Effects of cytosine arabinoside and hydroxyurea on the synthesis of deoxyribonucleotides and DNA replication in L1210 cells

Masahiko, Matsumoto; Rey, Daniel A.; Cory, Joseph G.

doi:10.1016/0065-2571(90)90008-p

Cited by 5 publications

(4 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to what has been observed with the reversible effects of HU on the cell cycle [36, 37], cells cannot re-enter the cell cycle after a decrease in dNTP pools due to decreased RRM2 (Figure 1) [38]. Therefore, the consequence of decreased dNTP pools must go beyond replication stress and the associated DDR.…”

Section: Role Of Nucleotide Metabolism In Oncogene-induced Senescencementioning

confidence: 83%

“…Indeed, suppression of S-phase progression is sufficient to block RAS-induced senescence [35]. Early studies showed that a decrease in dNTP pools by hydroxyurea (HU) leads to an S-phase arrest [36, 37]. Recent evidence from our lab suggests that the replication stress observed during OIS is specifically due to a decrease in dNTP levels (Figure 1) [38].…”

Section: Role Of Nucleotide Metabolism In Oncogene-induced Senescencementioning

confidence: 99%

See 1 more Smart Citation

Nucleotide metabolism, oncogene-induced senescence and cancer

2015

View full text Add to dashboard Cite

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.

show abstract

Section: Role Of Nucleotide Metabolism In Oncogene-induced Senescencementioning

confidence: 83%

Section: Role Of Nucleotide Metabolism In Oncogene-induced Senescencementioning

confidence: 99%

Nucleotide metabolism, oncogene-induced senescence and cancer

2015

View full text Add to dashboard Cite

show abstract

“…A recent study on the physiology of cancer cells showed an increase of dNTP pools was accompanied by higher mutation rates due to reduced fidelity of DNA replication 34 . In contrast, early studies showed that a decrease in dNTP pools by hydroxyurea (HU) lead to an S-phase arrest by replication stress 35,36 . It seems that not only are the overall levels of dNTPs important for genome stability but also the balance between individual dNTPs, which can lead to positive or negative effects on cancer cell therapy.…”

Section: Changes In Cellular Metabolism Following Transfection Of Ct ...mentioning

confidence: 99%

dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers

Kim

Kim²,

Mok

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Immunotherapy has a number of advantages over traditional anti-tumor therapy but can cause severe adverse reactions due to an overactive immune system. In contrast, a novel metabolic treatment approach can induce metabolic vulnerability through multiple cancer cell targets. Here, we show a therapeutic effect by inducing nucleotide imbalance and apoptosis in triple negative breast cancer cells (TNBC), by treating with cytosolic thymidylate 5'-phosphohydrolase (CT). We show that a sustained consumption of dTMP by CT could induce dNTP imbalance, leading to apoptosis as tricarboxylic acid cycle intermediates were depleted to mitigate this imbalance. These cytotoxic effects appeared to be different, depending on substrate specificity of the 5′ nucleotide or metabolic dependency of the cancer cell lines. Using representative TNBC cell lines, we reveal how the TNBC cells were affected by CT-transfection through extracellular acidification rate (ECAR)/oxygen consumption rate (OCR) analysis and differential transcription/expression levels. We suggest a novel approach for treating refractory TNBC by an mRNA drug that can exploit metabolic dependencies to exacerbate cell metabolic vulnerability.

show abstract

“…The drug hydroxyurea (HU) induces a reversible early S-phase arrest by causing deoxynucleotide triphosphate (dNTP) depletion [22][23][24]. HU is a venerable chemotherapeutic, used for its ability to inhibit cell proliferation, but also because it predisposes proliferating cells to genome instability.…”

Section: Introductionmentioning

confidence: 99%