Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase

Liew, Li Phing; Lim, Zun Yi; Cohen, Matan; Kong, Ziqing; Marjavaara, Lisette; Chabes, Andrei; Bell, Stephen D.

doi:10.1016/j.celrep.2016.10.024

Cited by 25 publications

(23 citation statements)

References 36 publications

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“…6). These include the primary ribonucleotide reductase NrdAB, as well as other targets that are required to maintain ongoing DNA synthesis, transcription, translation, and cell growth (12,13,58,61). Once the iron balance is restored or compensated for, replication can continue for several hours.…”

Section: Discussionmentioning

confidence: 99%

“…The most common mechanism of action proposed for hydroxyurea is the inhibition of ribonucleotide reductase, leading to depleted deoxyribonucleoside triphosphate (dNTP) pools that prevent DNA replication in both prokaryotes and eukaryotes (5)(6)(7)(8)(9)(10). However, other mechanisms of action have also been proposed and include general inhibition of metabolism due to disruption of iron-dependent enzymes in the cell (11)(12)(13) and direct induction of DNA damage (14,15).…”

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confidence: 99%

“…Alternatively, inactivation of ribonucleotide reductase by hydroxyurea may simply reflect a broad effect that the drug has on enzymes containing catalytic metals. Recent studies have found that hydroxyurea alters Fe-S centers that act as cofactors for various cellular enzymes (11)(12)(13). Hydroxyurea can also form complexes with iron and copper directly and may act as a weak chelator in vivo (29,30).…”

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confidence: 99%

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Replication Rapidly Recovers and Continues in the Presence of Hydroxyurea in Escherichia coli

et al. 2018

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In both prokaryotes and eukaryotes, hydroxyurea is suggested to inhibit DNA replication by inactivating ribonucleotide reductase and depleting deoxyribonucleoside triphosphate pools. In this study, we show that the inhibition of replication in is transient even at concentrations of 0.1 M hydroxyurea and that replication rapidly recovers and continues in its presence. The recovery of replication does not require the alternative ribonucleotide reductases, NrdEF and NrdDG, or translesion DNA polymerases, Pol II, Pol IV, or Pol V. Ribonucleotides are incorporated at higher frequencies during replication in the presence of hydroxyurea. However, these do not contribute significantly to the observed synthesis or toxicity. Hydroxyurea toxicity was only observed under conditions where the stability of hydroxyurea was compromised and byproducts, known to damage DNA directly, were allowed to accumulate. The results demonstrate that hydroxyurea is not a direct or specific inhibitor of DNA synthesis, and that the transient inhibition observed is most likely due to a general depletion of iron cofactors from enzymes when 0.1 M hydroxyurea is initially applied. Finally, the results support previous studies suggesting that hydroxyurea toxicity is mediated primarily through direct DNA damage induced by the breakdown products of hydroxyurea, rather than by inhibition of replication or depletion of deoxyribonucleotide levels in the cell. Hydroxyurea is commonly suggested to function by inhibiting DNA replication through the inactivation of ribonucleotide reductase and depleting deoxyribonucleoside triphosphate pools. Here, we show that hydroxyurea only transiently inhibits replication in before it rapidly recovers and continues in the presence of this drug. The recovery of replication does not depend on alternative ribonucleotide reductases, translesion synthesis, or RecA. Further we show that hydroxyurea toxicity is only observed after toxic intermediates that accumulate when hydroxyurea breaks down, damage DNA and induce lethality. The results demonstrate that hydroxyurea toxicity is mediated indirectly by the formation of DNA damage, rather than by an inhibition of replication or depletion of deoxyribonucleotide levels in the cell.

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Section: Discussionmentioning

confidence: 99%

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Replication Rapidly Recovers and Continues in the Presence of Hydroxyurea in Escherichia coli

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“…Hydroxyurea (HU) or hydroxycarbamide, is a non-alkylating hydroxylated urea analog mainly recognized as antineoplastic and antiviral agent (Spivak and Hasselbalch, 2011 ). The cytotoxic and genotoxic potential efficacy of hydroxyurea makes this molecule one of the most performing agent commonly used in chemotherapy (Spivak and Hasselbalch, 2011 ; Karsy et al, 2016 ; Liew et al, 2016 ). In addition, HU is usually involved in the treatment of Sickle Cell Disease (SCD) (Davies and Gilmore, 2003 ; Heeney and Ware, 2008 ; Italia et al, 2009 ; Flanagana et al, 2010 ; Candrilli et al, 2011 ), psoriasis (Yarbro and Leavell, 1969 ), Philadelphia-chromosome negative myeloproliferative syndromes (MPs) (Yarbro and Leavell, 1969 ), some types of solid cancers (Karsy et al, 2016 ), and in the therapy of HIV infection (Lori et al, 1994 ).…”

Section: Introductionmentioning

confidence: 99%

“…An important issue when dealing with HU is related to its harmful potential (Millicovsky et al, 1981 ; Woo et al, 2005 ) especially in prolonged exposure conditions (Elchuri et al, 2015 ; Broto et al, 2017 ), as it inhibits class I ribonucleotide reductase, leading to replication fork stalling (Quattrone et al, 2013 ; Liew et al, 2016 ). Workers involved in the manufacture of drugs, may be exposed to HU during manufacturing, transport, and distribution.…”

Section: Introductionmentioning

confidence: 99%

MicroNIR/Chemometrics Assessement of Occupational Exposure to Hydroxyurea

Risoluti

Materazzi

2018

Front. Chem.

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Portable Near Infrared spectroscopy (NIRs) coupled to chemometrics was investigated for the first time as a novel entirely on-site approach for occupational exposure monitoring in pharmaceutical field. Due to a significant increase in the number of patients receiving chemotherapy, the development of reliable, fast, and on-site analytical methods to assess the occupational exposure of workers in the manufacture of pharmaceutical products, has become more and more required. In this work, a fast, accurate, and sensitive detection of hydroxyurea, a cytotoxic antineoplastic agent commonly used in chemotherapy, was developed. Occupational exposure to antineoplastic agents was evaluated by collecting hydroxyurea on a membrane filter during routine drug manufacturing process. Spectra were acquired in the NIR region in reflectance mode by the means of a miniaturized NIR spectrometer coupled with chemometrics. This MicroNIR instrument is a very ultra-compact portable device with a particular geometry and optical resolution designed in such a manner that the reduction in size does not compromise the performances of the spectrometer. The developed method could detect up to 50 ng of hydroxyurea directly measured on the sampling filter membrane, irrespective of complexity and variability of the matrix; thus extending the applicability of miniaturized NIR instruments in pharmaceutical and biomedical analysis.

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Combination of hydroxyurea and tranilast suppresses gemcitabine resistance induced by ribonucleotide reductase M1 in gemcitabine‐resistant cells

Shinagawa

Minami

Ishida

et al. 2020

Oral Science International

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Introduction Gemcitabine (GEM; 2′,2′‐difluorodeoxycytidine) is widely used to treat pancreatic, biliary tract, non‐small cell lung, bladder, mammary, and ovarian cancers. Chemoradiotherapy with GEM is a promising treatment for patients with advanced and locally recurrent head and neck cancers, including those with oral cavity cancer. However, the development of GEM resistance limits its use for curative treatment. Overexpression of ribonucleotide reductase (RR) M1 is a major cause of GEM resistance. We previously established RRM1‐mediated GEM‐resistant cell lines (MGEM6 and MGEM8) and showed that the knockdown of RRM1 is a rationale strategy for overcoming GEM resistance. We further investigated the role of RR inhibition in enhancing the effects of GEM. Materials and methods We examined whether the combination treatment of hydroxyurea (HU), 3‐aminopyridine‐2‐carboxaldehyde thiosemicarbazone (3‐AP), and tranilast (TRL) could increase GEM sensitivity using the survival assay of MGEM6, MGEM8, and their parental cells. The effects of these compounds on the expression of RRM1 and RRM2 mRNA and protein were evaluated in the three cell lines by quantitative PCR (polymerase chain reaction) and immunoblotting. Results HU or/and TRL at nontoxic concentrations significantly improved the response of resistant cancer cells to GEM, whereas 3‐AP did not. This may have been because the two agents reduced the ratio of RRM1/RRM2. The three compounds have different effects on the mRNA and protein expression of RRM1 and RRM2. Conclusions The combination of HU and/or TRL with GEM enhances the toxic effect in gemcitabine‐resistant cells induced by RRM1.

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Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase

Cited by 25 publications

References 36 publications

Replication Rapidly Recovers and Continues in the Presence of Hydroxyurea in Escherichia coli

Replication Rapidly Recovers and Continues in the Presence of Hydroxyurea in Escherichia coli

MicroNIR/Chemometrics Assessement of Occupational Exposure to Hydroxyurea

Combination of hydroxyurea and tranilast suppresses gemcitabine resistance induced by ribonucleotide reductase M1 in gemcitabine‐resistant cells

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