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

• Published in: Drug design, development and therapy Vol. 9; no. default; pp. 993 - 1026
• Main Authors: Zhou, Shu-Feng, Wang, Yan-Yang, Yang, Yin-Xue, He, Zhixue, Zhao, Ren, Hong, Zhe, Zhang, Xueji, Pan, Shuting, Duan, Wei, Yang, Tianxin, Qiu, Jiaxuan
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2015; Taylor & Francis Ltd; Dove Press; Dove Medical Press
• Subjects: 1-Phosphatidylinositol 3-kinase; Acids; Akt; AKT protein; Anticancer properties; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; B-cell lymphoma; Bax protein; Bcl-2 protein; Bcl-x protein; Bmi protein; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Care and treatment; Caspase-9; CDDO-Me; cell cycle; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Cyclin-dependent kinase inhibitor p21; Cyclin-dependent kinases; Diabetes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; E-cadherin; EMT; Epithelial-Mesenchymal Transition - drug effects; Esophageal cancer; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma; Esophagus; Health aspects; Homeobox; Homology; Humans; Kidney diseases; Kinases; Lymphocytes B; Lymphoma; Mesenchyme; mTOR; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Nuclear engineering; Nuclear safety; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Original Research; Oxidative stress; p53 Protein; Patients; Phagocytosis; Poly(ADP-ribose) polymerase; Proteins; Rapamycin; Reactive oxygen species; Ribose; Signal transduction; Squamous cell carcinoma; stemness; Structure-Activity Relationship; Terpenoids; Tumor Cells, Cultured; Womens health; Zinc finger proteins; United States > US; China; Africa; esophageal squamous cell carcinoma; autophagy; CDDO-Me; cell cycle; stemness; mTOR; apoptosis; Akt; EMT
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S73493

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.