Department of Mycology and Genetics, Institute of Genetics and Microbiology, University of Wroclaw, 51-148 Wroclaw, Poland.
Department of Genetics and Cellular Physiology, Institute of Experimental Biology, University of Wroclaw, 50-328 Wroclaw, Poland.
Cells. 2020 May 8;9(5):1161. doi: 10.3390/cells9051161.
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.
3-溴丙酮酸（3-BP）是一种具有抗癌和抗菌活性的小分子。3-BP 被许多癌症高度过表达的癌细胞单羧酸转运蛋白（MCTs）选择性摄取。当 3-BP 进入癌细胞时，它会使几种糖酵解和线粒体酶失活，导致 ATP 耗竭和活性氧的产生。虽然 3-BP 的摄取机制及其对细胞代谢的影响已经得到很好的理解，但在特定浓度下 3-BP 对 DNA 完整性的影响从未被详细研究过。在这里，我们收集了一些证据表明，当 3-BP 的浓度足够低且大多数细胞仍然存活时，它可能会由于 ROS 的产生而在酵母和人类癌细胞中诱导 DNA 损伤。我们还证明，在酵母中，3-BP 处理仅在细胞周期的 S 期导致 DNA 双链断裂，可能是由于氧化 DNA 损伤所致。这会导致 DNA 损伤、检查点激活和 DNA 反应蛋白的焦点积累。有趣的是，人类癌细胞暴露于 3-BP 也会诱导引发 H2A.X 磷酸化的 DNA 断裂。我们目前的数据为 3-BP 以足够低的浓度在 DNA 水平上诱导细胞毒性的机制提供了新的线索，这一发现可能对未来抗癌疗法的设计很重要。
