Abstract
3-bromopuryvate (3-BP) is a compound with unique antitumor activity. It has a selective action against tumor cells that exhibit the Warburg effect. It has been proven that the action of 3-BP is pleiotropic: it acts on proteins, glycolytic enzymes, reduces the amount of ATP, induces the formation of ROS (reactive oxygen species), and induces nuclear DNA damage. Mitochondria are important organelles for the proper functioning of the cell. The production of cellular energy (ATP), the proper functioning of the respiratory chain, or participation in the production of amino acids are one of the many functions of mitochondria. Here, for the first time, we show on the yeast model that 3-BP acts in the eukaryotic cell also by influence on mitochondria and that agents inhibiting mitochondrial function can potentially be used in cancer therapy with 3-BP. We show that cells with functional mitochondria are more resistant to 3-BP than rho0 cells. Using an MTT assay (a colorimetric assay for assessing cell metabolic activity), we demonstrated that 3-BP decreased mitochondrial activity in yeast in a dose-dependent manner. 3-BP induces mitochondrial-dependent ROS generation which results in ∆sod2, ∆por1, or ∆gpx1 mutant sensitivity to 3-BP. Probably due to ROS mtDNA lesions rise during 3-BP treatment. Our findings may have a significant impact on the therapy with 3-BP.
Highlights
Yeast are facultative anaerobes which means that when grown on a medium with a non-fermentable carbon source the mitochondrial respiratory function is indispensable for yeast to survive
We showed in this work that 3-BP leads to generated mitochondrial-mediated reactive oxygen species (ROS), mitochondrial DNA (mtDNA) lesions, and that 3-BP impaired mitochondrial function
We know that S. cerevisiae can function without mtDNA [38], so we further investigate the role of the respiratory chain in dealing with stress induced can further investigate the role of the respiratory chain in dealing with stress induced by by the presence dye specifthe presenceofof3-BP
Summary
Many studies published on 3-BP indicate that after entering the cell (by monocarboxylate transporters—MCTs in human cancer cells [1,2] and through the lactate/pyruvate H+ symporter Jen in yeast [3]) it turns out to have a pleiotropic effect This effect results from numerous activities, where the best from described is the effect on metabolism by inhibition of key glycolytic enzymes including hexokinase II [4,5,6,7], glyceraldehyde 3-phosphate dehydrogenase (GAPDH) [8], and lactate dehydrogenase (LDH). Disturbances in the proper functioning of mitochondria are associated with extremely severe consequences for the cell: e.g., lack of cellular energy, excess free radicals, or disturbances in the repair of damaged DNA.
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