Oncotarget

Research Papers:

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 _

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Oncotarget. 2016; 7:12718-12730. https://doi.org/10.18632/oncotarget.7212

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Abstract

Charles C. Cates1,4, Angelo D. Arias1,5, Lynn S. Nakayama Wong1, Michael W. Lamé1, Maxim Sidorov1, Geraldine Cayanan1, Douglas J. Rowland2, Jennifer Fung2, Georg Karpel-Massler3, Markus D. Siegelin3, Lloyd A. Greene3 and James M. Angelastro1

1 Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA

2 Center for Molecular Genomic Imaging, Davis, CA, USA

3 Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

4 Cedars-Sinai Medical Center, Los Angeles, CA, USA

5 Moores-UCSD Cancer Center, La Jolla, CA, USA

Correspondence to:

James M. Angelastro, email:

Keywords: cell penetrating peptide, ATF5, d/n- ATF5, apoptosis, brain cancer

Received: December 08, 2015 Accepted: January 26, 2016 Published: February 05, 2016

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.


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