Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.6.99.3 (
diaphorase
)
5,903
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells. 3054 Sep 38
