An anti-apoptotic peptide improves survival in lethal total body irradiation

Jonathan E. McDunn; Jared T. Muenzer; Benjamin Dunne; Anthony Zhou; Kevin Yuan; Andrew Hoekzema; Carolyn Hilliard; Katherine C. Chang; Christopher G. Davis; Jacquelyn McDonough; Clayton Hunt; Perry Grigsby; David Piwnica-Worms; Richard S. Hotchkiss

doi:10.1016/j.bbrc.2009.03.080

An anti-apoptotic peptide improves survival in lethal total body irradiation

Jonathan E. McDunn
, Jared T. Muenzer
, Benjamin Dunne
, Anthony Zhou
, Kevin Yuan
, Andrew Hoekzema
, Carolyn Hilliard
, Katherine C. Chang
, Christopher G. Davis
, Jacquelyn McDonough
, Clayton Hunt
, Perry Grigsby
, David Piwnica-Worms
, Richard S. Hotchkiss

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Pages (from-to)	657-662
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	382
Issue number	4
DOIs	https://doi.org/10.1016/j.bbrc.2009.03.080
State	Published - May 15 2009

Keywords

Apoptosis
BH4
Bcl-2
Cell death
Cell penetrating motif
NLS
Necrosis
TAT
Total body irradiation

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10.1016/j.bbrc.2009.03.080

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McDunn, J. E., Muenzer, J. T., Dunne, B., Zhou, A., Yuan, K., Hoekzema, A., Hilliard, C., Chang, K. C., Davis, C. G., McDonough, J., Hunt, C., Grigsby, P., Piwnica-Worms, D., & Hotchkiss, R. S. (2009). An anti-apoptotic peptide improves survival in lethal total body irradiation. Biochemical and Biophysical Research Communications, 382(4), 657-662. https://doi.org/10.1016/j.bbrc.2009.03.080

@article{7610247f3ccc40c5863f45a7007dd4f3,

title = "An anti-apoptotic peptide improves survival in lethal total body irradiation",

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 = "Apoptosis, BH4, Bcl-2, Cell death, Cell penetrating motif, NLS, Necrosis, TAT, Total body irradiation",

author = "McDunn, \{Jonathan E.\} and Muenzer, \{Jared T.\} and Benjamin Dunne and Anthony Zhou and Kevin Yuan and Andrew Hoekzema and Carolyn Hilliard and Chang, \{Katherine C.\} and Davis, \{Christopher G.\} and Jacquelyn McDonough and Clayton Hunt and Perry Grigsby and David Piwnica-Worms and Hotchkiss, \{Richard S.\}",

note = "Funding Information: This work was supported by National Institutes of Health Grants GM055194, GM044118, K12HD0085020, CA104457, CA094056 and CA082841; Defense Threat Reduction Agency Contract HDTRA1-06-C0037; the Alan A. and Edith L. Wolff Foundation; and the Fred Hutchinson Cancer Research Center/University of Washington (FHCRC/UW) Center for Medical Countermeasures Against Radiation (CMCR). ",

year = "2009",

month = may,

day = "15",

doi = "10.1016/j.bbrc.2009.03.080",

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McDunn, JE, Muenzer, JT, Dunne, B, Zhou, A, Yuan, K, Hoekzema, A, Hilliard, C, Chang, KC, Davis, CG, McDonough, J, Hunt, C, Grigsby, P, Piwnica-Worms, D & Hotchkiss, RS 2009, 'An anti-apoptotic peptide improves survival in lethal total body irradiation', Biochemical and Biophysical Research Communications, vol. 382, no. 4, pp. 657-662. https://doi.org/10.1016/j.bbrc.2009.03.080

TY - JOUR

T1 - An anti-apoptotic peptide improves survival in lethal total body irradiation

AU - McDunn, Jonathan E.

AU - Muenzer, Jared T.

AU - Dunne, Benjamin

AU - Zhou, Anthony

AU - Yuan, Kevin

AU - Hoekzema, Andrew

AU - Hilliard, Carolyn

AU - Chang, Katherine C.

AU - Davis, Christopher G.

AU - McDonough, Jacquelyn

AU - Hunt, Clayton

AU - Grigsby, Perry

AU - Piwnica-Worms, David

AU - Hotchkiss, Richard S.

N1 - Funding Information: This work was supported by National Institutes of Health Grants GM055194, GM044118, K12HD0085020, CA104457, CA094056 and CA082841; Defense Threat Reduction Agency Contract HDTRA1-06-C0037; the Alan A. and Edith L. Wolff Foundation; and the Fred Hutchinson Cancer Research Center/University of Washington (FHCRC/UW) Center for Medical Countermeasures Against Radiation (CMCR).

PY - 2009/5/15

Y1 - 2009/5/15

N2 - 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.

AB - 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.

KW - Apoptosis

KW - BH4

KW - Bcl-2

KW - Cell death

KW - Cell penetrating motif

KW - NLS

KW - Necrosis

KW - TAT

KW - Total body irradiation

UR - https://www.scopus.com/pages/publications/64749093724

U2 - 10.1016/j.bbrc.2009.03.080

DO - 10.1016/j.bbrc.2009.03.080

M3 - Article

C2 - 19303399

AN - SCOPUS:64749093724

SN - 0006-291X

VL - 382

SP - 657

EP - 662

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 4

ER -

An anti-apoptotic peptide improves survival in lethal total body irradiation

Abstract

Keywords

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