title: Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide.
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.
authors: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.|Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Charles C
authors: CC
authors: Cates
authors: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.|Moores-UCSD Cancer Center, La Jolla, CA, USA.
authors: Angelo D
authors: AD
authors: Arias
authors: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.
authors: Lynn S
authors: LS
authors: Nakayama Wong
authors: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.
authors: Michael W
authors: MW
authors: Lamé
authors: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.
authors: Maxim
authors: M
authors: Sidorov
authors: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.
authors: Geraldine
authors: G
authors: Cayanan
authors: Center for Molecular Genomic Imaging, Davis, CA, USA.
authors: Douglas J
authors: DJ
authors: Rowland
authors: Center for Molecular Genomic Imaging, Davis, CA, USA.
authors: Jennifer
authors: J
authors: Fung
authors: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors: Georg
authors: G
authors: Karpel-Massler
authors: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors: Markus D
authors: MD
authors: Siegelin
authors: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors: Lloyd A
authors: LA
authors: Greene
authors: Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.
authors: James M
authors: JM
authors: Angelastro
mesh_terms: D051696:Activating Transcription Factors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms; D002352:Carrier Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides; D015195:Drug Design; D005910:Glioma; D006801:Humans; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D051696:Activating Transcription Factors; D000970:Antineoplastic Agents; C471855:Atf5 protein, mouse; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D010455:Peptides; C414409:penetratin
keywords: ATF5; apoptosis; brain cancer; cell penetrating peptide; d/n- ATF5