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Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models

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Abstract

Retaspimycin hydrochloride (IPI-504), an Hsp90 (heat shock protein 90) inhibitor, has shown activity in multiple preclinical cancer models, such as lung, breast and ovarian cancers. However, its biological effects in gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the expression pattern of Hsp90α/β mRNA in stable glioma cell lines, multiple glioma-derived primary cultures and human neural stem/progenitor cells. The effects of IPI-504 on cell proliferation, apoptosis, motility and expression of Hsp90 client proteins were evaluated in glioma cell lines. In vivo activity of IPI-504 was investigated in subcutaneous glioma xenografts. Our results showed Hsp90α and Hsp90β expression levels to be patient-specific, higher in high-grade glioma-derived primary cells than in low-grade glioma-derived primary cells, and strongly correlated with CD133 expression and differentiation status of cells. Hsp90 inhibition by IPI-504 induced apoptosis, blocked migration and invasion, and significantly decreased epidermal growth factor receptor levels, mitogen-activated protein kinase and/or Akt activities, and secretion of vascular endothelial growth factor in glioma cell lines. In vivo study showed that IPI-504 could mildly attenuate tumor growth in immunocompromised mice. These findings suggest that targeting Hsp90 by IPI-504 has the potential to become an active therapeutic strategy in gliomas in a selective group of patients, but further research into combination therapies is still needed.

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Acknowledgments

We thank Infinity Pharmaceuticals for providing IPI-504 and Dr. Julian Adams for his suggestions and comments. We gratefully acknowledge Dr. David A. Fruman for providing us phospho-AKT (Ser473) antibody, and the Core Facility of Department of Pathology & Laboratory Medicine of UC Irvine for help performing the immunocytochemistry experiments. This study was supported in part by research funds donated by Ralph and Suzanne Stern, start-up funds to Dr. Bota from the UC Irvine, and the National Cancer Institute of the National Institutes of Health under Award Number P30CA062203.

Conflict of interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Neurological Surgery, UC Irvine School of Medicine, Sprague Hall, Irvine, CA, 92697, USA

    Kaijun Di, Daniela Alexandru-Abrams & Daniela A. Bota

  2. Duke University Medical Center, DUMC Box 3624, Durham, NC, 27710, USA

    Stephen T. Keir & Henry S. Friedman

  3. Department of Neurology, UC Irvine School of Medicine, Sprague Hall, Irvine, CA, 92697, USA

    Xing Gong, Howard Nguyen & Daniela A. Bota

  4. UC Irvine Chao Family Comprehensive Cancer Center, 200 S. Manchester Ave., Suite 206, Orange, CA, 92868, USA

    Daniela A. Bota

Authors
  1. Kaijun Di
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  2. Stephen T. Keir
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  3. Daniela Alexandru-Abrams
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  4. Xing Gong
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  5. Howard Nguyen
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  7. Daniela A. Bota
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Correspondence to Daniela A. Bota.

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Di, K., Keir, S.T., Alexandru-Abrams, D. et al. Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models. J Neurooncol 120, 473–481 (2014). https://doi.org/10.1007/s11060-014-1579-y

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  • DOI: https://doi.org/10.1007/s11060-014-1579-y

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