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Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells

Wang, Yan-Yang, Yang, Yin-Xue, Zhao, Ren, Pan, Shu-Ting, Zhe, Hong, He, Zhi-Xu, Duan, Wei, Zhang, Xueji, Yang, Tianxin, Qiu, Jia-Xuan and Zhou, Shu-Feng 2015, Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells, Drug design, development and therapy, vol. 9, pp. 993-1026, doi: 10.2147/DDDT.S73493.

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Title Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells
Author(s) Wang, Yan-Yang
Yang, Yin-Xue
Zhao, Ren
Pan, Shu-Ting
Zhe, Hong
He, Zhi-Xu
Duan, WeiORCID iD for Duan, Wei orcid.org/0000-0001-5782-9184
Zhang, Xueji
Yang, Tianxin
Qiu, Jia-Xuan
Zhou, Shu-Feng
Journal name Drug design, development and therapy
Volume number 9
Start page 993
End page 1026
Total pages 34
Publisher Dove Medical Press
Place of publication Auckland, New Zealand
Publication date 2015
ISSN 1177-8881
Keyword(s) Akt
CDDO-Me
EMT
apoptosis
autophagy
cell cycle
esophageal squamous cell carcinoma
mTOR
stemness
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
TRITERPENOID CDDO-ME
ACUTE MYELOGENOUS LEUKEMIA
TRANSCRIPTION FACTORS
MOLECULAR-MECHANISMS
REGULATORY NETWORKS
SYNTHETIC OLEANANE
PROSTATE-CANCER
SELF-RENEWAL
SOLID TUMORS
PREVENTION
Summary Natural and synthetic triterpenoids have been shown to kill cancer cells via multiple mechanisms. The therapeutic effect and underlying mechanism of the synthetic triterpenoid bardoxolone methyl (C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; CDDO-Me) on esophageal cancer are unclear. Herein, we aimed to investigate the anticancer effects and underlying mechanisms of CDDO-Me in human esophageal squamous cell carcinoma (ESCC) cells. Our study showed that CDDO-Me suppressed the proliferation and arrested cells in G2/M phase, and induced apoptosis in human ESCC Ec109 and KYSE70 cells. The G2/M arrest was accompanied with upregulated p21Waf1/Cip1 and p53 expression. CDDO-Me significantly decreased B-cell lymphoma-extra large (Bcl-xl), B-cell lymphoma 2 (Bcl-2), cleaved caspase-9, and cleaved poly ADP ribose polymerase (PARP) levels but increased the expression level of Bcl-2-associated X (Bax). Furthermore, CDDO-Me induced autophagy in both Ec109 and KYSE70 cells via suppression of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. There were interactions between the autophagic and apoptotic pathways in Ec109 and KYSE70 cells subject to CDDO-Me treatment. CDDO-Me also scavenged reactive oxygen species through activation of the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) pathway in Ec109 and KYSE70 cells. CDDO-Me inhibited cell invasion, epithelial-mesenchymal transition, and stemness in Ec109 and KYSE70 cells. CDDO-Me significantly downregulated E-cadherin but upregulated Snail, Slug, and zinc finger E-box-binding homeobox 1 (TCF-8/ZEB1) in Ec109 and KYSE70 cells. CDDO-Me significantly decreased the expression of octamer-4, sex determining region Y-box 2 (Sox-2), Nanog, and B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), all markers of cancer cell stemness, in Ec109 and KYSE70 cells. Taken together, these results indicate that CDDO-Me is a promising anticancer agent against ESCC. Further studies are warranted to explore the molecular targets, efficacy and safety of CDDO-Me in the treatment of ESCC.
Language eng
DOI 10.2147/DDDT.S73493
Field of Research 111504 Pharmaceutical Sciences
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, Dove Medical Press
Free to Read? Yes
Use Rights Creative Commons Attribution non-commercial licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30073293

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.