Hydroxyurea: a key player in cancer chemotherapy

Madaan, Kapish; Kaushik, Darpan; Verma, Tarawanti

doi:10.1586/era.11.175

Cited by 114 publications

(89 citation statements)

References 63 publications

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“…In this review, we summarize the main cellular responses to dNTP depletion caused by treatment with hydroxyurea (HU), a reversible inhibitor of the ribonucleotide reductase (RNR) [7]. This agent is widely used in fundamental research and as chemotherapeutic agent [8]. Mechanistically, HU quenches the tyrosyl free radical at the active site of the RNR component M2, inactivating the RNR enzyme [9, 10].…”

Section: Sources Of Dna Replication Fork Pausing Slow-down and Arrestmentioning

confidence: 99%

“…The practical importance of studying the cellular responses to DNA replication fork arrest lies in the fact that many DNA replication inhibitors, such as HU, are chemotherapeutic agents [8]. Therefore, the knowledge of the underlying molecular mechanisms and responses can inform therapeutic approaches.…”

Section: Sources Of Dna Replication Fork Pausing Slow-down and Arrestmentioning

confidence: 99%

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S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion

Giannattasio

Branzei

2017

Cell. Mol. Life Sci.

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DNA replication stress, an important source of genomic instability, arises upon different types of DNA replication perturbations, including those that stall replication fork progression. Inhibitors of the cellular pool of deoxynucleotide triphosphates (dNTPs) slow down DNA synthesis throughout the genome. Following depletion of dNTPs, the highly conserved replication checkpoint kinase pathway, also known as the S-phase checkpoint, preserves the functionality and structure of stalled DNA replication forks and prevents chromosome fragmentation. The underlying mechanisms involve pathways extrinsic to replication forks, such as those involving regulation of the ribonucleotide reductase activity, the temporal program of origin firing, and cell cycle transitions. In addition, the S-phase checkpoint modulates the function of replisome components to promote replication integrity. This review summarizes the various functions of the replication checkpoint in promoting replication fork stability and genome integrity in the face of replication stress caused by dNTP depletion.

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Section: Sources Of Dna Replication Fork Pausing Slow-down and Arrestmentioning

confidence: 99%

Section: Sources Of Dna Replication Fork Pausing Slow-down and Arrestmentioning

confidence: 99%

S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion

Giannattasio

Branzei

2017

Cell. Mol. Life Sci.

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“…As tumor cells have a higher need for dNTPs [55, 56], many of the anti-tumor therapeutics affecting nucleotide metabolism are aimed at RNR [83–87]. The first class of drugs that were found to inhibit nucleotide metabolism are free radical scavengers, including hydroxyurea [88] and trimidox (Figure 2) [89]. Because these compounds are free radical scavengers, they can inhibit RNR by inactivating the tyrosyl radical on R2 necessary for its reductive capacity [89–94].…”

Section: Nucleotide Metabolism In Cancermentioning

confidence: 99%

Nucleotide metabolism, oncogene-induced senescence and cancer

2015

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Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a bona fide tumor suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic hit. OIS is often characterized by aberrant DNA replication and the associated DNA damage response. Nucleotides, in particular deoxyribonucleotide triphosphates (dNTPs), are necessary for both DNA replication and repair. Imbalanced dNTP pools play a role in a number of human diseases, including during the early stages of cancer development. This review will highlight what is currently known about the role of decreased nucleotide metabolism in OIS, how nucleotide metabolism leads to transformation and tumor progression, and how this pathway can be targeted as a cancer therapeutic by inducing senescence of cancer cells.

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“…In contrast, hydroxyurea (HU), a well-established antineoplastic drug, 63 was predicted by our method to be a potential carcinogen. A previous study showed that a specific dosage of HU may enhance skin carcinogenesis, 64 but no further study has indicated HU as a carcinogen.…”

Section: Carcinogenic and Non-carcinogenic Candidates With Low Structmentioning

confidence: 98%

A computational method for the identification of new candidate carcinogenic and non-carcinogenic chemicals

et al. 2015

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Cancer is one of the leading causes of human death. Based on current knowledge, one of the causes of cancer is exposure to toxic chemical compounds, including radioactive compounds, dioxin, and arsenic. The identification of new carcinogenic chemicals may warn us of potential danger and help to identify new ways to prevent cancer. In this study, a computational method was proposed to identify potential carcinogenic chemicals, as well as non-carcinogenic chemicals. According to the current validated carcinogenic and non-carcinogenic chemicals from the CPDB (Carcinogenic Potency Database), the candidate chemicals were searched in a weighted chemical network constructed according to chemical-chemical interactions. Then, the obtained candidate chemicals were further selected by a randomization test and information on chemical interactions and structures. The analyses identified several candidate carcinogenic chemicals, while those candidates identified as non-carcinogenic were supported by a literature search. In addition, several candidate carcinogenic/non-carcinogenic chemicals exhibit structural dissimilarity with validated carcinogenic/non-carcinogenic chemicals.

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Hydroxyurea: a key player in cancer chemotherapy

Cited by 114 publications

References 63 publications

S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion

S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion

Nucleotide metabolism, oncogene-induced senescence and cancer

A computational method for the identification of new candidate carcinogenic and non-carcinogenic chemicals

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