Abstract
Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and—recently—a promising factor in preventing cognitive decline in Alzheimer’s disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.
Highlights
Hydroxyurea (HU) is a well-known genotoxic agent whose biological impact on living organisms has been known for almost a century [1]
We examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects
It affects the activity of ribonucleotide reductase (RNR) by disrupting the proton-coupled electron transfer that catalyzes the production of new deoxyribonucleotides
Summary
Hydroxyurea (HU) is a well-known genotoxic agent whose biological impact on living organisms has been known for almost a century [1]. HU is an inhibitor of DNA replication [10] It affects the activity of ribonucleotide reductase (RNR) by disrupting the proton-coupled electron transfer that catalyzes the production of new deoxyribonucleotides (dNTPs). The presence of hydroxyurea in cells primarily activates the S-phase checkpoint, which delays mitosis and arrests the cell cycle progress until DNA replication is finished and any occurring DNA damage is fixed. This checkpoint activation is crucial for proper cell proliferation and it is carefully regulated by signaling kinases, e.g., ATR in higher eukaryotes, Mec in Saccharomyces cerevisiae, or Rad in Schizosaccharomyces pombe. The mechanisms that, on the one hand, are able to effectively cause stress and kill the cell may—on the other hand— be leveraged to the advantage of cancer therapy
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