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Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose

Suberoylanilide hydroxamic acid (SAHA) has been studied in adult solid and hematologic malignancies. However, little information has been reported on the effects of SAHA on central nervous system (CNS) tumors including medulloblastoma, the most common malignant brain tumor in children. We investigated SAHA in preclinical medulloblastoma models to determine its anti-cancer efficacy as well as its ability to␣affect intracranial lesions when administered systemically.

Experimental design and results

Tissue culture studies were performed treating primary human fibroblasts, established medulloblastoma cell lines, and primary human medulloblastoma tumors with SAHA. At 10 µM concentration, SAHA had little effect on normal fibroblasts but caused >90% apoptosis in cultured medulloblastoma cells. Primary medulloblastomas from patients were sensitive to SAHA compared to vehicle alone in ex vivo studies. In athymic mice with medulloblastoma xenograft tumors, oral SAHA resulted in apoptosis of tumor tissue and significantly slowed tumor growth. In the ND2:Smo transgenic mouse medulloblastoma model, SAHA treatment caused significant apoptosis in these cerebellar tumors.

Conclusions

SAHA effectively induces cell death in established medulloblastoma cell lines, human patient primary tumor cultures, medulloblastoma xenografts and intracranial spontaneous medulloblastomas. Fibroblasts in culture and mice treated with SAHA did not reveal prohibitive toxicity profiles. These findings support the advancement of SAHA to pediatric clinical trials.

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Abbreviations

SAHA:

suberoylanilide hydroxamic acid

HDI:

histone deacetylase inhibitor

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Acknowledgements

We thankfully acknowledge Victoria Richon, Paul Secrist, Andrew Hallahan and Stacey Hansen for helpful discussions. This work was supported by the Emily Dorfman Foundation Fellowship Award of the American Brain Tumor Association (S. E. S.), the Jordyn Dukelow Memorial Guild (S. E. S.), the Damon Runyon Clinical Investigator Award (J. M. O.) and NIH Grant CA112350-01 (J. M. O.)

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Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA, 98109, USA

    Susan E. Spiller, Ali C. Ravanpay, Andrew W. Hahn & James M. Olson

  2. Department of Pediatrics, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, WA, 98105, USA

    Susan E. Spiller & James M. Olson

  3. Program in Neurobiology and Behavior, University of Washington, Seattle, WA, 98195, USA

    Ali C. Ravanpay

Authors
  1. Susan E. Spiller
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  2. Ali C. Ravanpay
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  3. Andrew W. Hahn
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  4. James M. Olson
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Correspondence to James M. Olson.

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Spiller, S.E., Ravanpay, A.C., Hahn, A.W. et al. Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma. J Neurooncol 79, 259–270 (2006). https://doi.org/10.1007/s11060-006-9142-0

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  • DOI: https://doi.org/10.1007/s11060-006-9142-0

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