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

Cell Rep. 2018 Dec 11;25(11):3047-3058.e4. doi: 10.1016/j.celrep.2018.11.043.


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.

Keywords: MCT1; MCT4; cancer; lactate; metformin; synthetic lethality; syrosingopine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / metabolism
  • Animals
  • Cell Line, Tumor
  • Energy Metabolism / drug effects
  • Humans
  • Intracellular Space / metabolism
  • Lactic Acid / metabolism*
  • Male
  • Metformin / pharmacology*
  • Mice, Inbred C57BL
  • Monocarboxylic Acid Transporters / antagonists & inhibitors*
  • Monocarboxylic Acid Transporters / metabolism
  • Muscle Proteins / antagonists & inhibitors*
  • Muscle Proteins / metabolism
  • NAD / metabolism*
  • Neoplasms / metabolism*
  • Reserpine / analogs & derivatives
  • Reserpine / pharmacology
  • Symporters / antagonists & inhibitors*
  • Symporters / metabolism
  • Synthetic Lethal Mutations*


  • Acids
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • SLC16A4 protein, human
  • Symporters
  • monocarboxylate transport protein 1
  • NAD
  • Lactic Acid
  • Reserpine
  • Metformin
  • syrosingopine