ArticleBMC cancer2017
Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways.
Article in BMC cancer, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Harnessing p53 for targeted cancer therapy: new advances and future directions.Transcription · 2025Review
- Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesotheliomaFrontiers in pharmacology · 2022Article
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- Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma.Therapeutic advances in medical oncology · 2020Review
- Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists.Cancers · 2019Review
- Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1.Cancer science · 2019Article
- Metformin Inhibit Lung Cancer Cell Growth and Invasion in Vitro as Well as Tumor Formation in Vivo Partially by Activating PP2A.Medical science monitor : international medical journal of experimental and clinical research · 2019Article
- p53 and merlin tumor suppressors: Two of a kind.EBioMedicine · 2018Article
- TAM 2.0: tool for MicroRNA set analysis.Nucleic acids research · 2018Article
- Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma.Cancers · 2018Review
- Review
- Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53.Journal of oncology · 2018Article
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma.
methodsWe examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53.
resultsMetformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells.
conclusionThese data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways.
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