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Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents

SIMPLE SUMMARY: Natural products have continued to play an important role in new drug discovery with a considerable number of marketed drugs being derived from naturally occurring compounds, particularly in the area of cancer. Taccalonolides are a new class of microtube-stabilizing agents isolated f...

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Autores principales: Chen, Xiaoyan, Winstead, Angela, Yu, Hongtao, Peng, Jiangnan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926778/
https://www.ncbi.nlm.nih.gov/pubmed/33671665
http://dx.doi.org/10.3390/cancers13040920
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author Chen, Xiaoyan
Winstead, Angela
Yu, Hongtao
Peng, Jiangnan
author_facet Chen, Xiaoyan
Winstead, Angela
Yu, Hongtao
Peng, Jiangnan
author_sort Chen, Xiaoyan
collection PubMed
description SIMPLE SUMMARY: Natural products have continued to play an important role in new drug discovery with a considerable number of marketed drugs being derived from naturally occurring compounds, particularly in the area of cancer. Taccalonolides are a new class of microtube-stabilizing agents isolated from plants of the genus Tacca demonstrating effectiveness against drug-resistant tumors in cellular and animal models. This review article highlights the discovery history of taccalonolides and their microtubule-stabilizing activities, which summarizes the naturally derived and semi-synthesized structures that have been reported so far and the advances on the mechanism of action of taccalonolides. ABSTRACT: Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical practice is their intrinsic and acquired drug resistance, which is common to most anti-cancer chemotherapeutics. Taccalonolides are a new class of microtubule stabilizers isolated from the roots of a few species in the genus of Tacca. In early studies, taccalonolides demonstrated different effects on interphase and mitotic microtubules from those of paclitaxel and laulimalide suggesting a unique mechanism of action. This prompts the exploration of new taccalonolides with various functionalities through the identification of minor constituents of natural origin and semi-synthesis. The experiments on the new highly potent taccalonolides indicated that taccalonolides possessed a unique mechanism of covalently binding to the microtubule. An X-ray diffraction analysis of a crystal of taccalonolides AJ binding to tubulin indicated that the covalent binding site is at β-tubulin D226. Taccalonolides circumvent all three mechanisms of taxane drug resistance both in vitro and in vivo. To improve the activity, the structure modification through semi-synthesis was conducted and the structure-activity relationships (SARs) was analyzed based on natural and semi-synthetical taccalonolides. The C22–C23 epoxide can significantly increase the antiproliferation potency of taccalonolides due to the covalent link of C22 and the carboxylic group of D226. Great progress has been seen in the last few years in the understanding of the mechanism of this class of microtube-stabilizing agents. This review summarizes the structure diversity, structure-activity relationships (SARs), mechanism of action, and in vivo activities of taccalonolides.
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spelling pubmed-79267782021-03-04 Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents Chen, Xiaoyan Winstead, Angela Yu, Hongtao Peng, Jiangnan Cancers (Basel) Review SIMPLE SUMMARY: Natural products have continued to play an important role in new drug discovery with a considerable number of marketed drugs being derived from naturally occurring compounds, particularly in the area of cancer. Taccalonolides are a new class of microtube-stabilizing agents isolated from plants of the genus Tacca demonstrating effectiveness against drug-resistant tumors in cellular and animal models. This review article highlights the discovery history of taccalonolides and their microtubule-stabilizing activities, which summarizes the naturally derived and semi-synthesized structures that have been reported so far and the advances on the mechanism of action of taccalonolides. ABSTRACT: Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical practice is their intrinsic and acquired drug resistance, which is common to most anti-cancer chemotherapeutics. Taccalonolides are a new class of microtubule stabilizers isolated from the roots of a few species in the genus of Tacca. In early studies, taccalonolides demonstrated different effects on interphase and mitotic microtubules from those of paclitaxel and laulimalide suggesting a unique mechanism of action. This prompts the exploration of new taccalonolides with various functionalities through the identification of minor constituents of natural origin and semi-synthesis. The experiments on the new highly potent taccalonolides indicated that taccalonolides possessed a unique mechanism of covalently binding to the microtubule. An X-ray diffraction analysis of a crystal of taccalonolides AJ binding to tubulin indicated that the covalent binding site is at β-tubulin D226. Taccalonolides circumvent all three mechanisms of taxane drug resistance both in vitro and in vivo. To improve the activity, the structure modification through semi-synthesis was conducted and the structure-activity relationships (SARs) was analyzed based on natural and semi-synthetical taccalonolides. The C22–C23 epoxide can significantly increase the antiproliferation potency of taccalonolides due to the covalent link of C22 and the carboxylic group of D226. Great progress has been seen in the last few years in the understanding of the mechanism of this class of microtube-stabilizing agents. This review summarizes the structure diversity, structure-activity relationships (SARs), mechanism of action, and in vivo activities of taccalonolides. MDPI 2021-02-22 /pmc/articles/PMC7926778/ /pubmed/33671665 http://dx.doi.org/10.3390/cancers13040920 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Chen, Xiaoyan
Winstead, Angela
Yu, Hongtao
Peng, Jiangnan
Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents
title Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents
title_full Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents
title_fullStr Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents
title_full_unstemmed Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents
title_short Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents
title_sort taccalonolides: a novel class of microtubule-stabilizing anticancer agents
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926778/
https://www.ncbi.nlm.nih.gov/pubmed/33671665
http://dx.doi.org/10.3390/cancers13040920
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