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Comment
. 2023 Aug;260(4):365-367.
doi: 10.1002/path.6142. Epub 2023 Jun 16.

An acid test for metformin†

Don Benjamin  1
Affiliations
Comment

An acid test for metformin†

Don Benjamin. J Pathol. 2023 Aug.

Abstract

Lactic acid export from highly glycolytic cancer cells is critical to maintain cellular homeostasis. The identification of syrosingopine as an inhibitor of the lactate transporters monocarboxylate transporter (MCT) 1 and the tumor-induced isoform MCT4 suggests a potential therapeutic intervention. In a recent issue of this journal, Van der Vreken, Oudaert I and colleagues showed that syrosingopine, together with another drug metformin, had a synergistic effect in killing cultured multiple myeloma (MM) cell lines, primary MM blasts from patients, and in a mouse MM model. The antidiabetic drug metformin is currently also being investigated for anticancer efficacy. The synthetic lethality of these two drugs, which have good safety records and are approved for noncancer indications, raises the possibility of their combination for clinical anticancer therapy. © 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: cancer; drug repurposing; metformin; syrosingopine.

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References

    1. Benjamin D, Colombi M, Hindupur SK, et al. Syrosingopine sensitizes cancer cells to killing by metformin. Sci Adv 2016; 2: e1601756.
    1. Marchiq I, Albrengues J, Granja S, et al. Knock out of the BASIGIN/CD147 chaperone of lactate/H+ symporters disproves its pro-tumour action via extracellular matrix metalloproteases (MMPs) induction. Oncotarget 2015; 6: 24636-22448.
    1. Goldberg FW, Kettle JG, Lamont GM, et al. Discovery of clinical candidate AZD0095, a selective inhibitor of monocarboxylate transporter 4 (MCT4) for oncology. J Med Chem 2023; 66: 384-397.
    1. Benjamin D, Robay D, Hindupur SK, et al. Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD+ depletion in cancer cells. Cell Rep 2018; 25: 3047-3058.e4.
    1. Van der Vreken A, Oudaert I, Ates G, et al. Metformin confers sensitisation to syrosingopine in multiple myeloma cells by metabolic blockage and inhibition of protein synthesis. J Pathol 2023; 260: 112-123.

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