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7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth

7-Ethyl-10-hydroxycamptothecin (SN-38) is an active metabolite of CPT-11, which can inhibit DNA topoisomerase I, DNA synthesis and cause frequent DNA single-strand breaks. In our study, SN-38 was characterized as a potent and reversible BRD4 inhibitor [IC(50) = 660.2 nM against BRD4 (BD1) and IC(50)...

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Autores principales: Wang, Airong, Li, Lingling, Li, Mengya, Wang, Shujuan, Wang, Chong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117000/
https://www.ncbi.nlm.nih.gov/pubmed/33995089
http://dx.doi.org/10.3389/fphar.2021.664176
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author Wang, Airong
Li, Lingling
Li, Mengya
Wang, Shujuan
Wang, Chong
author_facet Wang, Airong
Li, Lingling
Li, Mengya
Wang, Shujuan
Wang, Chong
author_sort Wang, Airong
collection PubMed
description 7-Ethyl-10-hydroxycamptothecin (SN-38) is an active metabolite of CPT-11, which can inhibit DNA topoisomerase I, DNA synthesis and cause frequent DNA single-strand breaks. In our study, SN-38 was characterized as a potent and reversible BRD4 inhibitor [IC(50) = 660.2 nM against BRD4 (BD1) and IC(50) = 547.7 nM against BRD4 (BD2)] in biochemical assay using drug repurposing strategy. Additional cellular assay suggested that SN-38 can bind BRD4 in human leukemic cell K562 and inhibit cell growth with IC(50) = 0.2798 μM in a BRD4 dependent manner partially. Additionally, mechanism study indicated that SN-38 can induce the accumulation of BRD4 substrate c-Myc and cleavage of caspase 3. In sum, our findings identified BRD4 as a new target of SN-38 and reveals SN-38 as a modifier of histone acetylation reader for the first time, which may provide a new insight for further optimization of dual target inhibitor.
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spelling pubmed-81170002021-05-14 7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth Wang, Airong Li, Lingling Li, Mengya Wang, Shujuan Wang, Chong Front Pharmacol Pharmacology 7-Ethyl-10-hydroxycamptothecin (SN-38) is an active metabolite of CPT-11, which can inhibit DNA topoisomerase I, DNA synthesis and cause frequent DNA single-strand breaks. In our study, SN-38 was characterized as a potent and reversible BRD4 inhibitor [IC(50) = 660.2 nM against BRD4 (BD1) and IC(50) = 547.7 nM against BRD4 (BD2)] in biochemical assay using drug repurposing strategy. Additional cellular assay suggested that SN-38 can bind BRD4 in human leukemic cell K562 and inhibit cell growth with IC(50) = 0.2798 μM in a BRD4 dependent manner partially. Additionally, mechanism study indicated that SN-38 can induce the accumulation of BRD4 substrate c-Myc and cleavage of caspase 3. In sum, our findings identified BRD4 as a new target of SN-38 and reveals SN-38 as a modifier of histone acetylation reader for the first time, which may provide a new insight for further optimization of dual target inhibitor. Frontiers Media S.A. 2021-04-29 /pmc/articles/PMC8117000/ /pubmed/33995089 http://dx.doi.org/10.3389/fphar.2021.664176 Text en Copyright © 2021 Wang, Li, Li, Wang and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Airong
Li, Lingling
Li, Mengya
Wang, Shujuan
Wang, Chong
7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth
title 7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth
title_full 7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth
title_fullStr 7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth
title_full_unstemmed 7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth
title_short 7-Ethyl-10-Hydroxycamptothecin, a DNA Topoisomerase I Inhibitor, Performs BRD4 Inhibitory Activity and Inhibits Human Leukemic Cell Growth
title_sort 7-ethyl-10-hydroxycamptothecin, a dna topoisomerase i inhibitor, performs brd4 inhibitory activity and inhibits human leukemic cell growth
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117000/
https://www.ncbi.nlm.nih.gov/pubmed/33995089
http://dx.doi.org/10.3389/fphar.2021.664176
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