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 _

PDF |  HTML  |  Supplementary Files  |  Author Information  |  Order a Reprint

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

Metrics: PDF 527 views  |   HTML 882 views  |   ?  


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.

Author Information

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
Primary Contact  _


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 7212