Effect of dichloroacetate in combination with chemotherapy on human lung cancer cells

Abstract

14637 Background: Dichloroacetate (DCA) is a small molecule that blocks mitochondrial pyruvate dehydrogenase kinase (PDK) shifting metabolism from glycolysis to glucose oxidation. The compound has been used in patients with certain inherited mitochondrial diseases, but it has not yet been studied in patients with cancer. Recently, it has been shown that DCA has anticancer properties with minimal toxicity in animal models. We hypothesized that the shift in metabolism caused by DCA on mitochondrial PDK would enhance the effects of cytotoxic chemotherapy on lung cancer cells. Methods: In order to evaluate the effect of DCA alone and in combination with cytotoxic chemotherapy on cancer growth, induction of apoptosis in human non-small cell cancer, two non-small cell lung cancer cell lines (A549 and H719) were subjected to different concentrations of DCA alone and in combination with different chemotherapeutic agents (paclitaxel, cisplatin, mitomycin C, etoposide) in vitro. Analysis included MTT assay for proliferation, Annexin V staining for apoptosis induction, and Caspase 3 activation. Results: Our results demonstrated that DCA had no effect on inducing cellular apoptosis, decreasing proliferation, and inhibiting growth rate. When combined with cytotoxic chemotherapy, we did not demonstrate additive activity in these assays when combined with paclitaxel, etoposide or cisplatin. Iinterestingly, further study revealed DCA enhanced the anti-proliferative activity of nanomolar concentrations of Mitomycin C in H719 cells (though no effect was seen on A549 cells). Conclusions: Our results suggest that DCA may enhance the activity of certain chemotherapeutic agents on cancer cells. Further studies to address the effect of DCA in combination with traditional chemotherapies on human cancer may be warranted both in vitro and in vivo. No significant financial relationships to disclose.