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An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation
SIMPLE SUMMARY: We designed and synthesized a series of novel naphthoquinone derivatives, of which ZSW has a high activity to inhibit the growth of tumor cells and low toxicity. We determined that ZSW suppresses triple-negative breast cancer cell activity by targeting STAT3 and provides a new compou...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177496/ https://www.ncbi.nlm.nih.gov/pubmed/37173892 http://dx.doi.org/10.3390/cancers15092424 |
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author | Xie, Yuanzhu Zhu, Shuaiwen Chen, Ling Liu, Hongdou Peng, Ting Ming, Zhengnan Zou, Zizheng Hu, Xiyuan Luo, Wensong Peng, Kunjian Nie, Yuan Luo, Tiao Ma, Dayou Liu, Suyou Luo, Zhiyong |
author_facet | Xie, Yuanzhu Zhu, Shuaiwen Chen, Ling Liu, Hongdou Peng, Ting Ming, Zhengnan Zou, Zizheng Hu, Xiyuan Luo, Wensong Peng, Kunjian Nie, Yuan Luo, Tiao Ma, Dayou Liu, Suyou Luo, Zhiyong |
author_sort | Xie, Yuanzhu |
collection | PubMed |
description | SIMPLE SUMMARY: We designed and synthesized a series of novel naphthoquinone derivatives, of which ZSW has a high activity to inhibit the growth of tumor cells and low toxicity. We determined that ZSW suppresses triple-negative breast cancer cell activity by targeting STAT3 and provides a new compound structure candidate for TNBC clinical drug development. ABSTRACT: Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with shorter five-year survival than other breast cancer subtypes, and lacks targeted and hormonal treatment strategies. The signal transducer and activator of transcription 3 (STAT3) signaling is up-regulated in various tumors, including TNBC, and plays a vital role in regulating the expression of multiple proliferation- and apoptosis-related genes. Results: By combining the unique structures of the natural compounds STA-21 and Aulosirazole with antitumor activities, we synthesized a class of novel isoxazoloquinone derivatives and showed that one of these compounds, ZSW, binds to the SH2 domain of STAT3, leading to decreased STAT3 expression and activation in TNBC cells. Furthermore, ZSW promotes STAT3 ubiquitination, inhibits the proliferation of TNBC cells in vitro, and attenuates tumor growth with manageable toxicities in vivo. ZSW also decreases the mammosphere formation of breast cancer stem cells (BCSCs) by inhibiting STAT3. Conclusions: We conclude that the novel isoxazoloquinone ZSW may be developed as a cancer therapeutic because it targets STAT3, thereby inhibiting the stemness of cancer cells. |
format | Online Article Text |
id | pubmed-10177496 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101774962023-05-13 An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation Xie, Yuanzhu Zhu, Shuaiwen Chen, Ling Liu, Hongdou Peng, Ting Ming, Zhengnan Zou, Zizheng Hu, Xiyuan Luo, Wensong Peng, Kunjian Nie, Yuan Luo, Tiao Ma, Dayou Liu, Suyou Luo, Zhiyong Cancers (Basel) Article SIMPLE SUMMARY: We designed and synthesized a series of novel naphthoquinone derivatives, of which ZSW has a high activity to inhibit the growth of tumor cells and low toxicity. We determined that ZSW suppresses triple-negative breast cancer cell activity by targeting STAT3 and provides a new compound structure candidate for TNBC clinical drug development. ABSTRACT: Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with shorter five-year survival than other breast cancer subtypes, and lacks targeted and hormonal treatment strategies. The signal transducer and activator of transcription 3 (STAT3) signaling is up-regulated in various tumors, including TNBC, and plays a vital role in regulating the expression of multiple proliferation- and apoptosis-related genes. Results: By combining the unique structures of the natural compounds STA-21 and Aulosirazole with antitumor activities, we synthesized a class of novel isoxazoloquinone derivatives and showed that one of these compounds, ZSW, binds to the SH2 domain of STAT3, leading to decreased STAT3 expression and activation in TNBC cells. Furthermore, ZSW promotes STAT3 ubiquitination, inhibits the proliferation of TNBC cells in vitro, and attenuates tumor growth with manageable toxicities in vivo. ZSW also decreases the mammosphere formation of breast cancer stem cells (BCSCs) by inhibiting STAT3. Conclusions: We conclude that the novel isoxazoloquinone ZSW may be developed as a cancer therapeutic because it targets STAT3, thereby inhibiting the stemness of cancer cells. MDPI 2023-04-23 /pmc/articles/PMC10177496/ /pubmed/37173892 http://dx.doi.org/10.3390/cancers15092424 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Xie, Yuanzhu Zhu, Shuaiwen Chen, Ling Liu, Hongdou Peng, Ting Ming, Zhengnan Zou, Zizheng Hu, Xiyuan Luo, Wensong Peng, Kunjian Nie, Yuan Luo, Tiao Ma, Dayou Liu, Suyou Luo, Zhiyong An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation |
title | An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation |
title_full | An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation |
title_fullStr | An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation |
title_full_unstemmed | An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation |
title_short | An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation |
title_sort | isoxazoloquinone derivative inhibits tumor growth by targeting stat3 and triggering its ubiquitin-dependent degradation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177496/ https://www.ncbi.nlm.nih.gov/pubmed/37173892 http://dx.doi.org/10.3390/cancers15092424 |
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