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

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Summary

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.

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Abbreviations

FDG-PET:

18fluorodeoxyglucose positron-emission tomography

ATP:

adenosine triphosphate

3-BrPA:

3-bromopyruvate

2-DG:

2-deoxy-D-glucose

3-BrOP:

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

mTOR:

mammalian target of rapamycin

PARP1:

Poly (ADP-ribose) polymerase 1

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Acknowledgements

This work was supported by the Lorrie Olivier Neuroblastoma Research Fund (to PEZ, PAZ-M). We would like to thank the members of the Zweidler-McKay lab and the Department of Pediatric Research for technical and editorial assistance.

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Authors and Affiliations

  1. M. D. Anderson Cancer Center Orlando, 1400 S. Orange Ave, Orlando, FL, 32806, USA

    Alejandro G. Levy

  2. Cook Children’s Medical Center, 801 Seventh Ave, Fort Worth, TX, 76104, USA

    Lauren J. Akers

  3. Medical City Children’s Hospital, 7777 Forest Lane, Dallas, TX, 75230, USA

    Maurizio L. Ghisoli

  4. Molecular Pathology, UT M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Zhao Chen & Peng Huang

  5. Neuroscience Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    Peter E. Zage, Timothy Graham & Patrick A. Zweidler-McKay

  6. University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 87, Houston, TX, 77030, USA

    Peter E. Zage, Wendy Fang, Sankaranarayanan Kannan, Timothy Graham, Lizhi Zeng, Anna R. Franklin & Patrick A. Zweidler-McKay

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  1. Alejandro G. Levy
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  2. Peter E. Zage
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  11. Peng Huang
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  12. Patrick A. Zweidler-McKay
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Correspondence to Peter E. Zage.

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Authors Alejandro G. Levy and Peter E. Zage contributed equally to this work.

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Levy, A.G., Zage, P.E., Akers, L.J. et al. The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma. Invest New Drugs 30, 191–199 (2012). https://doi.org/10.1007/s10637-010-9551-y

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