Using 31P magnetic resonance spectroscopy, we have shown that LND selectively lowers the intracellular pH and decreases ATP levels in human melanoma xenografts. Tumor acidification results from inhibition of lactate export via the monocarboxylic acid transporters and inhibition of pyruvate transport and oxidation via the mitochondrial pyruvate carrier. Energetics is further attenuated by inhibition of electron transport at complex II. Under these conditions, temozolomide accumulates in the tumor as a result of decreases in intracellular pH, which inhibits DNA repair by O6-alkyltransferase via conversion to dacarbazine and formation of diazomethane, and also inhibits glutathione-S-transferase that deactivates the reactive alkylating intermediate.
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