Date of Award

1-17-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Applied Science

First Advisor

Nawab Ali

Abstract

Cancer cells are often characterized by anaerobic glycolysis due to dysfunctional mitochondria that limits pyruvate uptake for aerobic respiration. Dichloroacetic acid (DCA), used in this study as a potential cancer treatment agent, targets mitochondria in cancer cells and is likely to correct mitochondrial dysfunction by resuming pyruvate uptake and therefore normal aerobic respiration. Our results suggest that DCA causes a significantly higher cytotoxicity in aggressive MCF-7 breast cancer cells than in non-aggressive MC3T3 osteoblastic cells. Apparently lower doses of DCA induce apoptosis whereas higher doses lead to non-specific cytotoxicity or necrosis. Increased cytotoxicity might be related to oxidative stress due to an increased production of reactive oxygen species and decrease in mitochondrial membrane potential. DCA also affects cellular levels of inositol phosphates and the enzymes metabolizing them. However a definite correlation between the cytotoxic effects of DCA and inositol phosphate metabolism was not established. Cytotoxic effects of DCA were enhanced when used in a photodynamic treatment (PDT) approach using photosensitizers and He-Ne laser. The combined effects were more severe in aggressive than in non-aggressive cancer cells. Since DCA has been used previously in humans for treatment of lactic acidosis, it can safely be combined in a PDT approach to treat human cancer. However, further studies are needed to determine its suitability as a therapeutic drug using animal models. Nevertheless, this work has laid the foundation for future studies on the use of DCA as a potential agent for cancer treatment.

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