The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells
Magdalena Cal, Irwin Matyjaszczyk, Ireneusz Litwin, Daria Augustyniak, Rafał Ogórek, Young Hee Ko, Stanisław Ułaszewski
Abstract
3-bromopyruvate (3-BP) is a small molecule with anticancer and antimicrobial activities. 3-BP is taken up selectively by cancer cells' mono-carboxylate transporters (MCTs), which are highly overexpressed by many cancers. When 3-BP enters cancer cells it inactivates several glycolytic and mitochondrial enzymes, leading to ATP depletion and the generation of reactive oxygen species. While mechanisms of 3-BP uptake and its influence on cell metabolism are well understood, the impact of 3-BP at certain concentrations on DNA integrity has never been investigated in detail. Here we have collected several lines of evidence suggesting that 3-BP induces DNA damage probably as a result of ROS generation, in both yeast and human cancer cells, when its concentration is sufficiently low and most cells are still viable. We also demonstrate that in yeast 3-BP treatment leads to generation of DNA double-strand breaks only in S-phase of the cell cycle, possibly as a result of oxidative DNA damage. This leads to DNA damage, checkpoint activation and focal accumulation of the DNA response proteins. Interestingly, in human cancer cells exposure to 3-BP also induces DNA breaks that trigger H2A.X phosphorylation. Our current data shed new light on the mechanisms by which a sufficiently low concentration of 3-BP can induce cytotoxicity at the DNA level, a finding that might be important for the future design of anticancer therapies.