title: The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma.
abstract: 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.
authors.affiliation: M. D. Anderson Cancer Center Orlando, 1400 S. Orange Ave, Orlando, FL 32806, USA.
authors.forename: Alejandro G
authors.initials: AG
authors.lastname: Levy
authors.forename: Peter E
authors.initials: PE
authors.lastname: Zage
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Akers
authors.forename: Maurizio L
authors.initials: ML
authors.lastname: Ghisoli
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Wendy
authors.initials: W
authors.lastname: Fang
authors.forename: Sankaranarayanan
authors.initials: S
authors.lastname: Kannan
authors.forename: Timothy
authors.initials: T
authors.lastname: Graham
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zeng
authors.forename: Anna R
authors.initials: AR
authors.lastname: Franklin
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006019:Glycolysis / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption; D011422:Propionates / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C568307:3-bromo-2-oxopropionate-1-propyl ester; D000903:Antibiotics, Antineoplastic; D006842:Hydrocarbons, Brominated; D011422:Propionates; D047428:Protein Kinase Inhibitors; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus