Introduction
The primary hurdle for effective chemotherapy is the inherent or acquired drug resistance of cancer cells. The glycolytic phenotype (or Warburg effect) is a major metabolic signature of cancer cells. Recent studies have linked changes in cancer cell metabolism to multi-drug resistance phenotypes. Dichloroacetic acid (DCA) is a non-toxic drug, which can reverse the glycolytic phenotype by inhibiting pyruvate dehydrogenase kinases (PDKs). We have examined whether reversal of the glycolytic phenotype with DCA can restore drug sensitivity in resistant cancer cells.
Methodology
We examined DCA’s effects in doxorubicin (DOX)-resistant MDA-MB-231, MCF7 and PC3 cells (made by continuous exposure to increasing DOX concentrations for one month) and their DOX-sensitive counterparts by neutral red cell viability assay. Intracellular drug concentrations were measured by flow cytometry and western blotting was used to determine protein levels of drug transporters and PDKs.
Results
DCA treatment (1mM for 48hrs) significantly (p<0.05) enhanced DOX toxicity in DOX-resistant cells restoring sensitivity to a level similar to parental cells. This is despite DCA having no effect on DOX toxicity in parental cells. DCA pre-treatment increased the intracellular retention of DOX. DCA effectively reduced the expression of ATP-binding cassette (ABC) drug transporters such as P-glycoprotein and ABCG2. Drug resistant cells displayed elevated PDK2, which was repressed with DCA treatment.
Conclusion
DCA may be an effective chemo-sensitizing agent in drug resistant cancers, acting by reducing drug transporter expression and inhibiting PDK2.