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Int J Biol Sci. 2017 Nov 27;13(12):1560-1569. doi: 10.7150/ijbs.18830. eCollection 2017.

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

Yu C1,2, Jiao Y1,2, Xue J1,2, Zhang Q1,2, Yang H1,2, Xing L3, Chen G4, Wu J5, Zhang S1,2,6, Zhu W1,2, Cao J1,2.

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School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China.
Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, 250117, China.
Department of Gastroenterology, First People's Hospital of Xuzhou, Xuzhou, 221002, China.
Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215001, China.
Zhejiang Key Laboratory of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.


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 in vivo 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.


1-(diaminomethylidene)-3; 3-dimethylguanidine (metformin); NF-E2-related factor 2 (Nrf2); epigallocatechin-3-gallate (EGCG); heme oxygenase-1 (HO-1); non-small cell lung cancer (NSCLC)

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