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Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death

α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhi...

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Autores principales: Ebisu, Haruna, Shintani, Kana, Chinen, Takumi, Nagumo, Yoko, Shioda, Shuya, Hatanaka, Taisei, Sakakura, Akira, Hayakawa, Ichiro, Kigoshi, Hideo, Usui, Takeo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878676/
https://www.ncbi.nlm.nih.gov/pubmed/33584305
http://dx.doi.org/10.3389/fphar.2020.620185
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author Ebisu, Haruna
Shintani, Kana
Chinen, Takumi
Nagumo, Yoko
Shioda, Shuya
Hatanaka, Taisei
Sakakura, Akira
Hayakawa, Ichiro
Kigoshi, Hideo
Usui, Takeo
author_facet Ebisu, Haruna
Shintani, Kana
Chinen, Takumi
Nagumo, Yoko
Shioda, Shuya
Hatanaka, Taisei
Sakakura, Akira
Hayakawa, Ichiro
Kigoshi, Hideo
Usui, Takeo
author_sort Ebisu, Haruna
collection PubMed
description α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.
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spelling pubmed-78786762021-02-13 Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death Ebisu, Haruna Shintani, Kana Chinen, Takumi Nagumo, Yoko Shioda, Shuya Hatanaka, Taisei Sakakura, Akira Hayakawa, Ichiro Kigoshi, Hideo Usui, Takeo Front Pharmacol Pharmacology α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy. Frontiers Media S.A. 2021-01-29 /pmc/articles/PMC7878676/ /pubmed/33584305 http://dx.doi.org/10.3389/fphar.2020.620185 Text en Copyright © 2021 Ebisu, Shintani, Chinen, Nagumo, Shioda, Hatanaka, Sakakura, Hayakawa, Kigoshi and Usui. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/) . 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
Ebisu, Haruna
Shintani, Kana
Chinen, Takumi
Nagumo, Yoko
Shioda, Shuya
Hatanaka, Taisei
Sakakura, Akira
Hayakawa, Ichiro
Kigoshi, Hideo
Usui, Takeo
Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death
title Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death
title_full Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death
title_fullStr Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death
title_full_unstemmed Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death
title_short Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death
title_sort dual inhibition of γ-tubulin and plk1 induces mitotic cell death
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878676/
https://www.ncbi.nlm.nih.gov/pubmed/33584305
http://dx.doi.org/10.3389/fphar.2020.620185
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