Inhibition of nucleoside diphosphate reductase by hydroxybenzohydroxamic acid derivatives

Elford, Howard L.; Riet, Bart Van't

doi:10.1016/0163-7258(85)90031-2

Cited by 36 publications

(24 citation statements)

References 37 publications

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“…Others have shown that RRM2 regulates antiapoptotic proteins such as Bcl-2 in certain cancers (43). Here, we show that RRM2 overexpression protects against tamoxifen-induced apoptosis and results in lowered S139 gH2AX phosphorylation, reduced PARP and caspase-9 cleavage, and increased Bcl-2 levels, which are wellestablished mechanisms of chemoresistance (44). These RRM2-induced protective effects were reversed by the combination of tamoxifen and didox treatment (Fig.…”

Section: Discussionmentioning

confidence: 53%

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Shah

Wilson

Malla

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ERa)-positive tumors. However, the clinical benefit is often limited because of the emergence of drug resistance. In this study, overexpression of ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted in a reduction in the effectiveness of tamoxifen, through downregulation of ERa66 and upregulation of the 36-kDa variant of ER (ERa36). We identified that NF-kB, HIF1a, and MAPK/JNK are the major pathways that are affected by RRM2 overexpression and result in increased NF-kB activity and increased protein levels of EGFR, HER2, IKKs, Bcl-2, RelB, and p50. RRM2-overexpressing cells also exhibited higher migratory and invasive properties. Through time-lapse microscopy and protein profiling studies of tamoxifen-treated MCF-7 and T-47D cells, we have identified that RRM2, along with other key proteins, is altered during the emergence of acquired tamoxifen resistance. Inhibition of RRM2 using siRRM2 or the ribonucleotide reductase (RR) inhibitor didox not only eradicated and effectively prevented the emergence of tamoxifen-resistant populations but also led to the reversal of many of the proteins altered during the process of acquired tamoxifen resistance. Because didox also appears to be a potent inhibitor of NF-kB activation, combining didox with tamoxifen treatment cooperatively reverses ER-a alterations and inhibits NF-kB activation. Finally, inhibition of RRM2 by didox reversed tamoxifenresistant in vivo tumor growth and decreased in vitro migratory and invasive properties, revealing a beneficial effect of combination therapy that includes RRM2 inhibition to delay or abrogate tamoxifen resistance.

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Section: Discussionmentioning

confidence: 53%

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Shah

Wilson

Malla

et al. 2015

Molecular Cancer Therapeutics

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“…Ribonucleotide reductase inhibitors such as hydroxyurea 26 and gemcitabine 27,28 are potent radiosensitizers. Didox is a second generation RRI, which has been shown to be more potent than hydroxyurea, 6 with less associated hematopoietic toxicity. For the first time, this study demonstrates that Didox potentiates the effects of radiation in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…5 Didox has been shown to have anti-tumor effects in a variety of experimental systems including L1210 and P388 Leukemias, and several human tumor xenografts. 6 In this study, to overcome Bcl-2 mediated resistance, a novel second generation and less toxic ribonucleotide reductase inhibitor, 7 Didox was used both pre and immediately post ionizing radiation exposure. The data shown here demonstrates that Didox mediates its radiosensitizing effects by abrogating the radiationinduced upregulation of Bcl-2 expression and NFκ-B activity.…”

Section: Introductionmentioning

confidence: 99%

Didox (A Novel Ribonucleotide Reductase Inhibitor) Overcomes bcl-2 Mediated Radiation Resistance in Prostate Cancer Cell Line PC-3

Inayat

Damodaran²,

Mohiuddin³

et al. 2002

Cancer Biology & Therapy

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© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .[Cancer Biology & ABSTRACTIn this study, we investigated the influence of bcl-2 overexpression on the radiosensitizing potential of Didox (DX; 3,4-Dihydroxybenzohydroxamic acid), a novel ribonucleotide reductase inhibitor, in p53-null prostate cancer cell line PC-3. The PC-3 cells were transfected with vector alone or ectopically overexpressed with CMV-bcl-2 construct. The effect of radiation (IR) or DX alone and in combination (pre and post IR exposure of DX) on cell survival was determined by colony-forming assay. The impact of these two treatments on the cell cycle was determined by flow cytometry. To further understand the molecular mechanism of DX-mediated radiosensitization, induction of pro-survival and pro-apoptotic factors were determined by Western blot and gel-shift assays respectively. When compared to PC-3/bcl-2 cells (SF 2 =0.84; D 0 =437cGy), the PC-3/vector cells (SF 2 =0.4; D 0 =235cGy) were significantly sensitive to ionizing radiation (p<0.001). Exposure of DX at 5µM concentration prior or post to radiation in both PC-3/vector and PC-3/bcl-2 transfectants caused an increase in radiation enhancement ratios. A significant reduction in G 2 M phase was observed in cells exposed to DX post IR when compared to cells exposed to IR alone. Exposure to DX after radiation in PC-3/vector significantly abrogated radiation-induced bcl-2 upregulation, with a concomitant induction of bax protein. In PC-3/bcl-2 transfectants, DX exposure after IR caused an induction of bax protein. Gel shift assays indicated that in PC-3/vector cells when exposed to IR caused an induction of NFκ-B activity however, DX down regulated the NFκ-B activity. Radiation-induced NFκ-B activity was abrogated in pre and post DX exposure in combination with IR. These findings indicate that DX mediates a potent radiosensitizing effect in p53 null prostate cancer cells by overcoming radiation induced NFκ-B activity and bcl-2 expression.

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“…Recently, many hydroxyurea analogues have been tested in vivo and in vitro with didox (N, 3-4 trihydroxybenzamide) exhibiting activity in L1210 leukaemia bearing mice (van't Riet et al, 1979) and in the NCI tumour panel (Elford & van't Riet, 1985).…”

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confidence: 99%

A phase I and pharmacokinetic study of didox administered by 36 hour infusion

Carmichael

Cantwell²,

Mannix³

et al. 1990

Br J Cancer

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Summary Twelve patients were treated with didox, a new ribonucleotide reductase inhibitor, by 36 h infusion. The maximum tolerated dose was 6 g m2, above which dose-limiting hepatic toxicity was observed. Patient (Turner et al., 1968).Hydroxyurea is a specific inhibitor of ribonucleotide reductase (Thurman, 1964) and is the only inhibitor available clinically at present, although it is a relatively weak inhibitor of the enzyme in vitro (Elford, 1968). Recently, many hydroxyurea analogues have been tested in vivo and in vitro with didox (N, 3-4 trihydroxybenzamide) exhibiting activity in L1210 leukaemia bearing mice (van't Riet et al., 1979) and in the NCI tumour panel (Elford & van't Riet, 1985).Didox causes greater inhibition of the target enzyme (Elford et al., 1979) Analytical methods Didox levels were measured in plasma and urine by HPLC using a Beckman/Altex IOOA pump and stainless steel column (15 cm x 0.46 cm) packed with a A-Bondapack C18, 10 jim particle size, as previously described (Veale et al., 1988). Metabolites were identified using standards supplied by Elford. In order to resolve didox and its metabolites from interfering substances in plasma the following step-gradient system was employed: (1) 0.1 M sodium phosphate pH 6.0 for 2 min; (2) as above + 2% acetonitrile pH 6.0 for 2 min; (3) as above + 5% acetonitrile pH 6.0 for 4 min; (4) as above + 10% acetonitrile pH 6.0 for 0.5 min; (5) as above + 20% acetonitrile pH 6.0 for 0.5 min; (6) as above + 30% acetonitrile pH 6.0 for 10 min. The column was equilibrated with Correspondence: A.L. Harris.

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Inhibition of nucleoside diphosphate reductase by hydroxybenzohydroxamic acid derivatives

Cited by 36 publications

References 37 publications

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Didox (A Novel Ribonucleotide Reductase Inhibitor) Overcomes bcl-2 Mediated Radiation Resistance in Prostate Cancer Cell Line PC-3

A phase I and pharmacokinetic study of didox administered by 36 hour infusion

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