PPARs: Interference with Warburg’ Effect and Clinical Anticancer Trials

Figure 1

Metabolism of glycolysis-derived NADH and pyruvate in normoxia (a), anoxia and cancer (b). (a) Normoxic normal cells classically oxidize glucose to completion. Cytosolic enzymes convert 1 molecule of glucose to 2 molecules of pyuvate and along with 2 ATP and 2 NADH. Mitochondrial oxidations of glucose-derived pyruvate and NADH involve pyruvate dehydrogenase (PDH), Krebs cycle (KC), and respiratory chain electron transfer/oxidative phosphorylation (OXPHOS) complexes I, II, II, IV, and V, yielding classically 34 ATP. Complete oxidation of glucose therefore results in the production of 36 (2 cytosolic + 34 mitochondrial) ATP. (b) The contribution of mitochondria to glucose oxidation is disrupted in anoxic normal or cancer cells by the arrest of mitochondrial respiration (lack of oxygen in anoxia) and in normoxic and anoxic cancer cells by different convergent mechanisms. Among these, reduced pyruvate dehydrogenase activity may result from overexpressed pyruvate dehydrogenase kinase 1 and limited access of pyruvate to the mitochondria due to the closed state of mitochondrial outer membrane voltage-dependent anionic channel (VDAC). Reduced activities of the respiratory chain complexes I and IV and muted Krebs cycle enzymes may be also encountered. Pyruvate, formed intracytosolically from glucose via glycolysis, is no longer oxidized in mitochondria and is metabolized by cytosolic lactate dehydrogenase. In cancer cells, it must be stressed that the metabolic events mentioned above take place in the context of fuel producing glycolysis in which cytosolic net ATP formation occurs. In turn, the glycolytic flux may be blocked at the pyruvate kinase step (see Figure 4), resulting in biosynthetic precursor-producing glycolysis with little or no net glycolytic ATP or pyruvate production. Cytosolic pyruvate is then provided via other routes (precursors other than glucose) including serinolysis and glutaminolysis, pathways which refer to conversions of serine and glutamine to lactate, respectively.