Ribonucleotide Reductase Inhibitors and Future Drug Design

Abstract

Ribonucleotide reductase (RR) is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for DNA replication and repair. The key role of RR in DNA synthesis and cell growth control has made it an important target for anticancer therapy. Increased RR activity has been associated with malignant transformation and tumor cell growth. Efforts for new RR inhibitors have been made in basic and translational research. In recent years, several RR inhibitors, including Triapine, Gemcitabine, and GTI-2040, have entered clinical trial or application. Furthermore, the discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment. This review compiles recent studies on (1) the structure, function, and regulation of two forms of RR; (2) the role in tumorigenesis of RR and the effect of RR inhibition in cancer treatment; (3) the classification, mechanisms of action, antitumor activity, and clinical trial and application of new RR inhibitors that have been used in clinical cancer chemotherapy or are being evaluated in clinical trials; (4) novel approaches for future RR inhibitor discovery.

FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

“…Our data support the hypothesis that FBH1 controls a mechanism to eliminate cells via apoptosis under conditions of elevated replication stress (and oncogene activation) when too many forks have collapsed and restart efforts can be harmful in allowing the propagation of cells with genomic instability. Our results also have clinical relevance in providing insight into the response to genotoxic stress caused by HU, a chemotherapeutic drug used in the treatment of a number of malignancies, as well as polycythemia vera and sickle cell anemia 24,25 . Indeed, several DNA replication inhibitors, including gemcitabine, 6-thioguanine and Fludarabine phosphate, are used for the treatment of a number of a wide range of cancers 24 .…”

“…Our results also have clinical relevance in providing insight into the response to genotoxic stress caused by HU, a chemotherapeutic drug used in the treatment of a number of malignancies, as well as polycythemia vera and sickle cell anemia 24,25 . Indeed, several DNA replication inhibitors, including gemcitabine, 6-thioguanine and Fludarabine phosphate, are used for the treatment of a number of a wide range of cancers 24 . Finally, our findings suggest that the assessment of FBH1 functional status might potentially be used to identify patients that would benefit from treatment with HU or other drugs with a similar mechanism of action.…”

Break-induced ATR and Ddb1–Cul4Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast

“…A number of anti-cancer drugs function to inhibit RNR activity, including hydroxyurea (HU), gemcitabine 59-diphosphate, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3AP), [Tris(1,10-phenanthroline)-lanthanum(III)] trithiocyanate (KP772), motexafin gadolinium (MGd), triapine, and others (for review, see Shao et al 2006). Our findings indicate that these drugs are likely to not only inhibit DNA replication, but are expected also to block efficient HR, and therefore sensitize cells to the types of DNA damage and damaging agents that require HR repair.…”

Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

“…The higher demand for iron may at least partly be explained by the increased activity of iron dependent enzymes such as ribonucleotide reductase (RR), a rate-limiting step in DNA synthesis [34]. Indeed it has also been demonstrated that the activity and expression of RR is increased in tumor cells indicating a high level DNA synthesis in these cells [35].…”