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Open Access 01-12-2021 | Cancer Therapy | Research article

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

Authors: Jonas Parczyk, Jérôme Ruhnau, Carsten Pelz, Max Schilling, Hao Wu, Nicole Nadine Piaskowski, Britta Eickholt, Hartmut Kühn, Kerstin Danker, Andreas Klein

Published in: BMC Cancer | Issue 1/2021

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.

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Title: Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines
Authors: Jonas Parczyk
Jérôme Ruhnau
Carsten Pelz
Max Schilling
Hao Wu
Nicole Nadine Piaskowski
Britta Eickholt
Hartmut Kühn
Kerstin Danker
Andreas Klein
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Cancer Therapy
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08186-9

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