Abstract
Xanthatin is a natural sesquiterpene lactone purified from Xanthium strumarium L., which has shown prominent antitumor activity against a variety of cancer cells. In the current study, we investigated the effect of xanthatin on the growth of glioma cells in vitro and in vivo, and elucidated the underlying mechanisms. In both rat glioma C6 and human glioma U251 cell lines, xanthatin (1–15 μM) dose-dependently inhibited cell viability without apparent effect on the cell cycle. Furthermore, xanthatin treatment dose-dependently induced glioma cell apoptosis. In nude mice bearing C6 glioma tumor xenografts, administration of xanthatin (10, 20, 40 mg·kg−1·d−1, ip, for 2 weeks) dose-dependently inhibited the tumor growth, but did not affect the body weight. More importantly, xanthatin treatment markedly increased the expression levels of the endoplasmic reticulum (ER) stress-related markers in both the glioma cell lines as well as in C6 xenografts, including glucose-regulated protein 78, C/EBP-homologous protein (CHOP), activating factor 4, activating transcription factor 6, spliced X-box binding protein-1, phosphorylated protein kinase R-like endoplasmic reticulum kinase, and phosphorylated eukaryotic initiation factor 2a. Pretreatment of C6 glioma cells with the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 7 mM) or knockdown of CHOP using small interfering RNA significantly attenuated xanthatin-induced cell apoptosis and increase of proapoptotic caspase-3. These results demonstrate that xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating the ER stress-related unfolded protein response pathway involving CHOP induction. Xanthatin may serve as a promising agent in the treatment of human glioma.
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Acknowledgements
This study was financially supported by the National Natural Science Foundation of China (81673438 to YXS, 81302755 and 81973337 to LJF), the State’s Key Project of Research and Development Plan (YFC1305902 to YXS), the Key Projects of Anhui Provincial Natural Science Research in Colleges and Universities (KJ2017A167 to LJF), and the Scientific Research Foundation of the Institute for Translational Medicine of Anhui Province (2017zhyx34 to YXS and YQY).
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LJF, YXS, and YQY designed the research; YYM, ZMD, QC, WSX and SXB performed the research; YYM, ZMD, JSY, and YJS analyzed the data; and LJF and YXS wrote the paper.
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Ma, Yy., Di, Zm., Cao, Q. et al. Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway. Acta Pharmacol Sin 41, 404–414 (2020). https://doi.org/10.1038/s41401-019-0318-5
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DOI: https://doi.org/10.1038/s41401-019-0318-5
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