ArticleJournal of molecular biology2009
Cyanide, peroxide and nitric oxide formation in solutions of hydroxyurea causes cellular toxicity and may contribute to its therapeutic potency.
Article in Journal of molecular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 35 citations in OpenAlex.
- Hydroxyurea modulates thiol-disulfide homeostasis in the yeast endoplasmic reticulum.Life science alliance · 2025Article
- Genome-wide conditional degron libraries for functional genomics.The Journal of cell biology · 2025Article
- Article
- Catastrophic chromosome fragmentation probes the nucleoid structure and dynamics in Escherichia coli.Nucleic acids research · 2022Article
- Intracellular acidification is a hallmark of thymineless death in E. coli.PLoS genetics · 2022Article
- Thymine-starvation-induced chromosomal fragmentation is not required for thymineless death in Escherichia coli.Molecular microbiology · 2022Article
- Nitric oxide precipitates catastrophic chromosome fragmentation by bolstering both hydrogen peroxide and Fe(II) Fenton reactants in E. coli.The Journal of biological chemistry · 2022Article
- Oxidative Damage Blocks Thymineless Death and Trimethoprim Poisoning in Escherichia coli.Journal of bacteriology · 2022Article
- Electron Microscopy Reveals Unexpected Cytoplasm and Envelope Changes during Thymineless Death in Escherichia coli.Journal of bacteriology · 2021Article
- Hydroxyurea-The Good, the Bad and the Ugly.Genes · 2021Review
- Hydroxyurea Induces a Stress Response That Alters DNA Replication and Nucleotide Metabolism in Bacillus subtilis.Journal of bacteriology · 2021Article
- Catalase inhibition by nitric oxide potentiates hydrogen peroxide to trigger catastrophic chromosome fragmentation in Escherichia coli.Genetics · 2021Article
- Phenotypic Characterization ofFrontiers in microbiology · 2021Article
- Article
- Sources of thymidine and analogs fueling futile damage-repair cycles and ss-gap accumulation during thymine starvation in Escherichia coli.DNA repair · 2019Article
- Replication Rapidly Recovers and Continues in the Presence of Hydroxyurea in Escherichia coli.Journal of bacteriology · 2018Article
- Substrate Specificity for Bacterial RNases HII and HIII Is Influenced by Metal Availability.Journal of bacteriology · 2018Article
- Potentiation of hydrogen peroxide toxicity: From catalase inhibition to stable DNA-iron complexes.Mutation research. Reviews in mutation research · 2017Review
- Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase.Cell reports · 2016Article
- Static and Dynamic Factors Limit Chromosomal Replication Complexity in Escherichia coli, Avoiding Dangers of Runaway Overreplication.Genetics · 2016Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Hydroxyurea (HU) is a potent remedy against a variety of ailments and an efficient inhibitor of DNA synthesis, yet its pharmacology is unclear. HU acts in Escherichia coli by the same mechanism as it does in eukaryotes, via inhibition of ribonucleotide reductase. When examining a controversy about concentrations of HU that prevent thymineless death in E. coli, we found instability in HU solutions that avoided prior detection due to its peculiar nature. In contrast to freshly dissolved HU, which did not affect respiration and was bacteriostatic, 1-day-old HU solutions inhibited respiration and were immediately bactericidal. Respiration was inhibited by two gases, hydrogen cyanide (HCN) and nitric oxide (NO), whose appearance we detected in "aged" HU stocks by gas chromatography-mass spectrometry; however, neither gas was bactericidal. While determining the cause of toxicity, we found that HU damages DNA directly. We also demonstrated accumulation of peroxides in HU solutions by enzymatic assays, which explains the toxicity, as both NO and HCN are known to kill bacteria when combined with hydrogen peroxide. Remarkably, we found that bactericidal effects of NO+H(2)O(2) and HCN+H(2)O(2) mixtures were further synergistic. Accumulation of decomposition products in solutions of HU may explain the broad therapeutic effects of this drug.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.