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

Zakharenko, Alexandra L.; Dyrkheeva, Nadezhda S.; Lavrik, Olga I.

doi:10.1002/med.21587

Cited by 39 publications

(42 citation statements)

References 83 publications

(243 reference statements)

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“…However, TDP1 removes the stalled TOP1-DNA complex, reducing the efficacy of the drugs and leading to resistance [ 7 , 8 , 9 ]. As has been confirmed in gene knockout studies in mice and human cell lines, TDP1 contributes to the development of drug resistance in a number of cancers (see [ 3 ] and references therein). Indeed, human cell lines with mutant or missing TDP1 as well as TDP1-knockout mice are both hypersensitive to the well-established TOP1 inhibitor camptothecin and its derivatives.…”

Section: Introductionmentioning

confidence: 85%

“…Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a DNA repair enzyme and a promising therapeutic target to enhance established cancer treatment [ 1 , 2 , 3 , 4 ]. TDP1 plays a key role in the removal of DNA lesions, in particular those caused by DNA topoisomerase I (TOP1) inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, human cell lines with mutant or missing TDP1 as well as TDP1-knockout mice are both hypersensitive to the well-established TOP1 inhibitor camptothecin and its derivatives. Conversely, at high TDP1 expression levels, camptothecin and etoposide cause limited DNA damage [ 3 ]. Thus, a promising approach to increase the selectivity and potency of TOP1 poisons to cancer cells is to combine them with TDP1 inhibitors, which can significantly increase the chemotherapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

et al. 2020

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Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 −/− cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

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Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

et al. 2020

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“…TDP1/2 are enzymes responsible for the reparation of DNA breaks induced by topoisomerase poisons [ 57 , 211 , 212 ]. TDP1/2 inhibitors are capable of improving cancer cells’ sensitivity to these poisons [ 213 ].…”

Section: Future Strategies For Copper Complexes As Top Inhibitors mentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

119

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Organometallics, such as copper compounds, are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topology. Copper complexes inhibitors of topoisomerases 1 and 2 work by different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS production, and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.

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“…One of the current approaches to increase the efficacy of clinically-established antitumor therapy is the inhibition of DNA repair enzymes that counteract the effect of DNA-damaging chemotherapy agents [23][24][25]. One of these important enzymes is tyrosyl-DNA phosphodiesterase 1 (Tdp1) [26].…”

Section: Introductionmentioning

confidence: 99%

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Khomenko

Zakharenko

Chepanova

et al. 2019

IJMS

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons.

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

Cited by 39 publications

References 83 publications

Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

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