Parczyk0Jérôme Ruhnau1Carsten Pelz2Max Schilling3Hao Wu4Nicole Nadine Piaskowski5Britta Eickholt6Hartmut Kühn7Kerstin Danker8Andreas Klein9Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthAbstract 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.https://doi.org/10.1186/s12885-021-08186-9PX-478HIF-1α inhibitionDichloroacetateSynergismCancer therapyDrug combination
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Jonas Parczyk Jérôme Ruhnau Carsten Pelz Max Schilling Hao Wu Nicole Nadine Piaskowski Britta Eickholt Hartmut Kühn Kerstin Danker Andreas Klein
spellingShingle	Jonas Parczyk Jérôme Ruhnau Carsten Pelz Max Schilling Hao Wu Nicole Nadine Piaskowski Britta Eickholt Hartmut Kühn Kerstin Danker Andreas Klein Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines BMC Cancer PX-478 HIF-1α inhibition Dichloroacetate Synergism Cancer therapy Drug combination
author_facet	Jonas Parczyk Jérôme Ruhnau Carsten Pelz Max Schilling Hao Wu Nicole Nadine Piaskowski Britta Eickholt Hartmut Kühn Kerstin Danker Andreas Klein
author_sort	Jonas Parczyk
title	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_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_sort	dichloroacetate and px-478 exhibit strong synergistic effects in a various number of cancer cell lines
publisher	BMC
series	BMC Cancer
issn	1471-2407
publishDate	2021-04-01
description	Abstract 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.
topic	PX-478 HIF-1α inhibition Dichloroacetate Synergism Cancer therapy Drug combination
url	https://doi.org/10.1186/s12885-021-08186-9
work_keys_str_mv	AT jonasparczyk dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT jeromeruhnau dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT carstenpelz dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT maxschilling dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT haowu dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT nicolenadinepiaskowski dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT brittaeickholt dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT hartmutkuhn dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT kerstindanker dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines AT andreasklein dichloroacetateandpx478exhibitstrongsynergisticeffectsinavariousnumberofcancercelllines
_version_	1721491778707652608

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

Similar Items