ArticleTranslational lung cancer research2020
Metformin reverses chemoresistance in non-small cell lung cancer via accelerating ubiquitination-mediated degradation of Nrf2.
Article in Translational lung cancer research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 56 citations in OpenAlex.
- Combating Drug Resistance in Lung Cancer: Exploring the Synergistic Potential of Metformin and Cisplatin in a Novel Combination Therapy; A Systematic Review.Current topics in medicinal chemistry · 2025Pooled it
- Multi-Target Antitumor Effects of Natural Products and Approved Drug Repurposing in Non-Small Cell Lung Cancer: Advances in Mechanisms, Combination Regimens, Delivery System Optimization, and Clinical Challenges.International journal of molecular sciences · 2026Review
- Real-world performance of the machine learning-based prediction of chemotherapy-associated adverse effects in lung cancer.Oncology letters · 2026Article
- Inhibitory Effect of S0859 on the Antioxidant Master Switch Nuclear Factor Erythroid 2-Related Factor 2 in Lung Cancer Cells.Antioxidants (Basel, Switzerland) · 2025Article
- Are metformin-based combination approaches beneficial for non-small cell lung cancer: evidence from experimental and clinical studies.Military Medical Research · 2025Review
- Oxidative Stress Defense Module in Lung Cancers: Molecular Pathways and Therapeutic Approaches.Antioxidants (Basel, Switzerland) · 2025Review
- Targeting epigenetic and post-translational modifications of NRF2: key regulatory factors in disease treatment.Cell death discovery · 2025Review
- Poorly controlled type II diabetes mellitus significantly enhances postoperative chemoresistance in patients with stage III colon cancer.World journal of gastroenterology · 2025Article
- Metformin Enhances the Chemosensitivity of Gastric Cancer to Cisplatin by Downregulating Nrf2 Level.Analytical cellular pathology (Amsterdam) · 2025Article
- Therapy-induced senescence through the redox lens.Redox biology · 2024Review
- Astragalus Polysaccharides and Metformin May Have Synergistic Effects on the Apoptosis and Ferroptosis of Lung Adenocarcinoma A549 Cells.Current issues in molecular biology · 2024Article
- Macrophages as determinants and regulators of systemic sclerosis-related interstitial lung disease.Journal of translational medicine · 2024Article
- The role of STK11/LKB1 in cancer biology: implications for ovarian tumorigenesis and progression.Frontiers in cell and developmental biology · 2024Review
- Impact of Radiation Therapy on Serum Humanin and MOTS-c Levels in Patients with Lung or Breast Cancer.Current radiopharmaceuticals · 2024Observational
- Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux.Scientific reports · 2023Article
- A retrospective study of postoperative targeted therapy in ALK-positive lung cancer.Scientific reports · 2023Article
- Metformin sensitises osteosarcoma to chemotherapy <em>via</em> the IGF-1R/miR-610/FEN1 pathway.European journal of histochemistry : EJH · 2023Article
- BmCBP Catalyzes the Acetylation of BmApoLp-II Protein and Regulates Its Stability in Silkworm,Insects · 2023Article
- Oxidative Stress and Air Pollution: Its Impact on Chronic Respiratory Diseases.International journal of molecular sciences · 2023Review
- Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma.International journal of biological sciences · 2023Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe therapeutic efficacy of cisplatin-based chemotherapy for non-small cell lung cancer (NSCLC) is limited by drug resistance. In NSCLC, hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) counteracts oxidative stress to promote chemoresistance. Metformin-mediated downregulation of Nrf2 plays a pivotal role in overcoming drug resistance in NSCLC cells. Therefore, a deeper understanding of the molecular mechanisms of combination therapy and the role of Nrf2 in chemotherapeutic response is critical to clinical translation.
methodsThe effects of combination therapy with metformin and cisplatin on cell proliferation and apoptosis, intracellular reactive oxygen species (ROS) levels, and xenograft tumor formation were analyzed in NSCLC cells. Co-immunoprecipitation (co-IP) and Phos-tag assays were used to explore the mechanism of metformin-mediated Nrf2 suppression. Immunohistochemical (IHC) staining was performed to detect Nrf2 expression in matched tumor samples before and after neoadjuvant chemotherapy.
resultsMetformin was observed to synergistically augment cisplatin-induced cytotoxicity by strongly inhibiting the level of Nrf2, thereby weakening the antioxidant system and detoxification ability of Nrf2 and enhancing ROS-mediated apoptosis in NSCLC. The synergistic antitumor effect of combination therapy is blocked by treatment with the ROS scavenger N-acetyl cysteine (NAC) as well as overexpression of Nrf2 and its downstream antioxidant protein. Mechanistically, metformin extensively dephosphorylates Nrf2 by attenuating the interaction between Nrf2 and extracellular signal-regulated kinases 1/2 (ERK1/2), which then restores its polyubiquitination and accelerates its proteasomal degradation. Moreover, for the first time, an association of non-decreased Nrf2 expression in patients after neoadjuvant chemotherapy with poor survival and chemoresistance in NSCLC was revealed.
conclusionsOur findings illustrate the mechanism of metformin-mediated Nrf2 degradation through posttranslational modifications (PTMs), which weakens the ROS defense system in NSCLC. Fluctuations in Nrf2 expression have a strong predictive ability for chemotherapeutic response in neoadjuvant NSCLC patients. Targeting of the Nrf2 pathway could be a therapeutic strategy for overcoming chemoresistance, with metformin as the first choice for this strategy.
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