Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells

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. [Display omitted] •Syrosingopine inhibits lactate export by MCT1 and MCT4•Combined MCT1 and MCT4 inhibition elicits synthetic lethality with metformin•Synthetic lethality is due to loss of NAD+-regenerating capacity•Syrosingopine reduces metformin concentration required for anti-cancer activity Benjamin et al. show that the clinical drug syrosingopine potently inhibits the lactate transporters MCT1 and MCT4 and is thus a clinically relevant MCT4 inhibitor. Intracellular lactate accumulation by syrosingopine elicits synthetic lethality with metformin and potentiates metformin’s anti-cancer efficacy.