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Evaluating a Dichloroacetate and Metformin Combination in a Mouse Model of Metastatic Cancer
Author(s) -
Ward Nathan,
Poff Angela,
Van Putten Ashley,
Seyfried Thomas,
D'Agostino Dominic
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.725.10
Subject(s) - metformin , pyruvate dehydrogenase kinase , pyruvate dehydrogenase complex , pharmacology , glycolysis , cancer , cancer cell , pkm2 , medicine , cancer research , chemistry , pyruvate kinase , metabolism , biochemistry , enzyme , insulin
The increased focus on targeting the glycolytic dependency of cancer cells has yielded a number of new therapeutic options with varying promise. Among the therapies currently being investigated thoroughly are dichloroacetate (DCA) and metformin. These agents have been repurposed from other metabolic disorders because of their activities in altering glucose metabolism. Both have exhibited toxicity against a number of cancers without damaging normal tissue, and are also shown to enhance the efficacy of various chemotherapeutics. DCA, an inhibitor of pyruvate dehydrogenase kinase, promotes glucose oxidation through the activation of pyruvate dehydrogenase and subsequent flux of pyruvate through the TCA cycle. Metformin is shown to indirectly activate AMPK through inhibition of complex I of the mitochondrial respiratory chain. We hypothesize that combining these agents will severely alter energy metabolism in tumor cells, resulting in mitochondrial instability and cancer‐specific cell death. We tested the therapeutic efficacy of DCA and metformin in the VM‐M3 model of metastatic cancer. Dietary administration of 500 mg/kg doses of DCA and metformin significantly increased mean survival time (69%, p<.01 and 58%, p<.05 respectively) over untreated control animals. Tumor volume and metastatic spread were reduced in treated animals compared to controls. In vitro incubation with DCA and metformin resulted in a synergistic reduction of VM‐M3 proliferation and viability (p<.05). These data support the further study of a DCA and metformin combination as a potential metabolic therapy for cancer.