Targeting Glycolysis and MAPK Pathway: A Combined Pre-Clinical Approach on Acute Myeloid Leukemia

We have demonstrated that selective MEK inhibitors (MEK-I) significantly inhibit in vitro the growth of AML cell lines and primary AML blasts (Ricciardi et al., JMM 2012). However, these effects were mostly related to the inhibition of cell cycle progression, while apoptosis induction requires higher concentrations of the inhibitor and longer times of exposure. Among the many downstream effectors of MAPK pathway, metabolism is one of the key aspects that can be targeted at several levels for therapeutic perspectives (Ricciardi et al., Blood 2015). In this study, we have explored on AML cells the functional effects of combining the MEK1/2 inhibitor, PD0325901 (PD), with a metabolic modulator, dichloroacetate (DCA), which acts as pyruvate dehydrogenase kinase (PDHK) inhibitor. AML cell lines (OCI-AML3, U937, MOLM13, HL60) and AML primary samples were exposed to PD (2.5-1000nM) and DCA (0.5-2mM), alone or in combination.