The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in
Magdalena Cal1, Irwin Matyjaszczyk1, Ireneusz Litwin2
1Department of Mycology and Genetics, Institute of Genetics and Microbiology, University of Wroclaw, 51-148 Wroclaw, Poland.
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.
Insights
Low concentrations of 3-bromopyruvate (3-BP) induce DNA damage in cancer cells and yeast, likely through reactive oxygen species (ROS) generation. This DNA damage triggers cell cycle arrest, offering potential for novel anticancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- 3-bromopyruvate (3-BP) is a small molecule with known anticancer properties.
- Cancer cells overexpress monocarboxylate transporters (MCTs) for selective 3-BP uptake.
- 3-BP affects cancer cell metabolism by inhibiting key enzymes, depleting ATP, and generating reactive oxygen species (ROS).
Purpose of the Study:
- To investigate the impact of 3-BP on DNA integrity at specific concentrations.
- To explore the mechanisms underlying 3-BP-induced DNA damage.
- To assess the potential of 3-BP as a DNA-damaging agent in cancer therapy.
Main Methods:
- Treatment of yeast and human cancer cells with 3-BP.
- Analysis of DNA damage markers, including double-strand breaks and H2A.X phosphorylation.
- Cell cycle analysis to determine the phase-specific effects of 3-BP.
Main Results:
- 3-BP induces DNA damage in both yeast and human cancer cells at low concentrations.
- DNA double-strand breaks are generated in yeast during the S-phase of the cell cycle.
- 3-BP treatment leads to DNA damage, checkpoint activation, and H2A.X phosphorylation in human cancer cells.
Conclusions:
- 3-BP at low concentrations can induce significant DNA damage, likely via ROS generation.
- This DNA damage response is cell cycle-dependent in yeast and involves key signaling pathways in human cancer cells.
- Understanding 3-BP's DNA-damaging effects provides insights for developing targeted anticancer therapies.
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