The Lipophilic Purine Nucleoside-Tdp1 Inhibitor-Enhances DNA Damage Induced by Topotecan In Vitro and Potentiates the Antitumor Effect of Topotecan In Vivo

Molecules. 2022 Dec 31;28(1):323. doi: 10.3390/molecules28010323.

Abstract

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 μM 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.

Keywords: DNA repair; Tdp1 inhibitor; inhibiting activity; lipophilic nucleosides; synergy; topoisomerase I; topotecan; tyrosyl-DNA phosphodiesterase 1.

MeSH terms

  • Animals
  • DNA
  • DNA Damage
  • DNA Topoisomerases, Type I / metabolism
  • Esterases / metabolism
  • Humans
  • Mice
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases* / metabolism
  • Purine Nucleosides
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / pharmacology
  • Topotecan* / pharmacology

Substances

  • Topotecan
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase Inhibitors
  • Purine Nucleosides
  • Topoisomerase I Inhibitors
  • Esterases
  • DNA
  • DNA Topoisomerases, Type I
  • TDP1 protein, human