Evidence map›Paper›PMID 24858012›Full record

ArticlePloS one2014

Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells.

Eveline A I F Queiroz, Stephanie Puukila, Rosangela Eichler, Sandra C Sampaio, Heidi L Forsyth, Simon J Lees, Aneli M Barbosa, Robert F H Dekker, Zuleica B Fortes, Neelam Khaper

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
140citing papers in PubMed, 4 pooled it
10.1field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

140 citing papers in PubMed, 4 syntheses or guidelines pooled it, 280 citations in OpenAlex.

  1. Pooled it
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  5. Article
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  7. Repurposing metformin for choriocarcinoma: targeting the AMPK/mTOR pathway.Naunyn-Schmiedeberg's archives of pharmacology · 2026
    Review
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  11. [Role and mechanisms of FoxO3a-related signaling pathways in breast cancer cell apoptosis].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025
    Review
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80 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 2 countries.

Eveline A I F QueirozPharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil; Department of Physiological Sciences, State University of Londrina, Londrina, Paraná, Brazil.
Stephanie PuukilaBiology Department, Lakehead University, Thunder Bay, Ontario, Canada.
Rosangela EichlerPharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
Sandra C SampaioPharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
Heidi L ForsythNorthern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada.
Simon J LeesNorthern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada; Biology Department, Lakehead University, Thunder Bay, Ontario, Canada.
Aneli M BarbosaBiorefining Research Institute, Lakehead University, Thunder Bay, Ontario, Canada.
Robert F H DekkerBiorefining Research Institute, Lakehead University, Thunder Bay, Ontario, Canada.
Zuleica B FortesPharmacology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
Neelam KhaperNorthern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada; Biology Department, Lakehead University, Thunder Bay, Ontario, Canada.
Lakehead University · CAUniversidade de São Paulo · BRNOSM University · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Recent studies have demonstrated that the anti-diabetic drug, metformin, can exhibit direct antitumoral effects, or can indirectly decrease tumor proliferation by improving insulin sensitivity. Despite these recent advances, the underlying molecular mechanisms involved in decreasing tumor formation are not well understood. In this study, we examined the antiproliferative role and mechanism of action of metformin in MCF-7 cancer cells treated with 10 mM of metformin for 24, 48, and 72 hours. Using BrdU and the MTT assay, it was found that metformin demonstrated an antiproliferative effect in MCF-7 cells that occurred in a time- and concentration-dependent manner. Flow cytometry was used to analyze markers of cell cycle, apoptosis, necrosis and oxidative stress. Exposure to metformin induced cell cycle arrest in G0-G1 phase and increased cell apoptosis and necrosis, which were associated with increased oxidative stress. Gene and protein expression were determined in MCF-7 cells by real time RT-PCR and western blotting, respectively. In MCF-7 cells metformin decreased the activation of IRβ, Akt and ERK1/2, increased p-AMPK, FOXO3a, p27, Bax and cleaved caspase-3, and decreased phosphorylation of p70S6K and Bcl-2 protein expression. Co-treatment with metformin and H2O2 increased oxidative stress which was associated with reduced cell number. In the presence of metformin, treating with SOD and catalase improved cell viability. Treatment with metformin resulted in an increase in p-p38 MAPK, catalase, MnSOD and Cu/Zn SOD protein expression. These results show that metformin has an antiproliferative effect associated with cell cycle arrest and apoptosis, which is mediated by oxidative stress, as well as AMPK and FOXO3a activation. Our study further reinforces the potential benefit of metformin in cancer treatment and provides novel mechanistic insight into its antiproliferative role.

Indexed as

AMP-Activated Protein KinasesApoptosisBreast NeoplasmsCell Line, TumorEnzyme ActivationFemaleForkhead Box Protein O3Forkhead Transcription FactorsG1 Phase Cell Cycle CheckpointsHumansHydrogenHypoglycemic AgentsMetforminNeoplasm ProteinsOxidantsOxidative StressAMP-Activated Protein KinasesForkhead Box Protein O3Forkhead Transcription FactorsFOXO3 protein, humanHydrogenHypoglycemic AgentsMetforminNeoplasm ProteinsOxidants

Identifiers

PMID24858012
PMCPMC4032293
OpenAlexW2008540208

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.