Metformin Sensitizes Non-small Cell Lung Cancer Cells to an Epigallocatechin-3-Gallate (EGCG) Treatment by Suppressing the Nrf2/HO-1 Signaling Pathway

• Published in: International journal of biological sciences Vol. 13; no. 12; pp. 1560 - 1569
• Main Authors: Yu, Chenxiao, Jiao, Yang, Xue, Jiao, Zhang, Qi, Yang, Hongying, Xing, Ligang, Chen, Guangxia, Wu, Jinchang, Zhang, Shuyu, Zhu, Wei, Cao, Jianping
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2017; Ivyspring International Publisher
• Subjects: Animals; Anticancer properties; Apoptosis; Apoptosis - drug effects; Cancer; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Catechin - analogs & derivatives; Catechin - pharmacology; Cell Line; Cell Line, Tumor; Deacetylation; Diabetes mellitus; Epigallocatechin gallate; Female; Green tea; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; In vivo methods and tests; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Metformin; Metformin - pharmacology; Mice; Mice, Inbred BALB C; Mice, Nude; NF-E2-Related Factor 2 - metabolism; NF-κB protein; Non-small cell lung carcinoma; Oxygenase; Promoter Regions, Genetic; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research Paper; Signal transduction; Signal Transduction - drug effects; Signaling; SIRT1 protein; Studies; Xenografts; heme oxygenase-1 (HO-1); 1-(diaminomethylidene)-3; NF-E2-related factor 2 (Nrf2); epigallocatechin-3-gallate (EGCG); 3-dimethylguanidine (metformin); non-small cell lung cancer (NSCLC)
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.18830

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, is widely studied as a cancer chemopreventive agent with potential anti-cancer effects. The NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway is considered to mediate cellular resistance to EGCG. Metformin, a classical antidiabetic drug, has been shown to prevent cancer progression. Researchers have not reported whether metformin potentiates the anti-cancer efficacy of EGCG. In this study, metformin inhibited HO-1 expression and augmented the anti-tumor effect of EGCG. Metformin also enhanced ROS (reactive oxygen species) generation induced by EGCG (100 μM), subsequently resulting in apoptosis. Based on the results of the study, size of xenografts treated with the combination of metformin and EGCG was smaller than other groups. Mechanistically, metformin modulated the EGCG-activated Nrf2/HO-1 pathway through Sirtuin 1 (SIRT1)-dependent deacetylation of Nrf2. Moreover, metformin upregulated SIRT1 expression partially through the NF-kB pathway. Comparatively, the combination of EGCG and metformin showed little impact on normal lung epithelial BEAS-2B cells. Based on our findings, metformin sensitized NSCLC cells to the EGCG treatment by suppressing the Nrf2/HO-1 signaling pathway.