ß-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells.
Medicines (Basel)
; 8(6)2021 Jun 02.
Article
em En
| MEDLINE
| ID: mdl-34199423
ABSTRACT
Background:
ß-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 ß-thujaplicin sensitizes cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Additionally, western blotting was performed to clarify the effects of ß-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 ß-thujaplicin against XIAP-BIR3.Results:
ß- 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. ß-thujaplicin significantly potentiated the apoptosis induction effect of TRAIL on NCI-H460 cells, which was accompanied by enhanced caspase-3/7 activity. Interestingly, ß-thujaplicin treatment in NCI-H460 cells decreased XIAP levels. Furthermore, ß-thujaplicin was able to bind XIAP-BIR3 at the Smac binding site.Conclusions:
These findings indicate that ß-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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MEDLINE
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Ano de publicação:
2021
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Article