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Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

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DOI: 10.4236/jct.2014.513125    3,503 Downloads   4,290 Views   Citations

ABSTRACT

Cancer cells utilize cytosolic glycolysis for their energy production even in the presence of adequate levels of oxygen (Warbug effect) due to mitochondrial defects. Dichloroacetic acid (DCA) shifts cytosolic glucose metabolism to aerobic oxidation by inhibiting mitochondrial pyruvate dehydrogenase kinase (PDK) and increasing pyruvate uptake. Therefore, DCA has potential in reversing the glycolytic metabolism defect in cancerous cells. DCA is also known to induce apoptosis in a number of cancer cell lines, the mechanism of which is not well understood. In this study, an attempt has been made to investigate the effects of DCA on aggressive human breast cancer (MCF-7) cells as compared with less aggressive mouse osteoblastic (MC3T3) cells. Cell cytotoxicity was determined by MTT, crystal violet and Trypan blue exclusion assays. Western blot was used to detect any changes in the expression of apoptotic markers. Flow cytometry was used to measure apoptotic and necrotic effects of DCA. Mitochondrial integrity was determined by change in mitochondrial membrane potential (Δψm), whereas oxidative damage was determined by production of reactive oxygen species (ROS). DCA caused a concentration-dependent cytotoxicity both in MCF-7 and MC3T3 cell lines. MCF-7 cells were most affected. Flow cytometry results showed a significantly higher apoptosis in MCF-7 even at lower concentrations of DCA. However, higher concentrations of DCA were necrotic. Western blotting showed an increased expression of Mn-SOD-1 upon DCA treatment. Further, DCA decreased Δψm and increased ROS production. The effects of DCA were more pronounced on MCF-7 cells as compared to MC3T3 cells. Our results suggest that DCA-induced cytotoxicity in cancerous cells is mediated via changes in Δψm and production of ROS.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Alkarakooly, Z. , Kilaparty, S. , Al-Anbaky, Q. , Khan, M. and Ali, N. (2014) Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species. Journal of Cancer Therapy, 5, 1234-1248. doi: 10.4236/jct.2014.513125.

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