The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma

Alejandro G. Levy, Peter E. Zage, Lauren J. Akers, Maurizio L. Ghisoli, Zhao Chen, Wendy Fang, Sankaranarayanan Kannan, Timothy Graham, Lizhi Zeng, Anna R. Franklin, Peng Huang, Patrick A. Zweidler-McKay

Research output: Contribution to journalArticle

23 Scopus citations

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 treatmentwith 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 thatwarrants further investigation.

Original languageEnglish (US)
Pages (from-to)191-199
Number of pages9
JournalInvestigational New Drugs
Volume30
Issue number1
DOIs
StatePublished - Feb 2012

Keywords

  • 3-BrOP
  • Glycolysis
  • Neuroblastoma
  • Rapamycin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

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