Targeting leukemia cell metabolism

Recent evidences show that malignant cell undergo a metabolic reprogramming, acquiring new bioenergetic phenotypes. These new metabolic features grant them the capability of sustaining expensive processes such as cell growth and proliferation. Among the metabolic pathways involved, an increased glycolytic flux, the exploitation of alternative carbon source like glutamine, and an increase in fatty acid metabolism may be included. Metabolic reprogramming is strictly related to aberrant activation of signal transduction pathways, but the causal relationship between altered signalling and redesigned metabolism is currently under review, based on recent works showing a feedback mechanism, in which metabolites are involved in controlling signal fluxes through specific sensor kinases which monitor the cell bioenergetic status. Therefore, cancer cell metabolism represents a potential target for therapeutic intervention that may be integrated with conventional chemotherapy and molecularly targeted agents. In solid tumors, a great number of studies supports the potential of this approach while only few are published in hematologic malignancies. With the aim of extending the knowledge of leukemia cell metabolic phenotypes, we studied the role of the main catabolic pathways, such as glycolysis, glutaminolysis and fatty acid oxidation. This study involved the use of metabolic inhibitors, in order to identify novel molecular therapeutic strategies in hematological malignancies. Dichloroacetate (DCA) is a pyruvate-mimetic molecule, which acts as pyruvate dehydrogenase kinase (PDHK) inhibitor, thus activating pyruvate dehydrogenase (PDH). This activation causes a shift in leukemic cell metabolism, from aerobic glycolysis to glucose oxidation. Our results documented that acute myeloid leukemia (AML) cells are characterized by higher rates of glycolysis compared to normal cells and that the use of DCA, an inhibitor of glycolysis, acts in a short time (30-60 minutes), increasing the levels of oxidative phosphorylation and, in a longer time, reducing cell growth and inducing apoptosis in cells of AML. Aminooxyacetic Acid (AOA) is a cellular transaminase inhibitor. This compound is able to inhibit the conversion from glutamate to α-ketoglutarate, second step of the glutaminolytic process. ST1326 is an aminocarnitine derivative, able to block the activity of CPT1a, the enzyme which catalyze the rate-limiting step of fatty acid oxidation. The results obtained in our in vitro study showed a high pro-apoptotic activity of this inhibitor in models of cell lines and primary cells from acute leukemia. Overall, these preclinical results demonstrate the role of cell metabolism as a potential therapeutic target in hematologic malignancies, warranting further extension of this strategy.