Abstract
BackgroundOne 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.MethodsThe 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.ResultsThe 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.ConclusionsHere, 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.
Highlights
In the last decade, combinatorial approaches for cancer therapy have become increasingly popular [1]
We examined the effects of the combination of DCA and PX-478 on eight cancer cell lines and the non-cancerous cell line HEK-293
The combination of DCA and PX-478 produces synergistic effects in eight cancer cell lines and shows only minimal effects on the non-cancerous cell line HEK-293 In this study, we evaluated the effects of DCA and PX478 on eight cancer cell lines, including lung (A549 and H441), breast (MCF-7 and MDA-MB-231), cervical (HeLa), hepatocellular (HepG2), colon cancer (HT-29) and glioblastoma (U251) cell lines (Fig. 1)
Summary
Combinatorial approaches for cancer therapy have become increasingly popular [1]. Synergistic drug combinations can lead to reduced drug doses with less pronounced side effects, increased response rates and attenuated likelihoods of drug resistance [1,2,3]. In a previous work [4], we screened 14 selected compounds, including dichloroacetate (DCA) and PX478, for synergistic interactions in cancer cell lines. The combination of DCA and PX-478 displayed significantly stronger effects on cell viability than either single compound. One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. We aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms
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