Abstract
Targeting mitochondrial energy metabolism is a novel approach in cancer research and can be traced back to the description of the Warburg effect. Dichloroacetate, a controversially discussed subject of many studies in cancer research, is a pyruvate dehydrogenase kinase inhibitor. Dichloroacetate causes metabolic changes in cancerous glycolysis towards oxidative phosphorylation via indirect activation of pyruvate dehydrogenase in mitochondria. Canine mammary cancer is frequently diagnosed but after therapy prognosis still remains poor. In this study, canine mammary carcinoma, adenoma and non-neoplastic mammary gland cell lines were treated using 10 mM Dichloroacetate. The effect on cell number, lactate release and PDH expression and cell respiration was investigated. Further, the effect on apoptosis and several apoptotic proteins, proliferation, and microRNA expression was evaluated. Dichloroacetate was found to reduce cell proliferation without inducing apoptosis in all examined cell lines.
Highlights
Mammary tumors are the most frequent neoplasia in intact female dogs and often accompanied with high recurrence and metastasis rates [1]
A comparable significant effect was observed in the mammary adenoma cell line ZMTH3 (p = 0.0131) and could be constituted in the non-cancerous mammary gland derived cell line MTH53A (p = 0.0039)
The proliferation, assessed by detection of the proliferation marker Ki67, decreased significantly in all mammary cell lines with exception of the non-neoplastic mammary gland derived cell line MTH53A in comparison to non-treated control and further a significant decrease in proliferation can be observed within comparison of MTH53A and the other cell lines
Summary
Mammary tumors are the most frequent neoplasia in intact female dogs and often accompanied with high recurrence and metastasis rates [1]. In advanced tumor disease the prognosis still remains poor [1] new alternatives for chemotherapy have to be investigated. The Warburg effect was characterized in the early 1920s by Otto Warburg and describes the metabolic energy production of most cancer cells which rely on aerobic glycolysis in presence of oxygen [2, 3]. Hypoxia in early cancer transformation results in expression of hypoxia inducible factor 1 alpha (HIF-1α) activating pyruvate dehydrogenase kinase (PDK), a pyruvate dehydrogenase (PDH) inhibiting enzyme [4]. PDH inhibition prevents incorporation of pyruvate in mitochondria and is related with cytoplasmic metabolization of pyruvate to lactate [4]. Compensation of negative energy output during glycolysis occurs with increased expression of glycose transporters induced by HIF-1α [5].
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