An anti-apoptotic peptide improves survival in lethal total body irradiation
- Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO (United States)
- Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 South Euclid Avenue, Saint Louis, MO 63110 (United States)
- Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO (United States)
- Molecular Imaging Center, Mallinckrodt Institute of Radiology, Department of Radiology, and Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO (United States)
Cell penetrating peptides (CPPs) have been used to deliver the anti-apoptotic Bcl-xL-derived BH4 peptide to prevent injury-induced apoptosis both in vitro and in vivo. Here we demonstrate that the nuclear localization sequence (NLS) from the SV40 large T antigen has favorable properties for BH4 domain delivery to lymphocytes compared to sequences based on the HIV-1 TAT sequence. While both TAT-BH4 and NLS-BH4 protected primary human mononuclear cells from radiation-induced apoptotic cell death, TAT-BH4 caused persistent membrane damage and even cell death at the highest concentrations tested (5-10 {mu}M) and correlated with in vivo toxicity as intravenous administration of TAT-BH4 caused rapid death. The NLS-BH4 peptide has significantly attenuated toxicity compared to TAT-BH4 and we established a dosing regimen of NLS-BH4 that conferred a significant survival advantage in a post-exposure treatment model of LD90 total body irradiation.
- OSTI ID:
- 22199685
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 382, Issue 4; Other Information: Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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