Sodium dichloroacetate (DCA) is an investigational medicinal product which has a potential anticancer preparation as a metabolic regulator in cancer cells’ mitochondria. Inhibition of pyruvate dehydrogenase kinases by DCA keeps the pyruvate dehydrogenase complex in the active form, resulting in decreased lactic acid in the tumor microenvironment. This literature review displays the preclinical research data on DCA’s effects on the cell pyruvate dehydrogenase deficiency, pyruvate mitochondrial oxidative phosphorylation, reactive oxygen species generation, and the Na+–K+–2Cl− cotransporter expression regulation in relation to gender. It presents DCA pharmacokinetics and the hepatocarcinogenic effect, and the safety data covers the DCA monotherapy efficacy for various human cancer xenografts in vivo in male and female animals. Preclinical cancer researchers report the synergistic effects of DCA combined with different drugs on cancer by reversing resistance to chemotherapy and promoting cell apoptosis. Researchers note that female and male animals differ in the mechanisms of cancerogenesis but often ignore studying DCA’s effects in relation to gender. Preclinical gender-related differences in DCA pharmacology, pharmacological mechanisms, and the elucidation of treatment efficacy in gonad hormone dependency could be relevant for individualized therapy approaches so that gender-related differences in treatment response and safety can be proposed.

It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 μM dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) xenografts in a chicken chorioallantoic membrane (CAM) model, on PCNA and EZH2 immunohistochemical expression in the tumor and on the expression of NKCC1, KCC2, E- and N-cadherin genes in TMZ-treated and control cell groups in vitro. TMZ at a 100 μg dose reduced the incidence of PBT24 xenograft invasion into the CAM, CAM thickening and the number of blood vessels in the CAM (p < 0.05), but did not affect the SF8628 tumor in the CAM model. The TMZ impact on PBT24 and SF8628 tumor PCNA expression was similarly significantly effective but did not alter EZH2 expression in the studied tumors. The TMZ at 50 μM caused significantly increased RNA expression of the NKCC1 gene in both studied cell types compared with controls (p < 0.05). The expression of the KCC2 gene was increased in PBT24 TMZ-treated cells (p < 0.05), and no TMZ effect was found in SF8628-treated cells. The study supports the suggestion that individual sensitivity to TMZ should be assessed when starting treatment.

The study’s aim was to investigate the effectiveness of sodium dichloroacetate (NaDCA) or magnesium dichloroacetate (MgDCA) on adult U87 MG and pediatric PBT24 cell lines glioblastoma (GB) xenografts in a chicken chorioallantoic membrane (CAM) model. The study groups were: treated with 10 mM, 5 mM of NaDCA, and 5 mM, 2.5 mM of MgDCA, and controls. The U87 MG and PBT24 xenografts growth, frequency of tumor invasion into CAM, CAM thickening, and the number of blood vessels in CAM differed depending on the dichloroacetate salt treatment. NaDCA impact on U87 MG and PBT24 tumor on proliferating cell nunclear antigen (PCNA) and enhancer of zeste homolog 2 (EZH2) expression in the tumor was different, depending on the NaDCA dose. The 5 mM MgDCA impact was more potent and had similar effects on U87 MG and PBT24 tumors, and its impact was also reflected in changes in PCNA and EZH2 expression in tumor cells. The U87 MG and PBT24 tumor response variations to treatment with different NaDCA concentration on tumor growth or a contrast between NaDCA and MgDCA effectiveness may reflect some differences in U87 MG and PBT24 cell biology.

Valproic acid (VPA) is a histone deacetylase inhibitor with sex-specific immunomodulatory and anticancer effects. This study aimed to investigate the effect of 0.5 and 0.75 mM VPA on NKCC1 (SLC12A2), KCC2 (SLC12A5) and SLC5A8 (SLC5A8) co-transporter gene expressions in pediatric PBT24 (boy’s) and SF8628 (girl’s) glioblastoma cells. The SLC12A2, SLC12A5 and SLC5A8 RNA expressions were determined by the RT-PCR method. The SLC12A2 and SLC5A8 expressions did not differ between the PBT24 and SF8628 controls. The SLC12A5 expression in the PBT24 control was significantly higher than in the SF8628 control. VPA treatment significantly increased the expression of SLC12A2 in PBT24 but did not affect SF8628 cells. VPA increased the SLC12A5 expression in PBT24 and SF8628 cells. The SLC12A5 expression of the PBT24-treated cells was significantly higher than in corresponding SF8628 groups. Both VPA doses increased the SLC5A8 expression in PBT24 and SF8628 cells, but the expression was significantly higher in the PBT24-treated, compared to the respective SF8628 groups. The SLC5A8 expression in PBT24-treated cells was 10-fold higher than in SF8628 cells. The distinct effects of VPA on the expression of SLC12A2, SLC12A5 and SLC5A8 in PBT24 and SF8628 glioblastoma cells suggest differences in tumor cell biology that may be gender-related.

In this study, pyruvate dehydrogenase kinase-1 inhibition with dichloroacetate (DCA) was explored as an alternative cancer therapy. The study’s aim was to compare the effectiveness of NaDCA and MgDCA on pediatric glioblastoma PBT24 and SF8628 tumors and cells. The treatment effects were evaluated on xenografts growth on a chicken embryo chorioallantoic membrane. The PCNA, EZH2, p53, survivin expression in tumor, and the SLC12A2, SLC12A5, SLC5A8, CDH1, and CDH2 expression in cells were studied. The tumor groups were: control, cells treated with 10 mM and 5 mM of NaDCA, and 5 mM and 2.5 mM of MgDCA. The cells were also treated with 3 mM DCA. Both the 10 mM DCA preparations significantly reduced PBT24 and SF8624 tumor invasion rates, while 5 mM NaDCA reduced it only in the SF8628 tumors. The 5 mM MgDCA inhibited tumor-associated neoangiogenesis in PBT24; both doses of NaDCA inhibited tumor-associated neoangiogenesis in SF8628. The 10 mM DCA inhibited the expression of markers tested in PBT24 and SF8628 tumors, but the 5 mM DCA affect on their expression depended on the cation. The DCA treatment did not affect the SLC12A2, SLC12A5, and SLC5A8 expression in cells but increased CDH1 expression in SF8628. The tumor response to DCA at different doses indicated that a contrast between NaDCA and MgDCA effectiveness reflects the differences in the tested cells’ biologies.