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Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs.

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.

SUBMITTER: Leung E

PROVIDER: S-EPMC8593127 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs.

Leung Euphemia E Patel Jinal J Hollywood Jennifer A JA Zafar Ayesha A Tomek Petr P Barker David D Pilkington Lisa I LI van Rensburg Michelle M Langley Ries J RJ Helsby Nuala A NA Squire Christopher J CJ Baguley Bruce C BC Denny William A WA Reynisson Jóhannes J Leung Ivanhoe K H IKH

Oncology and therapy 20210623 2

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 ...[more]

PMID: 34159519

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Project description:BackgroundThe aim of this study was to design and evaluate hybrid cyclodextrin (CD) nanocapsules intended for the oral delivery of the anticancer agent camptothecin (CPT) in order to maintain drug stability in the body and to improve its eventual bioavailability. For this reason, an amphiphilic cyclodextrin (CD) derivative per-modified on the primary face 6OCAPRO was used as core molecule to form nanocapsules with the nanoprecipitation technique. Nanocapsules were further coated with the cationic polymer chitosan to improve the cellular uptake and interaction with biological membranes through positive surface charge. Nanocapsules were evaluated for their in vitro characteristics such as particle size, zeta potential, drug loading and release profiles followed by cell culture studies with the MCF-7 and Caco-2 cell line evaluating their anticancer efficacy and permeability. The CD nanocapsules were imaged by scanning electron microscopy (SEM). The concentration of CPT entrapped in nanocapsules was determined by reversed phase HPLC. The in vitro release study of CPT was performed with a dialysis bag method under sink conditions mimicking the gastric and intestinal pH. The hydrolytic stability of CPT in nanocapsules was investigated in simulated gastric and intestinal fluids (SGF, SIF).ResultsThe mean particle sizes of both anionic and cationic CPT-loaded nanocapsules were in the range of 180-200 nm with polydispersity indices lower than 0.400 indicating monodisperse size distribution of nanocapsules with favourable potential for intracellular drug delivery to tumour cells. Surface charges of anionic and cationic nanocapsules were demonstrated as -21 mV and +18 mV, respectively. The stability of CPT in simulated release media, SGF and SIF were maintained suggesting the improved protection of the drug molecule from rapid hydrolysis degradation or gastrointestinal pH in nanocapsule oily core. Furthermore CD nanocapsules showed higher anticancer efficacy than CPT solution against the MCF-7 cell line. Permeation of CPT across Caco-2 cells was found to be 3 fold higher when incorporated in hybrid CD nanocapsules compared with a DMSO solution.ConclusionOral CD nanocapsules indicating increased oral bioavailability might be a promising strategy to maintain the physiological stability and to improve the oral bioavailability of problematic anticancer drugs such as CPT which may contribute to patient quality of life and drug efficacy in cancer therapy.

Dataset Information

Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs.

Publications

Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs.

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