Increase in thiol oxidative stress via glutathione reductase inhibition as a novel approach to enhance cancer sensitivity to X-ray irradiation

Y. Zhao; T. Seefeldt; W. Chen; L. Carlson; A. Stoebner; S. Hanson; R. Foll; D.P. Matthees; S. Palakurthi; X. Guan

doi:10.1016/j.freeradbiomed.2009.04.022

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Increase in thiol oxidative stress via glutathione reductase inhibition as a novel approach to enhance cancer sensitivity to X-ray irradiation

Journal article

Peer reviewed

Increase in thiol oxidative stress via glutathione reductase inhibition as a novel approach to enhance cancer sensitivity to X-ray irradiation

Y. Zhao, T. Seefeldt, W. Chen, L. Carlson, A. Stoebner, S. Hanson, R. Foll, D.P. Matthees, S. Palakurthi and X. Guan

Free Radical Biology and Medicine, Vol.47(2), pp.176-183

2009

DOI: https://doi.org/10.1016/j.freeradbiomed.2009.04.022

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Abstract

Depletion of the reduced form of glutathione (GSH) has been extensively studied for its effect on sensitizing cancer to radiation. However, little is known about the effects of thiol oxidative stress created through an increase in glutathione disulfide (GSSG) on cancer sensitivity to radiation. In this study, an increase in GSSG was effectively created using 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA), an irreversible glutathione reductase (GR) inhibitor. Our results demonstrate that the GSSG increase significantly enhanced cancer sensitivity to X-ray irradiation in four human cancer cell lines (A431, MCF7, NCI-H226, and OVCAR-3). When cells were pretreated with 2-AAPA followed by X-ray irradiation, the IC50 values for X-ray irradiation of A431, MCF7, NCI-H226, and OVCAR-3 cells were reduced, from 24.2 ± 2.8, 42.5 ± 3.0, 43.0 ± 3.6, and 27.8 ± 3.5 Gy to 6.75 ± 0.9, 8.1 ± 1.1, 6.75 ± 1.0, and 12.1 ± 1.7 Gy, respectively. The synergistic effects observed from the combination of X-rays plus 2-AAPA were comparable to those from the combination of X-rays plus buthionine sulfoximine, a reference compound known to increase cancer sensitivity to radiation. The synergistic effect was correlated with an increase in cell thiol oxidative stress, which was reflected by a five-to sixfold increase in GSSG and 25% increase in total disulfides. No change in GSH or total thiols was observed as a result of GR inhibition.

Details

Title: Increase in thiol oxidative stress via glutathione reductase inhibition as a novel approach to enhance cancer sensitivity to X-ray irradiation
Authors/Creators: Y. Zhao (Author/Creator)
T. Seefeldt (Author/Creator)
W. Chen (Author/Creator)
L. Carlson (Author/Creator)
A. Stoebner (Author/Creator)
S. Hanson (Author/Creator)
R. Foll (Author/Creator)
D.P. Matthees (Author/Creator)
S. Palakurthi (Author/Creator)
X. Guan (Author/Creator)
Publication Details: Free Radical Biology and Medicine, Vol.47(2), pp.176-183
Publisher: Elsevier Inc.
Identifiers: 991005542507607891
Copyright: © 2009 Elsevier Inc.
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.127 Molecular & Cell Biology - Pharmacology; 1.127.973 Thiol-Disulfide Systems
Web Of Science research areas: Biochemistry & Molecular Biology; Endocrinology & Metabolism
ESI research areas: Biology & Biochemistry