Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Abstract

This review provides up-to-date information on the inhibition of ribonucleotide reductase (RNR), the enzyme that catalyses the reduction of ribonucleotides into deoxyribonucleotides. Taking in account that DNA replication and repair are essential mechanisms for cell integrity and are dependent on the availability of deoxyribonucleotides, many researchers are giving special attention to this enzyme, since it is an attractive target to treat several diseases of our time specially cancer. This investment has already given some benefits since some of these inhibitors show potent chemotherapeutic efficacy against a wide range of tumours such as non-small cell lung cancer, adenocarcinoma of pancreas, bladder cancer, leukaemia and some solid tumours. In fact a few of them have already been approved for the clinical treatment of some kinds of cancer. All aspects of RNR inhibition and corresponding inhibitors are the subjects of this review. The inhibitors are divided in three main groups: translation inhibitors, which unable the formation of the enzyme; dimerization inhibitors that prevent the complexation of the two RNR subunits (R1 and R2); and catalytic inhibitors that inactivate subunit R1 and/or subunit R2, leading to RNR inactivity. In this last group special focus will be addressed to substrate analogues.

Nonself Recognition Through Intermolecular Disulfide Bond Formation of Ribonucleotide Reductase in Neurospora

“…The development of peptide inhibitors that disrupt the quaternary structure of RNR is a field that may present an efficacious chemotherapeutic strategy (Cerqueira et al 2005;Cooperman et al 2005). Inherent within the N. crassa sequence of R1 already lies the potential for antibiotic-like activity, as manifested by the growth inhibition of cells resulting from nonself fusions in N. crassa.…”

Tranilast strongly sensitizes pancreatic cancer cells to gemcitabine via decreasing protein expression of ribonucleotide reductase 1

“…Ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides into the correspondent 2'-deoxyribonucleotides in the rate-limiting step for the biosynthesis of DNA (9,10,31). This enzyme thus has long been regarded as an important target for cancer therapies.…”

“…This enzyme thus has long been regarded as an important target for cancer therapies. The enzymatic activity of RNR was shown to be dependent on the formation of a complex between two different dimers composed of larger subunit (RRM1) and smaller subunit (RRM2) (31). Various inhibitors targeting on RRM1 or RRM2 have been developed and the in vitro and in vivo effects examined (31).…”

“…The enzymatic activity of RNR was shown to be dependent on the formation of a complex between two different dimers composed of larger subunit (RRM1) and smaller subunit (RRM2) (31). Various inhibitors targeting on RRM1 or RRM2 have been developed and the in vitro and in vivo effects examined (31). Among the RNR inhibitors, Gem inhibits RRM1 activity by which Gem metabolite, dFdCDP is misincorporated at the active site, leading to no more DNA replication (31).…”

Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol

“…In humans the enzyme is a dimer having one large subunit (hRRM1, Mr 170,000 dimer) and one of the two small subunits (hRRM2 and p53R2) identified separately [22,23]. Inhibition of RR activity has been tested as a potential treatment modality in anticancer settings [24].…”