Superior anti-tumor efficacy of diisopropylamine dichloroacetate compared with dichloroacetate in a subcutaneous transplantation breast tumor model

Abstract

Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, has anti-tumor properties in various carcinoma models. Diisopropylamine dichloroacetate (DADA), an over-the-counter drug for chronic liver disease, is a derivative of DCA. To date, few studies have evaluated the anticancer potential of DADA in breast cancer. In this study, MDA-MB-231 cells, a breast adenocarcinoma cell line, were used in in vitro and in vivo experiments to evaluate the anti-tumor efficacy of DADA and DCA. The half maximal inhibitory concentration (IC50) of DADA (7.1 ± 1.1 mmol/L) against MDA-MB-231 cells was significantly lower than that of DCA (15.6 ± 2.0 mmol/L); 100 mg/kg (0.0004 mol/kg) DADA was better than 100 mg/kg (0.0008 mol/kg) DCA at suppressing the growth of subcutaneous transplantation breast tumor at the same dose after 24 days intervention. Histological examination showed that both DCA and DADA interventions led to necrosis, inflammation, and fibrosis of tumor tissue in a mouse subcutaneous transplantation breast tumor model. DADA treatment inhibited Ki67 expression in tumor tissue. In vitro experiments showed that DADA could inhibit lactic acid production and glucose uptake in MDA-MB-231 cells at 10 mmol/L and these effects were stronger than DCA. DADA administration also induced complete autophagy during early treatment stages and incomplete autophagy and cell death at later treatment stages. In conclusion, DADA showed better anti-tumor efficacy than DCA in a breast cancer model.

Loss of PDK4 switches the hepatic NF‐κB/TNF pathway from pro‐survival to pro‐apoptosis

“…Intriguingly, the PDKs' pan‐inhibitor dichloroacetate and PDK4's specific inhibitor diisopropylamine dichloroacetate (DADA) exhibit antitumor efficacy in breast cancer models by inducing cell death . In this regard, PDK4 inhibitors might be particularly useful in triggering cell death in HCC and other cancers.…”

Metabolic host response and therapeutic approaches to influenza infection

“…Furthermore, dichloroacetate (DCA) is a pyruvate dehydrogenase kinase inhibitor with anti-tumor activity in a variety of carcinomas. Studies have also indicated that diisopropylamine dichloroacetate (DADA) could ameliorate the metabolism of hepatocytes in chronic liver disease [165]. In a study by Yamane et al attempting to evaluate the effect of DADA on influenza-infected mice (PR8), oral administration of DADA was found to not only restore the activity of PDH and ATP in affected organs but also suppress cytokine storm and viral replication [94].…”

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

“…Experimental human cancer xenograft studies in vivo with the DCA treatment monotherapy has been found to have antitumor properties in non-small cell lung cancer [83,170,171], lung adenocarcinoma [172], breast adenocarcinoma [171,173], colorectal cancer [174,175], neuroblastoma [176], glioblastoma [177], pancreatic cancer [178,179], hepatocellular carcinoma [53,180], and ovarian adenocarcinoma [181]. Other researchers found that DCA treatment did not exert antitumor activity against xenografted non-small cell lung cancer [170,182], breast adenocarcinoma [9,183], colon and colorectal cancer [184,185,186,187], and glioblastoma [188,189] in vivo (Table 2).…”

“…As shown in Table 2, a remarkable number of papers did not indicate the gender of animals used for research, and this concerns 46.7% of the DCA-treated groups described in the manuscripts. It is understandable when the researchers used female animals for breast or ovary cancer studies [9,173,183], but there was no grounded reason for why they chose to conduct the studies on different genders in other cancer localizations. As shown in Table 2, of all investigated animal groups, the sex was not indicated for 47% of cases.…”