(E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) induces cytoprotection in CCD18-Co human colon fibroblast cells through Nrf2/ARE pathway activation

• Published in: Scientific reports 2021-02, Vol.11 (1), p.4773-10, Article 4773
• Main Authors: Tan, Huan Huan, Thomas, Noel Francis, Inayat-Hussain, Salmaan Hussain, Chan, Kok Meng
• Format: Article
• Language: English
• Subjects: 631/337; 631/45; 631/80; Anticarcinogenic Agents - pharmacology; Antioxidant Response Elements - drug effects; Antioxidants; Carcinogenesis; Cell Line; Colon; Colon - cytology; Colon - drug effects; Colon - metabolism; Cytoprotection; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Furans - pharmacology; Glutamate-cysteine ligase; Glutathione transferase; Heme; Heme oxygenase (decyclizing); Humanities and Social Sciences; Humans; Mitochondrial DNA; Molecular modelling; multidisciplinary; NAD; NADPH quinone oxidoreductase; NF-E2-Related Factor 2 - metabolism; Oxygenase; Quinone oxidoreductase; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-83163-7

Cytoprotection involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important preventive strategy for normal cells against carcinogenesis. In our previous study, the chemopreventive potential of (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) has been elucidated through its cytoprotective effects against DNA and mitochondrial damages in the human colon fibroblast CCD-18Co cell model. Therefore this study aimed to investigate the molecular mechanisms underlying BK3C231-induced cytoprotection and the involvement of the Nrf2/ARE pathway. The cells were pretreated with BK3C231 before exposure to carcinogen 4-nitroquinoline N-oxide (4NQO). BK3C231 increased the protein expression and activity of cytoprotective enzymes namely NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), as well as restoring the expression of glutamate-cysteine ligase catalytic subunit (GCLC) back to the basal level. Furthermore, dissociation of Nrf2 from its inhibitory protein, Keap1, and ARE promoter activity were upregulated in cells pretreated with BK3C231. Taken together, our findings suggest that BK3C231 exerts cytoprotection by activating the Nrf2 signaling pathway which leads to ARE-mediated upregulation of cytoprotective proteins. This study provides new mechanistic insights into BK3C231 chemopreventive activities and highlights the importance of stilbene derivatives upon development as a potential chemopreventive agent.