Investigation on the mechanism of dichloroacetate (DCA) induced apoptosis in breast cancer

Investigation on the mechanism of dichloroacetate (DCA) induced apoptosis in breast cancer

investigation of how dichloroacetate (DCA) causes breast cancer cells to die

L. Ko and J. Allalunis-Turner

Cross Cancer Institute, Canada, Edmonton, AB

Journal of Clinical Oncology: Proceedings of the 2009 ASCO Annual Meeting
2009, May 20 Supplement, Vol. 27, No. 15S, e14637

© 2009 American Society of Clinical Oncology



Background: Lactic acidosis and mitochondrial disorders have long been treated with the generic, orally obtainable small chemical metabolic modulator DCA. Pyruvate dehydrogenase kinase (PDK), an inhibitor of pyruvate dehydrogenase, a crucial enzyme in the metabolism of glucose, is inhibited by DCA. DCA reverses the distinctive aerobic glycolysis characteristic in solid tumors by preferentially switching the glucose metabolism in cancer cells from glycolysis to glucose oxidation. As shown by the outflow of cytochrome c and apoptosis-inducing factor from the mitochondria, DCA caused apoptosis in cancer cells. Apoptosis induction by DCA has been proposed in recent research for glioblastoma, endometrial, prostate, and non-small cell lung malignancies. We try to establish a relationship between DCA and apoptosis in breast cancer cell lines in this study. Methods: Investigated were six cell lines for breast cancer (BT474, MCF-7, MDA-MB231, MDA- MB468, SKBR3, T47D). Taqman probes were used in a quantitative real-time polymerase chain reaction (RT-PCR) with DCA doses ranging from 0 to 20 mM to discover enhanced DNA templates for PDK isoforms 1-4. Western blots were used to detect elevated PDK isoform expression and correlate results with Taqman. To assess decreased mitochondrial activity and cytotoxicity, MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium) tests were used. For the purpose of measuring apoptosis and cell death, flow cytometry was carried out using annexin V and propidium iodide. Results: After DCA treatment, MDA-MB231 cells had higher DNA expression levels of all PDK isoforms, according to RT-PCR. The impact was greatest at 10 mM concentration. In MCF-7 cells and T47D cells, 10mM of DCA also boosted DNA expression of all PDK isoforms and PDK1. All six cell lines demonstrated enhanced cell death and decreased mitochondrial activity in MTS tests, with IC50 values ranging from 20 mM to 30 mM. DCA promoted apoptosis in BT474 and MCF-7 cell lines at IC50, according to flow cytometry. Conclusions: With elevated PDK isoform expression, cytotoxicity, and decreased mitochondrial function, apoptosis appears to be involved in the mechanism of DCA in breast cancer. Data from flow cytometry revealed that two cell lines were subject to DCA-induced apoptosis.

No significant financial relationships to disclose.