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An anti-apoptotic peptide improves survival in lethal total body irradiation |
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| Authors: | Jonathan E McDunn Jared T Muenzer Anthony Zhou Andrew Hoekzema Katherine C Chang Jacquelyn McDonough Perry Grigsby Richard S Hotchkiss |
| Institution: | a Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 South Euclid Avenue, Saint Louis, MO 63110, USA b Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA c Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, USA d Molecular Imaging Center, Mallinckrodt Institute of Radiology, Department of Radiology, and Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, USA |
| Abstract: | 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 μM) 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. |
| Keywords: | Cell penetrating motif NLS TAT Bcl-2 BH4 Cell death Apoptosis Necrosis Total body irradiation |
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