The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia

SIMPLE SUMMARY: In this study, we investigated and boosted the pro-apoptotic and pro-differentiating activity of MEDS433 in acute myeloid leukemia (AML). MEDS433 is an inhibitor of Dihydroorotate Dehydrogenase, a fundamental enzyme in the de novo pyrimidine biosynthesis. We discovered that MEDS433 alone and in combination with classical antileukemic agents had a good apoptotic activity, but it could be reduced in vivo due to the physiological presence of uridine. On the contrary, the combination of MEDS433 and dipyridamole, a blocker of the pyrimidine salvage pathway, induced metabolic lethality and myeloid differentiation in all our AML models, while being characterized by a limited toxicity on non-AML cells. ABSTRACT: Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the de novo pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting in human activity.