Journal of Neuro-Oncology

, Volume 105, Issue 2, pp 241–251 | Cite as

Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures

  • Jihong Xu
  • Deepa Sampath
  • Frederick F. Lang
  • Sujit Prabhu
  • Ganesh Rao
  • Gregory N. Fuller
  • Yuanfang Liu
  • Vinay K. Puduvalli
Laboratory Investigation - Human/Animal Tissue

Abstract

Chromatin modification through histone deacetylase inhibition has shown evidence of activity against malignancies. The mechanism of action of such agents are pleiotropic and potentially tumor specific. In this study, we studied the mechanisms of vorinostat-induced cellular effects in gliomas. The effects of vorinostat on proliferation, induction of apoptosis and cell cycle effects were studied in vitro (D54, U87 and U373 glioma cell lines). To gain additional insights into its effects on human gliomas, vorinostat-induced changes were examined ex vivo using a novel organotypic human glioma slice model. Vorinostat treatment resulted in increased p21 levels in all glioma cells tested in a p53 independent manner. In addition, cyclin B1 levels were transcriptionally downregulated and resulted in reduced kinase activity of the cyclin B1/cdk1 complex causing a G2 arrest. These effects were associated with a dose- and time-dependent inhibition of cellular proliferation and anchorage-independent growth in association with hyperacetylation of core histones and induction of apoptosis. Of particular significance, we demonstrate histone hyperacetylation and increased p21 levels in freshly resected human glioma specimens maintained as organotypic slice cultures and exposed to vorinostat similar to cell lines suggesting that human glioma can be targeted by this agent. Our data suggest that the effects of vorinostat are associated with modulation of cell cycle related proteins and activation of a G2 checkpoint along with induction of apoptosis. These effects are mediated by both transcriptional and post-translational mechanisms which provide potential options that can be exploited to develop new therapeutic approaches against gliomas.

Keywords

Histone deacetylase inhibitors Malignant glioma Apoptosis Cell cycle arrest Organotypic slice cultures 

Notes

Acknowledgments

This study was supported in part by funds from Brain Tumor SPORE 5P50CA12700102, The Gregory J. Jungeblut Fund for Brain Cancer Research, The Center for Targeted Therapy Grant and The Pennebaker Research Funds. The authors acknowledge Susan O. Graham, RN, Angele K. Saleeba, Kristin L. Parks, Lamonne Crutcher and Alicia A. Ledoux for their assistance with the study.

Conflict of interest

The authors declare no conflicts of interest related to this study.

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Jihong Xu
    • 1
  • Deepa Sampath
    • 2
  • Frederick F. Lang
    • 3
  • Sujit Prabhu
    • 3
  • Ganesh Rao
    • 3
  • Gregory N. Fuller
    • 4
  • Yuanfang Liu
    • 1
  • Vinay K. Puduvalli
    • 1
  1. 1.Department of Neuro-OncologyThe Brain Tumor Center, University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Experimental TherapeuticsUniversity of Texas M. D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of NeurosurgeryThe Brain Tumor Center, University of Texas M. D. Anderson Cancer CenterHoustonUSA
  4. 4.Department of NeuropathologyThe Brain Tumor Center, University of Texas M. D. Anderson Cancer CenterHoustonUSA

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