Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 1, pp 83–92 | Cite as

The histone deacetylase inhibitor valproic acid sensitizes human and canine osteosarcoma to doxorubicin

  • Luke A. Wittenburg
  • Liam Bisson
  • Barbara J. Rose
  • Christopher Korch
  • Douglas H. Thamm
Original Article

Abstract

Purpose

Osteosarcoma (OS) remains an incurable and ultimately fatal disease in many patients, and novel forms of therapy are needed. Improved models of OS that more closely mimic human disease would provide more robust information regarding the utility of novel therapies. Spontaneous OS in dogs may provide such a model. Pharmacologic inhibition of histone deacetylase (HDAC) enzymes has a variety of anti-tumor effects but may demonstrate the most utility when utilized in combination with standard cytotoxic therapies. We sought to determine the in vitro and in vivo effects of the HDAC inhibitor valproic acid (VPA) on doxorubicin (DOX) sensitivity in canine and human OS.

Methods

We evaluated the in vitro anti-proliferative and apoptotic effects of VPA/DOX combination treatment, alterations in histone acetylation and nuclear DOX accumulation resulting from VPA treatment, and the in vivo efficacy of combination therapy in a xenograft model.

Results

Treatment of canine and human OS cell lines with clinically achievable VPA concentrations resulted in increased histone acetylation but modest anti-proliferative effects. Pre-incubation with VPA followed by doxorubicin (DOX) resulted in significant growth inhibition and potentiation of apoptosis, associated with a dose-dependent increase in nuclear DOX accumulation. The combination of VPA and DOX was superior to either monotherapy in a canine OS xenograft model.

Conclusion

These results demonstrate a rationale for the addition of HDAC inhibitors to current protocols for the treatment of OS and illustrate the similarities in response to HDAC inhibitors between human and canine OS, lending further credibility to the canine OS model.

Keywords

Valproic acid Osteosarcoma HDAC Canine model Doxorubicin 

Supplementary material

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Supplementary material 1 (TIFF 296 kb)
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Supplementary material 3 (TIFF 3242 kb)
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Supplementary material 4 (TIFF 2879 kb)

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Luke A. Wittenburg
    • 1
    • 2
  • Liam Bisson
    • 1
  • Barbara J. Rose
    • 1
  • Christopher Korch
    • 3
  • Douglas H. Thamm
    • 1
    • 2
    • 3
  1. 1.Department of Clinical Sciences, James L. Voss Veterinary Teaching HospitalColorado State University Animal Cancer CenterFort CollinsUSA
  2. 2.Department of Cell and Molecular Biology, James L. Voss Veterinary Teaching HospitalColorado State University Animal Cancer CenterFort CollinsUSA
  3. 3.University of Colorado Cancer Center (UCCC)AuroraUSA

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