Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy

Wijerathna, Sanath R.; Ahmad, Md. Faiz; Xu, Hai; Fairman, J.W.; Zhang, Andrew; Kaushal, Prem S.; Wan, Qun; Kiser, Jianying; Dealwis, Chris

doi:10.3390/ph4101328

Cited by 10 publications

(10 citation statements)

References 119 publications

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“…Due to a higher demand for DNA replication and repair in tumor cells, ribonucleotide reductase is a suitable and well established molecular target for cancer therapy. It can be inhibited by radical scavengers that interfere with the tyrosyl radical (e.g., hydroxyurea), nucleoside and nucleotide analogs (e.g., gemcitabine, cytarabine), and iron chelators (e.g., desferrioxamine), which interact with the iron center of the enzyme (Wijerathna et al, 2011). For a-N-heterocyclic thiosemicarbazones, such as 3-AP, the suggested mode of action is the intracellular formation of very stable iron complexes and subsequent generation of reactive oxygen species (ROS) that inhibit ribonucleotide reductase by destruction of the tyrosyl radical (Shao et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

et al. 2013

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Triapine (3-AP; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a ribonucleotide reductase inhibitor, has been extensively evaluated in clinical trials in the last decade. This study addresses the role of endoplasmic reticulum (ER) stress in the anticancer activity of 3-AP and the derivative N 4 ,N 4 -dimethyltriapine (3-AP-Me), differing from 3-AP only by dimethylation of the terminal nitrogen. Treatment of colon cancer cells with 3-AP or 3-AP-Me activated all three ER stress pathways (PERK, IRE1a, ATF6) by phosphorylation of eIF2a and upregulation of gene expression of activating transcription factors ATF4 and ATF6. In particular, 3-AP-Me led to an upregulation of the alternatively spliced mRNA variant XBP1 (16-fold). Moreover, 3-AP and 3-AP-Me activated the cellular stress kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, and inhibition of JNK activity antagonized the cytotoxic effect of both compounds. Subsequent to induction of the unfolded protein response, a significant upregulation of proapoptotic proteins was detected, including the transcription factor CHOP and Bim, an essential factor for ER stress-related apoptosis. In correlation with the higher degree of ER stress after 3-AP-Me treatment, also a more potent depolarization of mitochondrial membranes was found. These data suggest that 3-AP and 3-AP-Me induce apoptosis via ER stress. This was further corroborated by showing that inhibition of protein biosynthesis with cycloheximide prior to 3-AP and 3-AP-Me treatment leads to a significant reduction of the antiproliferative properties of both compounds. Taken together, this study demonstrates that induction of ER stress contributes to the mode of action of 3-AP and that terminal dimethylation leads to an even more pronounced manifestation of this effect.

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Section: Introductionmentioning

confidence: 99%

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

et al. 2013

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“…73,74 Hence, hRR can be used in bench to bedside treatments. 30 The current interest in RR research is increasing our understanding of higher-order oligomerization, enzyme turnover, and the mechanism of allosteric regulation that governs specificity. The molecular basis of activation and deactivation by ATP and dATP was partially clarified by our recent study, which provided an explanation of how dATP achieves a 100-fold higher affinity than ATP for the A-site.…”

Section: Discussionmentioning

confidence: 99%

“…These proteins associate in dimeric or multimeric forms such as α 2 β 2 and (α) n (β2) m (where n = 4 or 6 and m = 1, 2, or 3). 24–30 Substrate catalysis occurs in RR1 (α) which contains two allosteric sites, the specificity site (S-site), and the activity site (A-site) in addition to the catalytic site (C-site) 29,31–34 (Fig. 14.1).…”

Section: Ribonucleotide Reductasementioning

confidence: 99%

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The Structural Basis for the Allosteric Regulation of Ribonucleotide Reductase

Ahmad

Dealwis

2013

Progress in Molecular Biology and Translational Science

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Ribonucleotide reductases (RRs) catalyze a crucial step of de novo DNA synthesis by converting ribonucleoside diphosphates to deoxyribonucleoside diphosphates. Tight control of the dNTP pool is essential for cellular homeostasis. The activity of the enzyme is tightly regulated at the S-phase by allosteric regulation. Recent structural studies by our group and others provided the molecular basis for understanding how RR recognizes substrates, how it interacts with chemotherapeutic agents, and how it is regulated by its allosteric regulators ATP and dATP. This review discusses the molecular basis of allosteric regulation and substrate recognition of RR, and particularly the discovery that subunit oligomerization is an important prerequisite step in enzyme inhibition.

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“…Several compounds targeting the ribonucletide reductase have been used for cancer treatment or are currently in clinical trials [95]. Hydroxyurea is the best-known of the RRM2 inhibitors although its effectiveness is reduced in the clinic due to its poor pharmacokinetic properties [96].…”

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

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107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy

Cited by 10 publications

References 119 publications

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

The Structural Basis for the Allosteric Regulation of Ribonucleotide Reductase

Replication stress and cancer: It takes two to tango

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