Most solid tumors are characterized by aerobic glycolysis in which pyruvate is converted to lactate by the enzyme lactate dehydrogenase in cytosol. Oxamate produces its cancer growth inhibition by inhibition of lactate dehydrogenase. The inhibition leads to accumulation of pyruvate. Dichloroacetate (DCA) inhibits cancer growth through an inhibition of pyruvate dehydrogenase kinase which allows for more pyruvate dehydrogenase available for mitochondria pyruvate oxidation. A combination of oxamate and DCA is expected to block aerobic glycolysis and facilitate mitochondria oxidation of pyruvate. Therefore, the combination is expected to inhibit cancer growth more effectively than either alone.
SDSU researchers have designed and synthesized prodrug candidates which combine DCA and oxamate using a nontoxic polyalcohol. These prodrugs have shown an increased ability to inhibit tumor formation in mice than DCA or oxamate either given alone or together.
A combination of oxamate and DCA should effectively inhibit cancer growth through blocking pyruvate conversion to lactate, and pushing pyruvate to mitochondria for oxidative oxidation. The prodrugs are showing an increase in tumor inhibition in comparison to giving oxamate and DCA alone or together to mice.