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Updated: Nov 1, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy
Euphemia Leung1,2,3, Jinal Patel4, Jennifer A Hollywood5
1Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland, 1142, New Zealand. e.leung@auckland.ac.nz.
Abstract:
Cancer chemotherapy sensitizers hold the key to maximizing the potential of standard anticancer treatments. We have a long-standing interest in developing and validating inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) as chemosensitizers for topoisomerase I poisons such as topotecan. Herein, by using thieno[2,3-b]pyridines, a class of TDP1 inhibitors, we showed that the inhibition of TDP1 can restore sensitivity to topotecan, results that are supported by TDP1 knockout cell experiments using CRISPR/Cas9. However, we also found that the restored sensitivity towards topoisomerase I inhibitors is likely regulated by multiple complementary DNA repair pathways. Our results showed that one of these pathways is likely modulated by PARP1, although it is also possible that other redundant and partially overlapping pathways may be involved in the DNA repair process. Our work thus raises the prospect of targeting multiple DNA repair pathways to increase the sensitivity to topoisomerase I inhibitors.
Insights
Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) restores cancer cells
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer chemotherapy sensitizers enhance standard anticancer treatments.
- Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme.
- Inhibiting TDP1 is a strategy to chemosensitize topoisomerase I poisons like topotecan.
Purpose of the Study:
- To investigate thieno[2,3-b]pyridines as TDP1 inhibitors.
- To evaluate the restoration of topotecan sensitivity by TDP1 inhibition.
- To explore the DNA repair pathways involved in restored sensitivity.
Main Methods:
- Utilized thieno[2,3-b]pyridines as TDP1 inhibitors.
- Employed CRISPR/Cas9 technology for TDP1 knockout cell experiments.
- Analyzed the role of DNA repair pathways, including PARP1 modulation.
Main Results:
- TDP1 inhibition using thieno[2,3-b]pyridines restored topotecan sensitivity.
- TDP1 knockout cell experiments validated the role of TDP1.
- Restored sensitivity involves multiple complementary DNA repair pathways, potentially including PARP1.
Conclusions:
- Inhibition of TDP1 is a viable strategy to chemosensitize topoisomerase I inhibitors.
- Multiple DNA repair pathways, such as PARP1-modulated pathways, contribute to resistance.
- Targeting multiple DNA repair pathways offers a promising approach to enhance chemotherapy efficacy.
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