Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase. Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase. The loss of NAD+ regeneration capacity due to combined metformin and syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. Accordingly, ATP levels can be partly restored by exogenously provided NAD+, the NAD precursor nicotinamide mononucleotide (NMN), or vitamin K2. Thus, pharmacological inhibition of MCT1 and MCT4 combined with metformin treatment is a potential cancer therapy.
Pubmed ID: 30540938 RIS Download
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View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
View all literature mentionsCell line HL-60 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line K-562 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name BALB/cJ from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets Integrin beta1 (E-11)
View all literature mentionsThis polyclonal targets GAPDH (HRP) - Loading Control
View all literature mentionsThis polyclonal targets CD147
View all literature mentionsThis monoclonal targets Human EMMPRIN MAb (Clone 109403)
View all literature mentionsThis polyclonal targets Human SLC16A8
View all literature mentionsThis monoclonal targets MCT4 (D-1)
View all literature mentionsThis polyclonal targets Human SLC16A7
View all literature mentionsThis monoclonal targets MCT1 (H-1)
View all literature mentionsThis polyclonal targets Human SLC16A1
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