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

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 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.

• Authors: Yong Zhao, Teresa Seefeldt, Wei Chen, Laura Carlson, Adam Stoebner, Sarah Hanson, Ryan Foll, Duane P Matthees, Srinath Palakurthi, Xiangming Guan
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 47 Issue 2 Pg. 176-83 (Jul 15 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19397999 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-acetylamino-3-(4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl)propionic acid
• Sulfhydryl Compounds
• Thiocarbamates
• Buthionine Sulfoximine
• Glutathione Reductase
• Glutathione
• Glutathione Disulfide
• Acetylcysteine

Topics

• Acetylcysteine (analogs & derivatives, pharmacology)
• Buthionine Sulfoximine (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects, radiation effects)
• Drug Synergism
• Glutathione (metabolism)
• Glutathione Disulfide (metabolism)
• Glutathione Reductase (antagonists & inhibitors, metabolism)
• Humans
• Oxidative Stress
• Radiation Tolerance
• Sulfhydryl Compounds (metabolism)
• Thiocarbamates (pharmacology)
• X-Rays