期刊
MOLECULES
卷 28, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/molecules28010323
关键词
DNA repair; topoisomerase I; tyrosyl-DNA phosphodiesterase 1; Tdp1 inhibitor; inhibiting activity; lipophilic nucleosides; topotecan; synergy
The use of cancer chemotherapy sensitizers is a promising approach to enhance the effect of clinically used anticancer treatments. In this study, we focused on Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), a DNA-repair enzyme, and investigated its inhibition as a strategy to sensitize cells towards the effect of the Topoisomerase 1 (Top1) inhibitor topotecan (Tpc). We synthesized lipophilic derivatives of purine nucleosides that efficiently suppressed Tdp1 activity and demonstrated their ability to enhance DNA damage induced by topotecan, both in vitro using human cell lines and in vivo using a mice ascitic Krebs-2 carcinoma model.
The use of cancer chemotherapy sensitizers is a promising approach to induce the effect of clinically used anticancer treatments. One of the interesting targets is Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), a DNA-repair enzyme, that may prevent the action of clinical Topoisomerase 1 (Top1) inhibitors, such as topotecan (Tpc). Tdp1 eliminates covalent Top1-DNA (Top1c) complexes that appear under the action of topotecan and determines the cytotoxic effect of this drug. We hypothesize that Tdp1 inhibition would sensitize cells towards the effect of Tpc. Herein, we report the synthesis and study of lipophilic derivatives of purine nucleosides that efficiently suppress Tdp1 activity, with IC50 values in the 0.3-22.0 mu M range. We also showed that this compound class can enhance DNA damage induced by topotecan in vitro by Comet assay on human cell lines HeLa and potentiate the antitumor effect of topotecan in vivo on a mice ascitic Krebs-2 carcinoma model. Thereby, this type of compound may be useful to develop drugs, that sensitize the effect of topotecan and reduce the required dose and, as a result, side effects.
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