TY - JOUR
T1 - The Lipophilic Purine Nucleoside-Tdp1 Inhibitor-Enhances DNA Damage Induced by Topotecan In Vitro and Potentiates the Antitumor Effect of Topotecan In Vivo
AU - Chernyshova, Irina A
AU - Zakharenko, Aleksandra L
AU - Kurochkin, Nikolay N
AU - Dyrkheeva, Nadezhda S
AU - Kornienko, Tatyana E
AU - Popova, Nelly A
AU - Nikolin, Valeriy P
AU - Ilina, Ekaterina S
AU - Zharkov, Timofey D
AU - Kupryushkin, Maxim S
AU - Oslovsky, Vladimir E
AU - Drenichev, Mikhail S
AU - Lavrik, Olga I
N1 - Funding: This research was funded by a grant from the Ministry of Science and Higher Education Russian Federation (agreement No. 075-15-2020-773).
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Humans
KW - Topotecan/pharmacology
KW - Phosphoric Diester Hydrolases/metabolism
KW - Phosphodiesterase Inhibitors/pharmacology
KW - Purine Nucleosides
KW - Structure-Activity Relationship
KW - Topoisomerase I Inhibitors/pharmacology
KW - Esterases/metabolism
KW - DNA Damage
KW - DNA
KW - DNA Topoisomerases, Type I/metabolism
KW - synergy
KW - Tdp1 inhibitor
KW - lipophilic nucleosides
KW - tyrosyl-DNA phosphodiesterase 1
KW - DNA repair
KW - inhibiting activity
KW - topoisomerase I
KW - topotecan
UR - https://www.mendeley.com/catalogue/d3c0f954-4d4d-3c74-b616-1a0f3f6ea7ca/
U2 - 10.3390/molecules28010323
DO - 10.3390/molecules28010323
M3 - Article
C2 - 36615517
VL - 28
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 1
M1 - 323
ER -