Ribonucleotide reductase and other redox-active antioxidant systems (RNR/Redox)

Ribonucleotide reductase (RNR) and its associated redox-active antioxidant systems, including the thioredoxin and glutaredoxin pathways, constitute a vital metabolic axis for DNA replication and cellular survival [1, 2]. RNR is the primary enzyme responsible for converting ribonucleotides into deoxyribonucleotides, a process that requires a constant supply of electrons provided by the thioredoxin or glutaredoxin systems [2, 5]. These systems also play a crucial role in maintaining the cellular redox state by neutralizing reactive oxygen species (ROS) and repairing oxidative damage to proteins [3, 4]. In many cancers, these pathways are overexpressed to support rapid cell division and provide resistance against oxidative stress induced by chemotherapy or radiation [1, 4]. Consequently, targeting this network—either by inhibiting RNR directly or by disrupting the supporting redox systems—is a major focus in oncology. Drugs like hydroxyurea and gemcitabine target RNR to halt DNA synthesis, while agents like auranofin and motexafin gadolinium inhibit thioredoxin reductase to induce oxidative stress [2, 3]. The synergy between these systems makes them attractive targets for combination therapies aimed at overcoming drug resistance. Understanding the interplay between dNTP pool regulation and redox balance is essential for developing more effective and selective anticancer agents.

Other names

Ribonucleotide reductase and thioredoxin/glutaredoxin systemsRedox-active antioxidant enzymesRNR-redox networkRNR and redox systems

Inhibition of deoxyribonucleotide synthesis through radical quenching or competitive binding of ribonucleotide reductase, and disruption of cellular redox balance by inhibiting electron donor systems like thioredoxin reductase [1, 2, 3].