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β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells

Background: β-thujaplicin, a natural tropolone derivative, has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. Methods: Trypan blue staining, a WST-8 assay, and a caspase-3/7 activity assay were us...

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Autores principales: Seno, Saki, Kimura, Minori, Yashiro, Yuki, Kimura, Ryutaro, Adachi, Kanae, Terabayashi, Aoi, Takahashi, Mio, Oyama, Takahiro, Abe, Hideaki, Abe, Takehiko, Tanuma, Sei-ichi, Takasawa, Ryoko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229775/
https://www.ncbi.nlm.nih.gov/pubmed/34199423
http://dx.doi.org/10.3390/medicines8060026
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author Seno, Saki
Kimura, Minori
Yashiro, Yuki
Kimura, Ryutaro
Adachi, Kanae
Terabayashi, Aoi
Takahashi, Mio
Oyama, Takahiro
Abe, Hideaki
Abe, Takehiko
Tanuma, Sei-ichi
Takasawa, Ryoko
author_facet Seno, Saki
Kimura, Minori
Yashiro, Yuki
Kimura, Ryutaro
Adachi, Kanae
Terabayashi, Aoi
Takahashi, Mio
Oyama, Takahiro
Abe, Hideaki
Abe, Takehiko
Tanuma, Sei-ichi
Takasawa, Ryoko
author_sort Seno, Saki
collection PubMed
description Background: β-thujaplicin, a natural tropolone derivative, has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. Methods: Trypan blue staining, a WST-8 assay, and a caspase-3/7 activity assay were used to investigate whether β-thujaplicin sensitizes cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Additionally, western blotting was performed to clarify the effects of β-thujaplicin on X-linked inhibitor of apoptosis protein (XIAP) in NCI-H460 cells and a fluorescence polarization binding assay was used to evaluate the binding-inhibitory activity of β-thujaplicin against XIAP-BIR3. Results: β- and γ-thujaplicins decreased the viability of NCI-H460 cells in a dose-dependent manner; they also sensitized the cells to TRAIL-induced cell growth inhibition and apoptosis. β-thujaplicin significantly potentiated the apoptosis induction effect of TRAIL on NCI-H460 cells, which was accompanied by enhanced caspase-3/7 activity. Interestingly, β-thujaplicin treatment in NCI-H460 cells decreased XIAP levels. Furthermore, β-thujaplicin was able to bind XIAP-BIR3 at the Smac binding site. Conclusions: These findings indicate that β-thujaplicin could enhance TRAIL-induced apoptosis in NCI-H460 cells via XIAP inhibition and degradation. Thus, the tropolone scaffold may be useful for designing novel nonpeptidic small-molecule inhibitors of XIAP and developing new types of anticancer drugs.
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spelling pubmed-82297752021-06-26 β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells Seno, Saki Kimura, Minori Yashiro, Yuki Kimura, Ryutaro Adachi, Kanae Terabayashi, Aoi Takahashi, Mio Oyama, Takahiro Abe, Hideaki Abe, Takehiko Tanuma, Sei-ichi Takasawa, Ryoko Medicines (Basel) Article Background: β-thujaplicin, a natural tropolone derivative, has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. Methods: Trypan blue staining, a WST-8 assay, and a caspase-3/7 activity assay were used to investigate whether β-thujaplicin sensitizes cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Additionally, western blotting was performed to clarify the effects of β-thujaplicin on X-linked inhibitor of apoptosis protein (XIAP) in NCI-H460 cells and a fluorescence polarization binding assay was used to evaluate the binding-inhibitory activity of β-thujaplicin against XIAP-BIR3. Results: β- and γ-thujaplicins decreased the viability of NCI-H460 cells in a dose-dependent manner; they also sensitized the cells to TRAIL-induced cell growth inhibition and apoptosis. β-thujaplicin significantly potentiated the apoptosis induction effect of TRAIL on NCI-H460 cells, which was accompanied by enhanced caspase-3/7 activity. Interestingly, β-thujaplicin treatment in NCI-H460 cells decreased XIAP levels. Furthermore, β-thujaplicin was able to bind XIAP-BIR3 at the Smac binding site. Conclusions: These findings indicate that β-thujaplicin could enhance TRAIL-induced apoptosis in NCI-H460 cells via XIAP inhibition and degradation. Thus, the tropolone scaffold may be useful for designing novel nonpeptidic small-molecule inhibitors of XIAP and developing new types of anticancer drugs. MDPI 2021-06-02 /pmc/articles/PMC8229775/ /pubmed/34199423 http://dx.doi.org/10.3390/medicines8060026 Text en © 2021 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
Seno, Saki
Kimura, Minori
Yashiro, Yuki
Kimura, Ryutaro
Adachi, Kanae
Terabayashi, Aoi
Takahashi, Mio
Oyama, Takahiro
Abe, Hideaki
Abe, Takehiko
Tanuma, Sei-ichi
Takasawa, Ryoko
β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells
title β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells
title_full β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells
title_fullStr β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells
title_full_unstemmed β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells
title_short β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells
title_sort β-thujaplicin enhances trail-induced apoptosis via the dual effects of xiap inhibition and degradation in nci-h460 human lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229775/
https://www.ncbi.nlm.nih.gov/pubmed/34199423
http://dx.doi.org/10.3390/medicines8060026
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