Trimidox, an inhibitor of ribonucleotide reductase, synergistically enhances the inhibition of colony formation by Ara-C in HL-60 human promyelocytic leukemia cells

Fritzer‐Szekeres, Monika; Salamon, Alexandra; Grusch, Michael; Horváth, Zsuzsanna; Höchtl, Thomas; Steinbrugger, Richard; Jäger, Walter; Krupitza, Georg; Elford, Howard L.; Szekeres, Thomas

doi:10.1016/s0006-2952(02)01186-3

Cited by 21 publications

(12 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Trimidox, another specific inhibitor for RRM2 (24,25), was also used to verify effects of RRM2 on decidualization. When pregnant mice on day 4 were treated with trimidox twice, the weight of the implantation site on day 7 was significantly reduced compared with control (Fig.…”

Section: Localization Of Rrm1 Rrm2 and Rrm2b In Mouse Uterusmentioning

confidence: 99%

Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice

Wei

Deng

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Ribonucleotide reductase M2 (RRM2) is a rate-limiting step for DNA synthesis. It is still unknown how RRM2 is involved in decidualization. Results: RRM2 is highly expressed in the decidua and up-regulated by progesterone and DNA damage. Decidualization is significantly inhibited by specific RRM2 inhibitors. Conclusion: RRM2 is essential for mouse decidualization. Significance: This study will shed light on understanding the mechanism underlying decidualization.

show abstract

Section: Localization Of Rrm1 Rrm2 and Rrm2b In Mouse Uterusmentioning

confidence: 99%

Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice

Wei

Deng

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Thus, because of its critical role in the de novo synthesis of DNA, RNR is considered to be a potential target for the development of cancer chemotherapeutic agents. At present, hydroxyurea is the only clinically used RNR inhibitor; however, several more potent and specific inhibitors of RNR have been developed and are currently being evaluated clinically (13)(14)(15)(16)(17). We have shown previously that the RNR inhibitor Triapine, in conjunction with a variety of DNA-damaging agents, produces synergistic inhibition of transplanted L1210 leukemia cells, presumably by inhibiting the ability of cancer cells to repair druginduced damage to DNA (18).…”

Section: Ribonucleotide Reductase (Rnr)mentioning

confidence: 99%

Stable Suppression of the R2 Subunit of Ribonucleotide Reductase by R2-targeted Short Interference RNA Sensitizes p53(–/–) HCT-116 Colon Cancer Cells to DNA-damaging Agents and Ribonucleotide Reductase Inhibitors

Lin

Belcourt

Cory

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ribonucleotide reductase catalyzes the production of deoxyribonucleoside diphosphates, the precursors of deoxyribonucleoside triphosphates for DNA synthesis. Mammalian ribonucleotide reductase (RNR) is a tetramer consisting of two non-identical homodimers, R1 and either R2 or p53R2, which are considered to be involved in DNA replication and repair, respectively. We have demonstrated that DNA damage by doxorubicin and cisplatin caused a steady elevation of the R2 protein in p53(؊/؊) HCT-116 human colon carcinoma cells but induced degradation of the protein in p53(؉/؉) cells. To evaluate the involvement of R2 in response to DNA damage, p53(؊/؊) HCT-116 cells were stably transfected with an expression vector transcribing short hairpin/short interference RNA directed against R2 mRNA. Stably transfected clones exhibited a pronounced reduction of the R2 protein with no change in the cellular growth rate. Furthermore, short interference RNA-mediated reduction of the R2 protein caused a marked increase in sensitivity to the DNA-damaging agent cisplatin as well as to the RNR inhibitors Triapine® and hydroxyurea. Ectopic expression of p53R2 partially reversed the cytotoxicity of cisplatin but not that of RNR inhibitors to R2 knockdown cells. The increase in sensitivity to cisplatin and RNR inhibitors was correlated with the suppression of dATP and dGTP levels caused by stable expression of R2-targeted short interference RNA. These results indicated that DNA damage resulted in elevated levels of the R2 protein and dNTPs and, consequently, enhanced the survival of p53(؊/؊) HCT-116 cells. The findings provide evidence that R2-RNR can be employed to supply dNTPs for the repair of DNA damage in cells with an impaired p53-dependent induction of p53R2. Ribonucleotide reductase (RNR)1 catalyzes a rate-limiting reaction in which ribonucleoside diphosphates are converted to their corresponding deoxyribonucleoside diphosphates, the precursors of deoxyribonucleoside triphosphates (dNTPs) required for DNA synthesis and repair (1). In mammalian cells, the catalytically active RNR is considered to be an ␣ 2 ␤ 2 heterotetramer consisting of two large R1 subunits and two small R2 subunits. To maintain a balanced size of dNTP pools (2), the enzymatic activity of RNR is tightly regulated by the binding of nucleoside triphosphates (ATP, dATP, dGTP, and dTTP) to allosteric sites in the R1 subunit (1). In proliferating cells, the level of the R2 protein is low in the G 1 phase of the cell cycle but accumulates and reaches maximal levels during the S phase, followed by degradation when passing through the G 2 /M phase (3-6). Thus, the activity of RNR is additionally controlled by cell cycle-specific availability of the R2 subunit, whereas the R1 protein level remains relatively constant throughout the cell cycle (3, 4). When cells undergo G 1 arrest following DNA damage, the supply of dNTPs for DNA repair is, in turn, provided by transcriptional activation of the recently identified R2 homologue, p53R2 (7, 8). Thus, DNA damage causes p53-depend...

show abstract

“…Ara-C is one of the most effective anticancer agents for the treatment of AML, and its therapeutic effect at low or high doses has been extensively studied (24)(25)(26)(27)(28)(29)(30)(31). It has been reported that the metabolism of Ara-C in vitro was greatly enhanced by RNR inhibitors, such as amidox and trimidox (32)(33)(34). Clinical combination studies of Ara-C with RNR inhibitors such as fludarabine and chlorodeoxyadenosine demonstrated significant accumulation of Ara-CTP in lymphocytes and sustained inhibition of DNA synthesis in circulating leukemia blasts from patients with leukemia (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Biochemical Modulation of Aracytidine (Ara-C) Effects by GTI-2040, a Ribonucleotide Reductase Inhibitor, in K562 Human Leukemia Cells

Chen

Aimiuwu

Xie

et al. 2010

AAPS J

View full text Add to dashboard Cite

Abstract. GTI-2040 is a potent antisense to the M2 subunit of the ribonucleotide reductase (RNR), an enzyme involved in the de novo synthesis of nucleoside triphosphates. We hypothesized that combination of GTI-2040 with the cytarabine (Ara-C) could result in an enhanced cytotoxic effect with perturbed intracellular deoxynucleotide/nucleotide (dNTP/NTP) pools including Ara-C triphosphate (Ara-CTP). This study aims to provide a direct experimental support of this hypothesis by monitoring the biochemical modulation effects, intracellular levels of Ara-CTP, dNTPs/NTPs following the combination treatment of Ara-C, and GTI-2040 in K562 human leukemia cells. GTI-2040 was introduced into cells via electroporation. A hybridization-ligation ELISA was used to quantify intracellular GTI-2040 concentrations. Real-time PCR and Western blot methods were used to measure the RNR M2 mRNA and protein levels, respectively. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay was used to measure the cytotoxicity following various drug treatments. A non-radioactive HPLC-UV method was used for measuring the intracellular Ara-CTP, while a LC-MS/ MS method was used to quantify intracellular dNTP/NTP pools. GTI-2040 was found to downregulate M2 mRNA and protein levels in a dose-dependent manner and showed significant decrease in dNTP but not NTP pool. When combining GTI-2040 with Ara-C, a synergistic cytotoxicity was observed with no further change in dNTP/NTP pools. Importantly, pretreatment of K562 cells with GTI-2040 was found to increase Ara-CTP level for the first time, and this effect may be due to inhibition of RNR by GTI-2040. This finding provides a laboratory justification for the current phase I/II evaluation of GTI-2040 in combination with Ara-C in patients with acute myeloid leukemia.

show abstract

Trimidox, an inhibitor of ribonucleotide reductase, synergistically enhances the inhibition of colony formation by Ara-C in HL-60 human promyelocytic leukemia cells

Cited by 21 publications

References 25 publications

Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice

Progesterone and DNA Damage Encourage Uterine Cell Proliferation and Decidualization through Up-regulating Ribonucleotide Reductase 2 Expression during Early Pregnancy in Mice

Stable Suppression of the R2 Subunit of Ribonucleotide Reductase by R2-targeted Short Interference RNA Sensitizes p53(–/–) HCT-116 Colon Cancer Cells to DNA-damaging Agents and Ribonucleotide Reductase Inhibitors

Biochemical Modulation of Aracytidine (Ara-C) Effects by GTI-2040, a Ribonucleotide Reductase Inhibitor, in K562 Human Leukemia Cells

Contact Info

Product

Resources

About