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

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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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.

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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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Authors and Affiliations

  1. Department of Neuro-Oncology, The Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX, 77030, USA

    Jihong Xu, Yuanfang Liu & Vinay K. Puduvalli

  2. Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Deepa Sampath

  3. Department of Neurosurgery, The Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Frederick F. Lang, Sujit Prabhu & Ganesh Rao

  4. Department of Neuropathology, The Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Gregory N. Fuller

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  1. Jihong Xu
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  2. Deepa Sampath
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  3. Frederick F. Lang
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  4. Sujit Prabhu
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  5. Ganesh Rao
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  6. Gregory N. Fuller
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  7. Yuanfang Liu
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  8. Vinay K. Puduvalli
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Corresponding author

Correspondence to Vinay K. Puduvalli.

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Xu, J., Sampath, D., Lang, F.F. et al. Vorinostat modulates cell cycle regulatory proteins in glioma cells and human glioma slice cultures. J Neurooncol 105, 241–251 (2011). https://doi.org/10.1007/s11060-011-0604-7

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  • DOI: https://doi.org/10.1007/s11060-011-0604-7

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