Regression/Eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide

Charles C. Cates, Angelo D. Arias, Lynn S. Nakayama Wong, Michael W. Lamé, Maxim Sidorov, Geraldine Cayanan, Douglas J. Rowland, Jennifer Fung, Georg Karpel-Massler, Markus D. Siegelin, Lloyd A. Greene, James M Angelastro

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Malignant gliomas have poor prognosis and urgently require new therapies. Activating Transcription Factor 5 (ATF5) is highly expressed in gliomas, and interference with its expression/function precipitates targeted glioma cell apoptosis in vitro and in vivo. We designed a novel deliverable truncated-dominant-negative (d/n) form of ATF5 fused to a cell-penetrating domain (Pen-d/n-ATF5-RP) that can be intraperitoneally/subcutaneously administered to mice harboring malignant gliomas generated; (1) by PDGF-B/sh-p53 retroviral transformation of endogenous neural progenitor cells; and (2) by human U87-MG xenografts. In vitro Pen-d/n-ATF5-RP entered into glioma cells and triggered massive apoptosis. In vivo, subcutaneously-administered Pen-d/n-ATF5-RP passed the blood brain barrier, entered normal brain and tumor cells, and then caused rapid selective tumor cell death. MRI verified elimination of retrovirus-induced gliomas within 8-21 days. Histopathology revealed growth-suppression of intracerebral human U87-MG cells xenografts. For endogenous PDGF-B gliomas, there was no recurrence or mortality at 6-12 months versus 66% mortality in controls at 6 months. Necropsy and liver-kidney blood enzyme analysis revealed no adverse effects on brain or other tissues. Our findings thus identify Pen-d/n-ATF5-RP as a potential therapy for malignant gliomas.

Original languageEnglish (US)
Pages (from-to)12718-12730
Number of pages13
JournalOncotarget
Volume7
Issue number11
DOIs
StatePublished - Mar 15 2016

Keywords

  • Apoptosis
  • ATF5
  • Brain cancer
  • Cell penetrating peptide
  • d/n- ATF5

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Cates, C. C., Arias, A. D., Nakayama Wong, L. S., Lamé, M. W., Sidorov, M., Cayanan, G., Rowland, D. J., Fung, J., Karpel-Massler, G., Siegelin, M. D., Greene, L. A., & Angelastro, J. M. (2016). Regression/Eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide. Oncotarget, 7(11), 12718-12730. https://doi.org/10.18632/oncotarget.7212