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Article

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

1
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
2
Hinoki Shinyaku Co. Ltd., Chiyoda-ku, Tokyo 102-0084, Japan
3
Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: William Cho
Medicines 2021, 8(6), 26; https://doi.org/10.3390/medicines8060026
Received: 12 May 2021 / Revised: 31 May 2021 / Accepted: 31 May 2021 / Published: 2 June 2021
(This article belongs to the Special Issue Feature Papers in Cancer Biology and Anticancer Therapeutics)
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. View Full-Text
Keywords: β-thujaplicin; XIAP; TRAIL; apoptosis; cancer; NCI-H460 cells β-thujaplicin; XIAP; TRAIL; apoptosis; cancer; NCI-H460 cells
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MDPI and ACS Style

Seno, S.; Kimura, M.; Yashiro, Y.; Kimura, R.; Adachi, K.; Terabayashi, A.; Takahashi, M.; Oyama, T.; Abe, H.; Abe, T.; Tanuma, S.-i.; Takasawa, R. β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells. Medicines 2021, 8, 26. https://doi.org/10.3390/medicines8060026

AMA Style

Seno S, Kimura M, Yashiro Y, Kimura R, Adachi K, Terabayashi A, Takahashi M, Oyama T, Abe H, Abe T, Tanuma S-i, Takasawa R. β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells. Medicines. 2021; 8(6):26. https://doi.org/10.3390/medicines8060026

Chicago/Turabian Style

Seno, Saki, Minori Kimura, Yuki Yashiro, Ryutaro Kimura, Kanae Adachi, Aoi Terabayashi, Mio Takahashi, Takahiro Oyama, Hideaki Abe, Takehiko Abe, Sei-ichi Tanuma, and Ryoko Takasawa. 2021. "β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells" Medicines 8, no. 6: 26. https://doi.org/10.3390/medicines8060026

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