Dichloroacetate Modifies Tumor Cell Mitochondria

Cancer researchers have found that the small molecule dichloroacetate (DCA) can selectively modify the physical state of tumor cell mitochondria thereby slowing or stopping tumor growth.

Dichloroacetate stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenase kinase. As such it decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. This property has been used to treat lactic acidosis in humans.

Compared to normal cells, several human cancers have high mitochondrial membrane potentials and low potassium channel levels. These properties apparently make the cancer cell less vulnerable to apoptosis. Investigators at the University of Alberta (Edmonton, CA) worked with both cancer cell cultures and animal cancer models to study the possible therapeutic benefits of DCA. They based their study on previous findings that DCA inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases levels of mitochondrial hydrogen peroxide, and activates potassium channels in all types of cancer (without effecting the mitorchondria of normal cells).

They reported in the January 2007 issue of Cancer Cell that DCA-induced apoptosis, decreased proliferation, and inhibited tumor growth, without apparent toxicity. "I think DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells,” said senior author Dr. Evangelos Michelakis, assistant professor of medicine at the University of Alberta. "Cancer cells actively suppress their mitochondria, which alters their metabolism, and this appears to offer cancer cells a significant advantage in growth compared to normal cells, as well as protection from many standard chemotherapies. Because mitochondria regulate cell death--or apoptosis--cancer cells can thus achieve resistance to apoptosis, and this appears to be reversed by DCA.”

Since DCA has been used in to treat patients with mitochondrial diseases, researchers already know that it is a relatively non-toxic molecule that can be immediately tested in cancer patients.



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