The Anti-Proliferative Effect of Metformin in Triple-Negative MDA-MB-231 Breast Cancer Cells Is Highly Dependent on Glucose Concentration: Implications for Cancer Therapy and Prevention

Zordoky, Beshay N.M.; Bark, Diana; Soltys, Carrie L.; Sung, Miranda M.; Dyck, Jason R.B.

doi:10.1016/j.bbagen.2014.01.023

Cited by 98Metabolism, Diabetes, and CancerCancer, Hypoxia, and MetabolismPI3K/AKT/mTOR signaling in cancer

The Anti-Proliferative Effect of Metformin in Triple-Negative MDA-MB-231 Breast Cancer Cells Is Highly Dependent on Glucose Concentration: Implications for Cancer Therapy and Prevention

Zordoky, Beshay N.M., Bark, Diana, Soltys, Carrie L., Sung, Miranda M., Dyck, Jason R.B.·2014·Biochimica et Biophysica Acta (BBA) - General Subjects

DOI 10.1016/j.bbagen.2014.01.023

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Abstract

Background Metformin has been shown to have a strong anti-proliferative effect in many breast cancer cell lines, mainly due to the activation of the energy sensing kinase, AMP-activated protein kinase (AMPK). MDA-MB-231 cells are aggressive and invasive breast cancer cells that are known to be resistant to several anti-cancer agents as well as to the anti-proliferative effect of metformin. As metformin is a glucose lowering drug, we hypothesized that normoglycemia will sensitize MDA-MB-231 cells to the anti-proliferative effect of metformin.Methods MDA-MB-231 cells were treated with increasing metformin concentrations in hyperglycemic or normoglycemic conditions. The growth inhibitory effect of metformin was assessed by MTT assay. The expression of several proteins involved in cell proliferation was measured by Western blotting.Results In agreement with previous studies, treatment with metformin did not inhibit the growth of MDA-MB-231 cells cultured in hyperglycemic conditions. However, metformin significantly inhibited MDA-MB-231 growth when the cells were cultured in normoglycemic conditions. In addition, we show that metformin-treatment of MDA-MB-231 cells cultured in normoglycemic conditions and not in hyperglycemic conditions caused a striking activation of AMPK, and an AMPK-dependent inhibition of multiple molecular signaling pathways known to control protein synthesis and cell proliferation.Conclusion Our data show that normoglycemia sensitizes the triple negative MDA-MB-231 breast cancer cells to the anti-proliferative effect of metformin through an AMPK-dependent mechanism.General significance These findings suggest that tight normoglycemic control may enhance the anti-proliferative effect of metformin in diabetic cancer patients.

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Zordoky et al. reported that metformin significantly inhibited growth in cells cultured in normoglycemic conditions, and only for the cells grown in normoglycemic conditions did metformin induce significant AMPK activation.
“Zordoky et al. reported that metformin significantly inhibited growth in cells cultured in normoglycemic conditions, and only for the cells grown in normoglycemic conditions did metformin induce significant AMPK activation (251).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [251]

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Authors: Zordoky, B. N. M., Bark, D., Soltys, C. L., Sung, M. M., & Dyck, J. R. B.
Affiliations: University of Alberta (CA)
Corresponding author: Dyck, Jason R.B.
ORCID: Zordoky, Beshay N.M.
Bark, Diana
Soltys, Carrie L.
Dyck, Jason R.B.
Venue: Biochimica et Biophysica Acta (BBA) - General Subjects
Publisher: Elsevier BV
Published: 2014-06
Volume: 1840
Issue: 6
Pages: 1943-1957
ISSN: 0304-4165 (ISSN-L)
DOI: 10.1016/j.bbagen.2014.01.023
OpenAlex: W2082970014
Cited by: 98
References: 74
Citations by year: 2026: 3 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 11 · 2019: 11 · 2018: 8 · 2017: 11 · 2016: 8 · 2015: 13 · 2014: 4
FWCI: 4.92
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research (CIHR)
Alberta Innovates — Health Solutions (AIHS)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: metformin, triple-negative breast cancer, MDA-MB-231 cells, AMPK, glucose concentration, hyperglycemia, normoglycemia, antiproliferative activity, cancer therapy, diabetes and cancer
MeSH terms: Antineoplastic Agents, Glucose, Humans, Insulin, Metformin, Signal Transduction, MAP Kinase Signaling System, Ribosomal Protein S6 Kinases, 70-kDa, Cell Line, Tumor, Octamer Transcription Factor-1, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases, Triple Negative Breast Neoplasms

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The Anti-Proliferative Effect of Metformin in Triple-Negative MDA-MB-231 Breast Cancer Cells Is Highly Dependent on Glucose Concentration: Implications for Cancer Therapy and Prevention

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