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A sphingosine kinase inhibitor induces cell death in temozolomide resistant glioblastoma cells

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Abstract

Purpose

Sphingosine kinase is an oncogene that is up-regulated in several solid tumors. The product of the sphingosine kinase activity, sphingosine-1-phosphate is a potent mitogen involved in diverse cell processes such as cell survival and migration. Current standard therapy in the treatment of glioblastoma multiforme (GBM) is a combination of surgery, radiation, and chemotherapy using the drug temozolomide (TMZ). However, virtually all tumors become resistant to TMZ. Therefore, new drug targets are necessary. In this study, we investigated whether inhibiting sphingosine kinase could induce cell death in TMZ-resistant GBM cells.

Methods

To study TMZ resistance in vitro, we have generated TMZ-resistant cell lines from established GBM cells. We used a potent inhibitor of sphingosine kinase to study its effect on colony formation and cell growth in GBM cells with a limited dilution and WST assay. Moreover, cell death was determined by measuring caspase-3 activity using flow cytometry.

Results

A sphingosine kinase inhibitor reduced cell colony formation and activated caspase-3 in both TMZ-sensitive and resistant GBM cells.

Conclusion

Addition of a sphingosine kinase inhibitor to the standard chemotherapy regimen against GBM may be beneficial.

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Fig. 1
Fig. 2

Abbreviations

GBM:

Glioblastoma multiforme

TMZ:

Temozolomide

S1P:

Sphingosine-1-phosphate

Sphk1:

Sphingosine kinase 1

SK1:

Sphk1 inhibitor

O 6-BG:

O 6-Benzylguanine

MGMT:

Methylguanine-methyltransferase

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Acknowledgment

This work was supported by NIH Grant 5P50CA108786.

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Authors and Affiliations

  1. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    Meryem Bektas, William E. Poe & Darell D. Bigner

  2. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    Stewart P. Johnson & Henry S. Friedman

  3. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    Henry S. Friedman

  4. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Henry S. Friedman

Authors
  1. Meryem Bektas
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  2. Stewart P. Johnson
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  3. William E. Poe
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  4. Darell D. Bigner
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  5. Henry S. Friedman
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Corresponding author

Correspondence to Meryem Bektas.

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Bektas, M., Johnson, S.P., Poe, W.E. et al. A sphingosine kinase inhibitor induces cell death in temozolomide resistant glioblastoma cells. Cancer Chemother Pharmacol 64, 1053–1058 (2009). https://doi.org/10.1007/s00280-009-1063-0

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  • DOI: https://doi.org/10.1007/s00280-009-1063-0

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