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

Abstract

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.

The Effectiveness of Dichloroacetate on Human Glioblastoma Xenograft Growth Depends on Na+ and Mg2+ Cations

“…17,18,41 The monotherapy with NaDCA, as a mitochondrial regulator, illustrates antitumor effects in in vivo models. 24 The study of U87 and PBT24 tumors control peculiarities indicate their similar malignancy. The biomicroscopic, histomorphological analysis revealed that U87 and PBT24 tumors exhibit different sensitivity between treatment with NaDCA and MgDCA; that the efficacy of investigational medicines for xenograft growth, invasion into CAM, angiogenesis depends not only on the dichloroacetate anion concentration but also on the cation in the salt.…”

“… 17 , 18 , 41 The monotherapy with NaDCA, as a mitochondrial regulator, illustrates antitumor effects in in vivo models. 24 …”

“…21,22 The unequal anticancer efficacy of NaDCA in in vitro and in vivo studies raises some questions about the effectiveness of the medicine used in the research. 23 The NaDCA effectiveness problem may arise as some investigators do not consider the Na þ concentration state using high NaDCA doses in in vitro studies 24 ; it is essential to assess whether the NaDCA concentration in the assay medium will not result in a hypernatraemic state. In humans, a level higher than the 150 mM level of Na þ in the blood serum represents hypernatraemia.…”

Novel ammonium dichloroacetates with enhanced herbicidal activity for weed control

“…Dichloroacetic acid (DCA) and its sodium or diisopropylammonium salt, pyruvate dehydrogenase kinase (PDK) inhibitors, have been well known to possess diverse pharmacologic properties, e.g., antitumor, 26 anticancer, 27 antimetabolic agents, 28 therapeutic agents, 29 oral antidiabetic agents, 30 and more. However, the phytotoxicity of DCA to weed plants has been barely investigated.…”

Mitochondria and Cancer

“…Another interesting point in gender-related anticancer treatment is the topic of the review of Stakisaitis et al: "The Importance of Gender-Related Anticancer Research on Mitochondrial regulator Sodium Dichloroacetate in Preclinical Studies In Vivo" [2]. The review describes an excellent example of such gender-related effect by cancer treatment with sodium dichloroacetate.…”