Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models

Zakharenko, Alexandra L.; Luzina, O. A.; Sokolov, D. N.; Каледин, В. И.; Николин, В. П.; Попова, Н. А.; Patel, Jinal; Zakharova, Olga D.; Chepanova, Arina A; Zafar, Ayesha; Reynisson, Jóhannes; Leung, Euphemia; Leung, Ivanhoe K. H.; Волчо, К. П.; Salakhutdinov, N. F.; Lavrik, Olga I.

doi:10.1016/j.ejmech.2018.10.055

Cited by 57 publications

(77 citation statements)

References 72 publications

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“…Intrinsic protein fluorescence assay were conducted according to the protocol as described in references [35,45,49]. The concentrations of recombinant Tdp1 and ligand were 10 µM and 1 mM, respectively.…”

Section: Binding Studiesmentioning

confidence: 99%

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The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

et al. 2019

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Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 M. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 M concentration, displaying strong synergism. This effect was only seen for 46a (IC50—3.3 M) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

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Section: Binding Studiesmentioning

confidence: 99%

“…The binding and inhibition potency of the compounds were tested against purified recombinant Tdp1. Binding experiments were conducted using thermal shift assay [71] and an intrinsic fluorescence binding assay that we previously developed [35,45,49]. Thermal shift assay measures the stability of proteins against thermal degradation.…”

Section: Inhibition Studiesmentioning

confidence: 99%

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

et al. 2019

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“…Therefore, the screening of TDP1 inhibitors is a promising venue for developing new cancer therapies. 18, 41, 42…”

Section: Discussionmentioning

confidence: 99%

Tyrosyl-DNA phosphodiesterase 1 and topoisomerase I activities as predictive indicators for Glioblastoma susceptibility to genotoxic agents

Wang

Rodriguez-Silva

Rocha

et al. 2019

Preprint

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34Background. Glioblastoma (GBM) patients have an estimated survival of ~15 months with 35 treatment, and the standard of care only modestly enhances patient survival. Identifying 36 biomarkers representing vulnerabilities may allow for selection of efficacious chemotherapy 37 options to address personalized variations in GBM tumors. Irinotecan, currently in clinical trials 38 for GBM, targets topoisomerase I (TOP1) by forming a ternary DNA-TOP1 cleavage complex 39 (TOP1cc) inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair 40 enzyme that may reduce the effectiveness of irinotecan. 41 42 3 Methods. We treated GBM cell lines with increasing concentrations of irinotecan and compared 43 the IC50 values. TOP1 and TDP1 protein levels from each cell type as well as GBM patient tumors 44 were determined by Western blot analysis, while activity levels were ascertained by specific 45 enzymatic assays. Cellular TDP1 was elevated by ectopic expression of wild-type or mutant TDP1. 46 47 Results. After comparing cellular susceptibility to TDP1 and TOP1 concentrations and activities, 48we found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation 49 coefficient R = 0.92) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 50 activity ratio by ectopic expression of wild-type TDP1 increased in irinotecan IC50, while 51 expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. 52 53 Conclusions. TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability 54 to irinotecan, allowing for selection of individual patients for irinotecan treatment based on risk-55 benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to 56 improve GBM patient responsiveness to genotoxic chemotherapies. 57 58 Keywords: glioblastoma, DNA repair, TOP1, TDP1, irinotecan 59 60 Key Points 61 1. TDP1/TOP1 activity ratio correlates with irinotecan sensitivity in GBM cell lines. 62

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“…C , Aryliden‐ ( 6 × ) derivative of UA . D , Hydrazinothiazole derivative 20d . Tdp1, tyrosyl‐DNA phosphodiesterase 1…”

Section: Tdp1 Inhibitors: Sensitizing Tumors To Camptothecin and Its mentioning

confidence: 99%

“…The most effective Tdp1 inhibitor reported till date belongs to this class of compounds and inhibits Tdp1 at a concentration of 26 nM (Figure D). Studies on the acute toxicity of compound 20d on mice showed that the compound is nontoxic (LD 50 > 5,000 mg/kg), thus significantly increasing antitumor and antimetastatic effects of topotecan in mice . It is currently undergoing preclinical trials as a sensitizer of Lewis lung carcinoma to topotecan.…”

Section: Tdp1 Inhibitors: Sensitizing Tumors To Camptothecin and Its mentioning

confidence: 99%

Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

Zakharenko

Dyrkheeva

Lavrik

2019

Medicinal Research Reviews

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Tyrosyl‐DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that catalyzes the hydrolysis of the phosphodiester bond in the DNA‐topoisomerase 1 (Top1) covalent complex and repairs some other 3′‐end DNA adducts. Currently, Tdp1 functions as an important target in cancer drug design owing to its ability to break down various DNA adducts induced by chemotherapeutics. Tdp1 inhibitors may sensitize tumor cells to the action of Top1 poisons, thereby potentiating their effects. This mini‐review summarizes findings from studies reporting the combined inhibition of Top1 and Tdp1. Two different approaches have been considered for developing such drug precursors.

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Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models

Cited by 57 publications

References 72 publications

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

Tyrosyl-DNA phosphodiesterase 1 and topoisomerase I activities as predictive indicators for Glioblastoma susceptibility to genotoxic agents

Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

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