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Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells
Taxol is a first-line chemotherapeutic for numerous cancers, including the highly refractory triple-negative breast cancer (TNBC). However, it is often associated with toxic side effects and chemoresistance in breast cancer patients, which greatly limits the clinical utility of the drug. Hence, comp...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137698/ https://www.ncbi.nlm.nih.gov/pubmed/34016960 http://dx.doi.org/10.1038/s41420-021-00495-z |
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author | Fang, Chieh-Ting Kuo, Hsiao-Hui Yuan, Chia-Jung Yao, Jhong-Syuan Yih, Ling-Huei |
author_facet | Fang, Chieh-Ting Kuo, Hsiao-Hui Yuan, Chia-Jung Yao, Jhong-Syuan Yih, Ling-Huei |
author_sort | Fang, Chieh-Ting |
collection | PubMed |
description | Taxol is a first-line chemotherapeutic for numerous cancers, including the highly refractory triple-negative breast cancer (TNBC). However, it is often associated with toxic side effects and chemoresistance in breast cancer patients, which greatly limits the clinical utility of the drug. Hence, compounds that act in concert with taxol to promote cytotoxicity may be useful to improve the efficacy of taxol-based chemotherapy. In this study, we demonstrated that mdivi-1, a putative inhibitor of mitochondrial fission protein Drp1, enhances the anticancer effects of taxol and overcomes taxol resistance in a TNBC cell line (MDA-MB-231). Not only did mdivi-1 induce mitotic spindle abnormalities and mitotic arrest when used alone, but it also enhanced taxol-induced antimitotic effects when applied in combination. In addition, mdivi-1 induced pronounced spindle abnormalities and cytotoxicity in a taxol-resistant cell line, indicating that it can overcome taxol resistance. Notably, the antimitotic effects of mdivi-1 were not accompanied by prominent morphological or functional alterations in mitochondria and were Drp1-independent. Instead, mdivi-1 exhibited affinity to tubulin at μM level, inhibited tubulin polymerization, and immediately disrupted spindle assembly when cells entered mitosis. Together, our results show that mdivi-1 associates with tubulin and impedes tubulin polymerization, actions which may underlie its antimitotic activity and its ability to enhance taxol cytotoxicity and overcome taxol resistance in MDA-MB-231 cells. Furthermore, our data imply a possibility that mdivi-1 could be useful to improve the therapeutic efficacy of taxol in breast cancer. |
format | Online Article Text |
id | pubmed-8137698 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81376982021-06-03 Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells Fang, Chieh-Ting Kuo, Hsiao-Hui Yuan, Chia-Jung Yao, Jhong-Syuan Yih, Ling-Huei Cell Death Discov Article Taxol is a first-line chemotherapeutic for numerous cancers, including the highly refractory triple-negative breast cancer (TNBC). However, it is often associated with toxic side effects and chemoresistance in breast cancer patients, which greatly limits the clinical utility of the drug. Hence, compounds that act in concert with taxol to promote cytotoxicity may be useful to improve the efficacy of taxol-based chemotherapy. In this study, we demonstrated that mdivi-1, a putative inhibitor of mitochondrial fission protein Drp1, enhances the anticancer effects of taxol and overcomes taxol resistance in a TNBC cell line (MDA-MB-231). Not only did mdivi-1 induce mitotic spindle abnormalities and mitotic arrest when used alone, but it also enhanced taxol-induced antimitotic effects when applied in combination. In addition, mdivi-1 induced pronounced spindle abnormalities and cytotoxicity in a taxol-resistant cell line, indicating that it can overcome taxol resistance. Notably, the antimitotic effects of mdivi-1 were not accompanied by prominent morphological or functional alterations in mitochondria and were Drp1-independent. Instead, mdivi-1 exhibited affinity to tubulin at μM level, inhibited tubulin polymerization, and immediately disrupted spindle assembly when cells entered mitosis. Together, our results show that mdivi-1 associates with tubulin and impedes tubulin polymerization, actions which may underlie its antimitotic activity and its ability to enhance taxol cytotoxicity and overcome taxol resistance in MDA-MB-231 cells. Furthermore, our data imply a possibility that mdivi-1 could be useful to improve the therapeutic efficacy of taxol in breast cancer. Nature Publishing Group UK 2021-05-20 /pmc/articles/PMC8137698/ /pubmed/34016960 http://dx.doi.org/10.1038/s41420-021-00495-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Fang, Chieh-Ting Kuo, Hsiao-Hui Yuan, Chia-Jung Yao, Jhong-Syuan Yih, Ling-Huei Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells |
title | Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells |
title_full | Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells |
title_fullStr | Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells |
title_full_unstemmed | Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells |
title_short | Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells |
title_sort | mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in mda-mb-231 cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137698/ https://www.ncbi.nlm.nih.gov/pubmed/34016960 http://dx.doi.org/10.1038/s41420-021-00495-z |
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