Biochim Biophys Acta. 2016 Jun;1860(6):1202-10. doi: 10.1016/j.bbagen.2016.01.024. Epub 2016 Feb 2.

GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate.

Jahn SC¹, Solayman MH², Lorenzo RJ¹, Langaee T³, Stacpoole PW⁴, James MO⁵.

Author information

1: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
2: Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
3: Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
4: Department of Medicine, University of Florida, Gainesville, FL 32610-0226, United States; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, United States.
5: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States. Electronic address: mojames@ufl.edu.

Abstract

Dichloroacetate (DCA), commonly used to treat metabolic disorders, is under investigation as an anti-cancer therapy due to its ability to reverse the Warburg effect and induce apoptosis in tumor cells. While DCA's mechanism of action is well-studied, other factors that influence its potential as a cancer treatment have not been thoroughly investigated. Here we show that expression of glutathione transferase zeta 1 (GSTZ1), the enzyme responsible for conversion of DCA to its inactive metabolite, glyoxylate, is downregulated in liver cancer and upregulated in some breast cancers, leading to abnormal expression of the protein. The cellular concentration of chloride, an ion that influences the stability of GSTZ1 in the presence of DCA, was also found to be abnormal in tumors, with consistently higher concentrations in hepatocellular carcinoma than in surrounding non-tumor tissue. Finally, results from experiments employing two- and three-dimensional cultures of HepG2 cells, parental and transduced to express GSTZ1, demonstrate that high levels of GSTZ1 expression confers resistance to the effect of high concentrations of DCA on cell viability. These results may have important clinical implications in determining intratumoral metabolism of DCA and, consequently, appropriate oral dosing.