The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells
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 mitochondri...
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MDPI AG
2020-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/5/1161 |
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| author | Magdalena Cal Irwin Matyjaszczyk Ireneusz Litwin Daria Augustyniak Rafał Ogórek Young Ko Stanisław Ułaszewski |
| author_facet | Magdalena Cal Irwin Matyjaszczyk Ireneusz Litwin Daria Augustyniak Rafał Ogórek Young Ko Stanisław Ułaszewski |
| author_sort | Magdalena Cal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:58:30Z |
| format | Article |
| id | doaj.art-8168ad7a51fb4b16aaeba53ded80a652 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:58:30Z |
| publishDate | 2020-05-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-8168ad7a51fb4b16aaeba53ded80a6522023-11-19T23:46:50ZengMDPI AGCells2073-44092020-05-0195116110.3390/cells9051161The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer CellsMagdalena Cal0Irwin Matyjaszczyk1Ireneusz Litwin2Daria Augustyniak3Rafał Ogórek4Young Ko5Stanisław Ułaszewski6Department of Mycology and Genetics, Institute of Genetics and Microbiology, University of Wroclaw, 51-148 Wroclaw, PolandDepartment of Mycology and Genetics, Institute of Genetics and Microbiology, University of Wroclaw, 51-148 Wroclaw, PolandDepartment of Genetics and Cellular Physiology, Institute of Experimental Biology, University of Wroclaw, 50-328 Wroclaw, PolandDepartment of Pathogen Biology and Immunology, Institute of Genetics and Microbiology, University of Wroclaw, 51-148 Wroclaw, PolandDepartment of Mycology and Genetics, Institute of Genetics and Microbiology, University of Wroclaw, 51-148 Wroclaw, PolandKoDiscovery, LLC, UM BioPark, Baltimore, MD 21201, USADepartment of Mycology and Genetics, Institute of Genetics and Microbiology, University of Wroclaw, 51-148 Wroclaw, Poland3-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.https://www.mdpi.com/2073-4409/9/5/11613-bromopyruvateDNA damageDNA double-strand breakoxidative stressyeasthuman monocytes |
| spellingShingle | Magdalena Cal Irwin Matyjaszczyk Ireneusz Litwin Daria Augustyniak Rafał Ogórek Young Ko Stanisław Ułaszewski The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells Cells 3-bromopyruvate DNA damage DNA double-strand break oxidative stress yeast human monocytes |
| title | The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells |
| title_full | The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells |
| title_fullStr | The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells |
| title_full_unstemmed | The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells |
| title_short | The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells |
| title_sort | anticancer drug 3 bromopyruvate induces dna damage potentially through reactive oxygen species in yeast and in human cancer cells |
| topic | 3-bromopyruvate DNA damage DNA double-strand break oxidative stress yeast human monocytes |
| url | https://www.mdpi.com/2073-4409/9/5/1161 |
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