Pharmacological interventions part IV: Metabolic modifiers

Four cell acidifiers, of which three are metabolic modifiers and one is an immunomodulator, are discussed in this chapter: 2-deoxy- d -glucose, metformin and dichloroacetate as metabolic acidifiers and cimetidine as immunomodulator and acidifier. The first one acts mainly through a glycolytic stop depleting cellular energy that decreases the activity of NHE1. Metformin is a mitochondrial Complex I inhibitor that while decreasing OXPHOS and as a consequence, increases glycolysis and lactate production. Dichloroacetate restores oxidative phosphorylation by inhibiting phosphodehydrogenase kinase (PDK). The different mechanisms of action of these compounds allow certain synergistic combination among them. The only metabolic modifier in clinical use (FDA approved) is metformin. Cimetidine however, although FDA approved is not available in most countries.