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Single agent efficacy of the HDAC inhibitor DATS in preclinical models of glioblastoma

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Abstract

Purpose/introduction

Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models.

Methods

Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS.

Results

Our results showed 72-h treatments of 25 µM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function.

Conclusions

DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB.

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Funding

Completion of this project was made possible in part by the Jerry Zucker Fund for Brain Tumor Research and Funds from the Department of Neurosurgery. This work was conducted in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR015455.

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Authors and Affiliations

  1. Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA

    Arabinda Das, Fraser Henderson Jr., Stephen Lowe, Gerald C. Wallace IV, William A. Vandergrift III, Scott M. Lindhorst, Abhay K. Varma, Libby K. Infinger, Narendra L. Banik, Sunil J. Patel & David Cachia

  2. Department of Neurological Surgery, Ohio State University Wexner Medical College, Columbus, OH, USA

    Pierre Giglio

  3. Research, Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina, United States

    Narendra L. Banik

Authors
  1. Arabinda Das
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  2. Fraser Henderson Jr.
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  3. Stephen Lowe
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  4. Gerald C. Wallace IV
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  5. William A. Vandergrift III
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  6. Scott M. Lindhorst
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  7. Abhay K. Varma
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  8. Libby K. Infinger
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  9. Pierre Giglio
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  10. Narendra L. Banik
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  11. Sunil J. Patel
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  12. David Cachia
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Corresponding author

Correspondence to Arabinda Das.

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Conflict of interest

All authors declared that they have no conflict of interest.

Ethical approval

All procedures involving animals conformed to the Institutional Animal Care and Use Committee’s and the National Institute of Health’s guidelines. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the non therapeutic human study.

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Das, A., Henderson, F., Lowe, S. et al. Single agent efficacy of the HDAC inhibitor DATS in preclinical models of glioblastoma. Cancer Chemother Pharmacol 82, 945–952 (2018). https://doi.org/10.1007/s00280-018-3684-7

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  • DOI: https://doi.org/10.1007/s00280-018-3684-7

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