Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment

Simple Summary Acute Myeloid Leukemias (AMLs) are rapidly progressive clonal neoplastic diseases. The overall 5-year survival rate is very poor: less than 5% in older patients aged over 65 years old. Elderly AML patients are often unfit for intensive chemotherapy, further highlighting the need of highly effective, well-tolerated new treatment options for AMLs. Growing evidence indicates that AML blasts feature a highly diverse and flexible metabolism consistent with the aggressiveness of the disease. Based on these evidences, we targeted the metabolic peculiarity and plasticity of AML cells with an association of ascorbate, which causes oxidative stress and interferes with hexokinase activity, and buformin, which completely shuts down mitochondrial contributions in ATP production. The ascorbate-buformin combination could be an innovative therapeutic option for elderly AML patients that are resistant to therapy. In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias' (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate-buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options.

Automated summary

Acute Myeloid Leukemias (AMLs) are rapidly progressing and clonal neoplastic diseases. In this study, the metabolic background of AML cells was characterized, and the combination of ascorbate and buformin was shown to be a potential innovative therapeutic option for elderly AML patients resistant to traditional therapy.