Hydroxyurea—The Good, the Bad and the Ugly

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.

Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity

“…These compounds are small nonnucleosidic molecules that alter the dNTP pools, therefore interfering with polymerase fidelity. Their effects in mutagenesis have been investigated in experiments using gemcitabine [2,2( )-difluoro-2( )deoxycytidine] and clofarabine [(2 S)-2 -deoxy-2 -fluoro-2-chloro-adenosine] as deoxynucleoside analogs (Figure 1) [58][59][60][61]. It has been noted that 5-azacytidine has anti-HIV-1 activity (i.e., EC 50 around 200 nM) and low cytotoxicity, and it has been shown to act in synergy with gemcitabine and resveratrol [62,63].…”

Rad53 arrests leading and lagging strand DNA synthesis via distinct mechanisms in response to DNA replication stress

“…The enrichment of PCNA at leading strands was also detected in cells treated with the DNA alkylating agent methyl methanesulfonate (MMS), which also induces DNA replication stress. [ 71–73 ] This observation prompted us to analyze how PCNA binds to DNA replication forks under normal conditions. We found that PCNA is enriched at lagging strands of DNA replication forks when cells are arrested at G1 by α‐factor treatment and released into S phase at 16°C where DNA synthesis is slowed.…”

The Advent of Omics Sciences in Clinical Trials of Motor Neuron Diseases

“…A repurposing drug strategy was exploited in trial NCT00485511 where the efficacy and safety of Hydroxyurea (HU) was tested in children with SMN1 - SMN2 mutations. By reducing the need for blood transfusions in patients with sickle cell anaemia, this drug is used for the treatment of chronic myeloid leukaemia as well as in the prevention of painful episodes [ 37 ].…”