Increase in thiol oxidative stress via glutathione reductase inhibition as a novel approach to enhance cancer sensitivity to X-ray irradiation.
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 IC(50) 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.
Zhao
Yong
Y
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Seefeldt
Teresa
T
Chen
Wei
W
Carlson
Laura
L
Stoebner
Adam
A
Hanson
Sarah
S
Foll
Ryan
R
Matthees
Duane P
DP
Palakurthi
Srinath
S
Guan
Xiangming
X
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D011836:Radiation Tolerance; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology*; D014965:X-Rays
C539612:2-acetylamino-3-(4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl)propionic acid; D013438:Sulfhydryl Compounds; D013859:Thiocarbamates; D019328:Buthionine Sulfoximine; D005980:Glutathione Reductase; D005978:Glutathione; D019803:Glutathione Disulfide; D000111:Acetylcysteine