sirolimus and 3-bromo-2-oxopropionate-1-propyl-ester

Children with high-risk and recurrent neuroblastoma have poor survival rates, and novel therapies are needed. Many cancer cells have been found to preferentially employ the glycolytic pathway for energy generation, even in the presence of oxygen. 3-BrOP is a novel inhibitor of glycolysis, and has demonstrated efficacy against a wide range of tumor types. To determine whether human neuroblastoma cells are susceptible to glycolysis inhibition, we evaluated the role of 3-BrOP in neuroblastoma model systems. Neuroblastoma tumor cell lines demonstrated high rates of lactate accumulation and low rates of oxygen consumption, suggesting a potential susceptibility to inhibitors of glycolysis. In all ten human tested neuroblastoma tumor cell lines, 3-BrOP induced cell death via apoptosis in a dose and time dependent manner. Furthermore, 3-BrOP-induced depletion of ATP levels correlated with decreased neuroblastoma cell viability. In a mouse neuroblastoma xenograft model, glycolysis inhibition with 3-BrOP demonstrated significantly reduced final tumor weight. In neuroblastoma tumor cells, treatment with 3-BrOP induced mTOR activation, and the combination of 3-BrOP and mTOR inhibition with rapamycin demonstrated synergistic efficacy. Based on these results, neuroblastoma tumor cells are sensitive to treatment with inhibitors of glycolysis, and the demonstrated synergy with rapamycin suggests that the combination of glycolysis and mTOR inhibitors represents a novel therapeutic approach for neuroblastoma that warrants further investigation.

Topics: Adenosine Triphosphate; Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Glycolysis; HEK293 Cells; Humans; Hydrocarbons, Brominated; Lactic Acid; Mice; Mice, Inbred NOD; Mice, SCID; Neuroblastoma; Oxygen Consumption; Propionates; Protein Kinase Inhibitors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Rapidly proliferating solid tumor cells are often dependent on glycolysis for ATP production even in normoxia (the Warburg effect), however it is not yet clear whether acute leukemias have a similarly increased dependence on aerobic glycolysis. We report that all acute leukemia subtypes (pre-B ALL, T-ALL and AML) demonstrated growth arrest and cell death when treated the novel glycolysis inhibitor 3-BrOP. Potentiated ATP depletion and pro-apoptotic effects were seen for 3-BrOP combinations with the cytochrome-c-reductase inhibitor antimycin A and the mTOR inhibitor rapamycin. These results reveal a potential role for glycolysis inhibition in acute leukemia subtypes and suggest potential combinations.

Topics: Acute Disease; Adenosine Triphosphate; Antimycin A; Apoptosis; Caspase 3; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Glycolysis; HL-60 Cells; Humans; Hydrocarbons, Brominated; Immunoblotting; Jurkat Cells; Leukemia; Propionates; Sirolimus; Time Factors; U937 Cells