A ribonucleotide reductase inhibitor with deoxyribonucleoside‐reversible cytotoxicity

Crona, Mikael; Codó, Paula; Jonna, Venkateswara Rao; Hofer, Anders; Fernandes, Aristi P.; Tholander, Fredrik

doi:10.1016/j.molonc.2016.07.008

Cited by 17 publications

(14 citation statements)

References 59 publications

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“…Still, considering the improved thermal stability of the NrdA and NrdB protein induced by NSC45384 and NSC228155, respectively, it is unlikely that the inhibition mechanism is limited to ROS-induced effects. Conversely, and similarly to what was earlier observed for human RNR [23], we found that several of the compounds rather conferred decreased thermal stability to P. aeruginosa NrdB. In our study, four of the six compounds that quench the tyrosyl radical in the NrdB protein also decreased the thermal stability of the protein.…”

Section: Discussionsupporting

confidence: 91%

“…This might be explained as oligomerization of the inhibited subunit or loss of cofactor, but unspecific binding cannot be ruled out. Moreover, four of the compounds studied here have earlier been tested as potential inhibitors of human RNR, but only NSC73735 showed a positive binding to human NrdA, and was found to lower all dNTP pools in HL-60 cells [23]. In our hands, NSC73735 increases the thermal stability of P. aeruginosa NrdA and quenches the NrdB radical in the active holoenzyme complex.…”

Section: Discussionmentioning

confidence: 69%

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Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase

et al. 2019

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Ribonucleotide reductase (RNR) has been extensively probed as a target enzyme in the search for selective antibiotics. Here we report on the mechanism of inhibition of nine compounds, serving as representative examples of three different inhibitor classes previously identified by us to efficiently inhibit RNR. The interaction between the inhibitors and Pseudomonas aeruginosa RNR was elucidated using a combination of electron paramagnetic resonance spectroscopy and thermal shift analysis. All nine inhibitors were found to efficiently quench the tyrosyl radical present in RNR, required for catalysis. Three different mechanisms of radical quenching were identified, and shown to depend on reduction potential of the assay solution and quaternary structure of the protein complex. These results form a good foundation for further development of P. aeruginosa selective antibiotics. Moreover, this study underscores the complex nature of RNR inhibition and the need for detailed spectroscopic studies to unravel the mechanism of RNR inhibitors.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 69%

Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase

et al. 2019

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“…In the same TCGA study, RRM2 and RRM1 showed low and rare copy number changes, respectively, in the malignancies examined. RNR has long been recognised as an important target for anticancer therapy . Small‐molecule inhibitors that target RNR can be classified into two categories depending on which subunit they target.…”

Section: Rrm2b As a Clinical Targetmentioning

confidence: 99%

Challenges to DNA replication in hypoxic conditions

Purshouse

Foskolou

et al. 2018

The FEBS Journal

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The term hypoxia refers to any condition where insufficient oxygen is available and therefore encompasses a range of actual oxygen concentrations. The regions of tumours adjacent to necrotic areas are at almost anoxic levels and are known to be extremely therapy resistant (radiobiological hypoxia). The biological response to radiobiological hypoxia includes the rapid accumulation of replication stress and subsequent DNA damage response, including both ATR‐ and ATM‐mediated signalling, despite the absence of detectable DNA damage. The causes and consequences of hypoxia‐induced replication stress will be discussed.

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“…Hydroxyurea (also known as hydroxycarbamide) is an antimetabolite S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase (rNDP) enzyme [ 16 ]. This enzyme catalyses the conversion of ribonucleotides to deoxyribonucleotides which is an essential step in DNA biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic

Yasara

Premawardhena

Mettananda

2021

Orphanet J Rare Dis

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Background Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include β-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in β-thalassaemia major and haemoglobin E β-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with β-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in β-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. Main body Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with β-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent β-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent β-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. Conclusion Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with β-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent β-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent β-thalassaemia which should be confirmed by randomised clinical trials.

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A ribonucleotide reductase inhibitor with deoxyribonucleoside‐reversible cytotoxicity

Cited by 17 publications

References 59 publications

Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase

Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase

Challenges to DNA replication in hypoxic conditions

A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic

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