CoChat
Sign Up
Cited by 88Metabolism, Diabetes, and CancerGenomics, phytochemicals, and oxidative stressTea Polyphenols and Effects

The DOI matches its Crossref record; the references it cites are not checked yet.

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

Open access
Yu, Chenxiao, Jiao, Yang, Xue, Jiao, Zhang, Qi, Yang, Hongying, Xing, Ligang, Chen, Guangxia, Wu, Jinchang, Zhang, Shuyu, Zhu, Wei, Cao, Jianping·2017·International Journal of Biological Sciences
DOI 10.7150/ijbs.18830PMC PMC5723922
Open this paper in CoChat — free accountOpen PDF

Abstract

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.Key words: non-small cell lung cancer (NSCLC),

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.7150/ijbs.18830

Cites

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • EGCG inhibits the initiation, promotion, and progression of different types of tumors in vitro and in vivo.

    “Numerous studies, both in vitro using various cancer cell lines and in vivo in animal models, have consistently demonstrated the ability of EGCG to inhibit the initiation, promotion, and progression of different types of tumors.141–145”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [141]

    The Discussion (page unavailable) says EGCG inhibits multiple types of cancer cells in vitro and in vivo, and the Results report reduced growth of NSCLC xenografts. Our copy does not establish that EGCG inhibits all three stages named in the claim—tumor initiation, promotion, and progression. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

The citation lists haven’t been fetched yet

References 47 · Cited by 88

Research works printed but not linked: 39

  1. [1]Siegel RL Miller KD Jemal A Cancer statistics, 2015 CA Cancer J Clin 2015 1 65 1 5 29 25559415
  2. [3]Carney DN Lung cancer-time to move on from chemotherapy The New England journal of medicine 2002 346 126 8 11784881
  3. [4]Hwang J T Ha J Park I J Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway Cancer Lett 2007 3 247 1 115 121 16797120
  4. [5]Nakachi K Matsuyama S Miyake S Suganuma M Imai K Preventive effects of drinking green tea on cancer and cardiovascular disease: epidemiological evidence for multiple targeting prevention Biofactors 2000 13 1-4 49 54 11237198
  5. [6]Shankar S Ganapathy S Hingorani S R EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer Front Biosci 2008 1 13 440 452 17981559
  6. [7]Tachibana H Koga K Fujimura Y A receptor for green tea polyphenol EGCG Nat Struct Mol Biol 2004 5 11 4 380 15024383
  7. [8]Zaveri NT Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications Life Sci 2006 3 78 18 2073 80 16445946
  8. [9]Kweon M-H Adhami VM Lee J-S Mukhtar H Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate J Biol Chem 2006 11 281 44 33761 72 16950787
  9. [10]Ryter SW Choi AMK Heme oxygenase-1: redox regulation of a stress protein in lung and cell culture models Antioxid Redox Signal 2005 12 7 1-2 80 91 15650398
  10. [11]Fang J Akaike T Maeda H Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment Apoptosis 2004 1 9 1 27 35 14739596
  11. [12]Kobayashi M Yamamoto M Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation Antioxid Redox Signal 2005 2 7 3-4 385 94 15706085
  12. [13]I Nguyen T Nioi P Pickett C B The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress J Biol Chem 2009 1 284 20 13291 13295 19182219 PMC2679427
  13. [14]Niture SK Jain AK Jaiswal AK Antioxidant-induced modification of INrf2 cysteine 151 and PKC-delta-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance J Cell Sci 2009 12 122 Pt 24 4452 64 19920073 PMC2787459
  14. [15]Huang H-C Nguyen T Pickett CB Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription J Biol Chem 2002 11 277 45 42769 74 12198130
  15. [16]Sun Z Chin YE Zhang DD Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response Mol Cell Biol 2009 5 29 10 2658 72 19273602 PMC2682049
  16. [17]Lee J-S Surh Y-J Nrf2 as a novel molecular target for chemoprevention Cancer Lett 2005 6 224 2 171 84 15914268
  17. [18]Sahin K Tuzcu M Gencoglu H Dogukan A Timurkan M Sahin N Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats Life Sci 2010 8 87 7-8 240 5 20619277
  18. [19]Lord JM Flight IHK Norman RJ Metformin in polycystic ovary syndrome: systematic review and meta-analysis BMJ 2003 10 327 7421 951 3 14576245 PMC259161
  19. [20]Type 2 Diabetes National Clinical Guideline for Management in Primary and Secondary Care (Update), Royal College of Physicians of London. London: 2008 London 2008 21678628
  20. [22]Evans JMM Donnelly LA Emslie-Smith AM Alessi DR Morris AD Metformin and reduced risk of cancer in diabetic patients BMJ 2005 6 330 7503 1304 5 15849206 PMC558205
  21. [23]Akinyeke T Matsumura S Wang X Wu Y Schalfer ED Saxena A Metformin targets c-MYC oncogene to prevent prostate cancer Carcinogenesis 2013 12 34 12 2823 32 24130167 PMC3845895
  22. [24]Gotlieb WH Saumet J Beauchamp M-C Gu J Lau S Pollak MN In vitro metformin anti-neoplastic activity in epithelial ovarian cancer Gynecol Oncol 2008 8 110 2 246 50 18495226
  23. [27]Goldstein BH Sandelin AM Golbus JR Warnke N Gooding L King KK Impact of vitamin C on endothelial function and exercise capacity in patients with a Fontan circulation Congenit Heart Dis 2012 7 3 226 34 22176653
  24. [28]Kalender A Selvaraj A Kim SY Gulati P Brule S Viollet B Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner Cell Metab 2010 5 11 5 390 401 20444419 PMC3081779
  25. [29]Cantrell LA Zhou C Mendivil A Malloy KM Gehrig PA Bae-Jump VL Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy Gynecol Oncol 2010 1 116 1 92 8 19822355 PMC2789879
  26. [30]Kato K Gong J Iwama H Kitanaka A Tani J Miyoshi H The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo Mol Cancer Ther 2012 3 11 3 549 60 22222629
  27. [31]Allred DC Harvey JM Berardo M Clark GM Prognostic and predictive factors in breast cancer by immunohistochemical analysis Mod Pathol an Off J United States Can Acad Pathol Inc 1998 2 11 2 155 68 9504686
  28. [32]Elbling L Weiss R-M Teufelhofer O Uhl M Knasmueller S Schulte-Hermann R Green tea extract and (-)-epigallocatechin-3-gallate, the major tea catechin, exert oxidant but lack antioxidant activities FASEB J Off Publ Fed Am Soc Exp Biol 2005 5 19 7 807 9 15738004
  29. [33]Cheng H-L Mostoslavsky R Saito S Manis JP Gu Y Patel P Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice Proc Natl Acad Sci U S A 2003 9 100 19 10794 9 12960381 PMC196882
  30. [35]Kawai Y Garduno L Theodore M Yang J Arinze IJ Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization J Biol Chem 2011 3 286 9 7629 40 21196497 PMC3045017
  31. [36]Khan N Afaq F Saleem M Ahmad N Mukhtar H Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate Cancer Res 2006 3 66 5 2500 5 16510563
  32. [37]Yang GY Liao J Kim K Yurkow EJ Yang CS Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols Carcinogenesis 1998 4 19 4 611 6 9600345
  33. [38]Yamamoto T Hsu S Lewis J Wataha J Dickinson D Singh B Green tea polyphenol causes differential oxidative environments in tumor versus normal epithelial cells J Pharmacol Exp Ther 2003 10 307 1 230 6 12954803
  34. [39]Naidu S Vijayan V Santoso S Kietzmann T Immenschuh S Inhibition and genetic deficiency of p38 MAPK up-regulates heme oxygenase-1 gene expression via Nrf2 J Immunol 2009 6 182 11 7048 57 19454702
  35. [40]Yao P Nussler A Liu L Hao L Song F Schirmeier A Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways J Hepatol 2007 8 47 2 253 61 17433488
  36. [41]Nakaso K Yano H Fukuhara Y Takeshima T Wada-Isoe K Nakashima K PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells FEBS Lett 2003 7 546 2-3 181 4 12832036
  37. [42]Sahin K Tuzcu M Sahin N Ali S Kucuk O Nrf2/HO-1 signaling pathway may be the prime target for chemoprevention of cisplatin-induced nephrotoxicity by lycopene Food Chem Toxicol 2010 10 48 10 2670 4 20603177
  38. [43]Berberat PO Dambrauskas Z Gulbinas A Giese T Giese N Kunzli B Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment Clin Cancer Res 2005 5 11 10 3790 8 15897578
  39. [44]Choi B-M Kim Y-M Jeong Y-R Pae H-O Song C-E Park J-E Induction of heme oxygenase-1 is involved in anti-proliferative effects of paclitaxel on rat vascular smooth muscle cells Biochem Biophys Res Commun 2004 8 321 1 132 7 15358225

Metadata

Authors
Yu, C., Jiao, Y., Xue, J., Zhang, Q., Yang, H., Xing, L., Chen, G., Wu, J., Zhang, S., Zhu, W., & Cao, J.
Affiliations
  • Soochow University (CN)
  • Shandong University (CN)
  • Xuzhou No.1 People's Hospital (CN)
  • Nanjing Medical University (CN)
Corresponding author
  • Zhu, Wei
  • Cao, Jianping
ORCID
Venue
International Journal of Biological Sciences
Publisher
Ivyspring International Publisher
Published
2017
Volume
13
Issue
12
Pages
1560-1569
ISSN
1449-2288 (ISSN-L)
DOI
10.7150/ijbs.18830
PMC
PMC5723922
OpenAlex
W2774518245
Cited by
88
References
47
Citations by year
2026: 3 · 2025: 8 · 2024: 12 · 2023: 5 · 2022: 12 · 2021: 17 · 2020: 16 · 2019: 10 · 2018: 5
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • International Journal of Biological Sciences (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81602101, 81673100, 81573080, 2016YFC0904702)
  • Government of Jiangsu Province
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Tea Polyphenols and Effects
Keywords
metformin, epigallocatechin gallate, non-small cell lung cancer, Nrf2/HO-1 pathway, heme oxygenase-1, SIRT1, reactive oxygen species, apoptosis, NF-κB signaling, combination therapy, green tea polyphenols, chemosensitization
MeSH terms
Animals, Carcinoma, Non-Small-Cell Lung, Catechin, Cell Line, Female, Humans, Lung Neoplasms, Metformin, Mice, Inbred BALB C, Mice, Nude, Promoter Regions, Genetic, Signal Transduction, Apoptosis, Reactive Oxygen Species, Cell Line, Tumor, NF-E2-Related Factor 2, Mice, Heme Oxygenase-1

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review