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. Further, the likelihood of drug resistance is reduced. Distinct alterations in tumour metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for a synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor and HIF1-α 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 MTT or 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 cancer metabolism-targeting compounds exhibited 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.

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts

“…The increased activity of glycolytic genes and enzymes in tumors represents an important resistance factor against apoptosis [446]. DCA anti-tumor effects are significantly increased when used in association with PX-478, a HIF-1α inhibitor [447].…”

Hypoxia and the Tumor Microenvironment

“…HIF inhibitors are an important type of hypoxia targeted therapy drugs and a large number of studies have shown that HIF inhibitors (such as PX-478, LW6), either as a single agent or in combination with other therapeutic agents, exhibited promising anti-tumor effects. 81- 84…”