Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma

• Published in: PloS one Vol. 13; no. 4; p. e0195151
• Main Authors: Nagane, Masaki, Kanai, Eiichi, Shibata, Yuki, Shimizu, Takuto, Yoshioka, Chie, Maruo, Takuya, Yamashita, Tadashi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.04.2018; Public Library of Science (PLoS)
• Subjects: Antibiotics; Arthritis; Biochemistry; Biology and life sciences; Biosynthesis; Breast cancer; Cancer therapies; Cell cycle; Cystine; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Dosage and administration; Drug therapy; Embryo fibroblasts; Embryos; Fibroblasts; Glutathione; Hydrogen peroxide; Immunoglobulins; Inflammatory bowel disease; Inhibitors; Irradiation; Laboratories; Medicine and Health Sciences; Melanoma; Membrane proteins; Oxidative stress; Polymerase chain reaction; Radiation; Radiation damage; Radiation therapy; Radiosensitivity; Repair; Rodents; Senescence; Sensitizing; Sodium; Sulfasalazine; Tumors; Veterinary colleges; Veterinary medicine; Veterinary services; X-rays; United Kingdom > UK; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0195151

The sodium-independent cystine-glutamate antiporter plays an important role in extracellular cystine uptake. It comprises the transmembrane protein, xCT and its chaperone, CD98. Because glutathione is only weakly cell membrane permeable, cellular uptake of its precursor, cystine, is known to be a key step in glutathione synthesis. Moreover, it has been reported that xCT expression affects the progression of tumors and their resistance to therapy. Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential. Here, we describe a radio-sensitizing effect of sulfasalazine using a B16F10 melanoma model. Sulfasalazine decreased glutathione concentrations and resistance to H2O2 in B16F10 melanoma cells, but not in mouse embryonic fibroblasts. It synergistically enhanced the cyto-killing effect of X-irradiation in B16F10 cells. It inhibited cellular DNA damage repair and prolonged cell cycle arrest after X-irradiation. Furthermore, in an in vivo transplanted melanoma model, sulfasalazine decreased intratumoral glutathione content, leading to enhanced susceptibility to radiation therapy. These results suggest the possibility of using SAS to augment the treatment of radio-resistant cancers.