The purpose of this research has been deciphering the Warburg paradox, the biochemical enigma unsolved since 1923. We solved it by demonstrating that its specific character, i.e. the forced aerobic lactate exportation, represents a crucial metabolic device to counteract the cytotoxic effect produced by an excess of pyruvate at the connection of glycolysis with the Krebs cycle. This solution was verified by exposing cancer cells of different histogenesis to pyruvate concentrations higher than the physiological ones, after showing that these concentrations are totally innocuous when injected into mice. The mechanism of the pyruvate cytotoxicity relies on the saturation of the respiratory chain, leading to a negative shift of the cytosolic NADP/NADPH ratio and the consequent restriction of the purine synthesis and the related cell apoptosis. The reducing equivalents generated by glycolysis and by cytosolic metabolism compete each other for their disposal trough the respiratory chain; this makes it that the cytotoxicity of pyruvate is inversely related to the mitochondrial number and efficiency of various cell types. Thus, the cytotoxicity is high in anaplastic cancer stem cells, whose mitochondria are extremely few and immature (cristae-poor); on the contrary, no inhibition is brought about in adult differentiated cells, physiologically rich of mature mitochondria. All this generates the pyruvate anticancer selectivity, together with the lack of a general toxicity, making pyruvate represent an ideal candidate for a radical non toxical anticancer treatment.
Keywords: NADP/NADPH ratio; Warburg effect; mitochondrial features; pyruvate cytotoxicity; stem cell targeting.