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

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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,

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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 - http://www.scopus.com/inward/record.url?scp=64749093724&partnerID=8YFLogxK

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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