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 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.

DCA Protects against Oxidation Injury Attributed to Cerebral Ischemia‐Reperfusion by Regulating Glycolysis through PDK2‐PDH‐Nrf2 Axis

“…Previous studies have shown that DCA is a pharmacological agent that activates PDH by inhibiting PDK and also shows significant neuroprotective potential. The administration of DCA has been suggested to facilitate local lactic acid removal [ 32 ], tumor therapy [ 33 ], and pulmonary hypertension [ 34 ]. However, the protective effect, molecular mechanism, and blood-brain barrier permeability of DCA in cerebral IS and I/R injury have been rarely investigated.…”

Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo

“…Synergism has been reported when DCA is combined with different drugs for anti-cancer research: DCA/cisplatin or gefitnib or elotinib ( Al-Azawi et al, 2021 ), DCA/metformin ( Kim et al, 2021 ; Klose et al, 2021 ; Korsakova et al, 2021 ), DCA/3-bromopyruvate ( Nikravesh et al, 2021 ), DCA/sorafenib ( Sun et al, 2021 ), DCA/PX-478 ( Parczyk et al, 2021 ) and DCA/erlotinib ( Dyrstad et al, 2021 ). Said synergistic effect has also been observed when Nic is combined with other agents: Nic/gemcitabine ( Guo et al, 2022b ), Nic/metformin ( Kang et al, 2021 ) and Nic/doxorubicin ( Lohiya and Katti, 2021 ).…”

“…DCA has been shown to elevate hydrogen peroxide ( Xie et al, 2011 ) and ROS ( Kumar et al, 2012 ; Duan et al, 2013 ; Kim et al, 2021 ; Klose et al, 2021 ; Nikravesh et al, 2021 ). In addition, ROS is increased when DCA is combined with sorafenib ( Sun et al, 2021 ) or PX-478 ( Parczyk et al, 2021 ). Nic also increases ROS ( Zhou et al, 2017 ; Shangguan et al, 2020 ; Kaushal et al, 2021 ; Lohiya and Katti, 2021 ).…”

Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment

“…However, in recent years, no additional clinical studies on PX-478 have been reported, and more studies on PX-478 in combination with other drugs are needed to reduce the side effects of the drug itself and improve efficacy. The combination of DCA and PX-478 demonstrated synergistic effects in a variety of cancers, inhibiting cancer proliferation through the production of ROS and apoptosis ( 110 ). Currently, phase I clinical trials are ongoing in patients with advanced solid tumors.…”