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

Abstract

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.

Anti-Melanoma Activities of Artemisone and Prenylated Amino-Artemisinins in Combination With Known Anticancer Drugs

“…However, the anticancer drugs sulfasalazine 8 and etoposide 9 were more selective with etoposide having a therapeutic index of >297. These results are consistent with those of other studies involving these drugs on melanoma cells (Calvani et al, 2016;Nagane et al, 2018). The proposal to combine the oxidant artemisone 4 and the redox active elesclomol-Cu(II) 1-Cu to target proliferating cancer cells based on the susceptibility of cancer cells to oxidative stress was evaluated.…”

“…Sulfasalazine 8 was the least active but was still selectively active against melanoma cells. These results are consistent with those of Nagane et al (Nagane et al, 2018). The dose-response curves of the amino-artemisinins and the amino-artemisinins in combination with elesclomol-Cu 1-Cu are illustrated in Figure 6A.…”

“…to X-ray irradiation (Nagane et al, 2018). Etoposide 9 ( Figure 5) exerts antitumor activity by inhibiting DNA topoisomerase II.…”

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

“…xCT was related to radioresistance in human breast cancer and mouse melanoma cell lines [93,94]. CD98 contributed to radioresistance in head and neck squamous cell carcinoma [95].…”

Integrin αvβ3‐Akt signalling plays a role in radioresistance of melanoma

“…[ 44–47 ] Moreover, melanoma is a representative carcinoma resistant to radiation therapy. [ 1,2 ] Several recent studies have reported that inhibition of MAPK in a BRAF‐mutated human melanoma cell line [ 48 ] and inhibition of cystine‐glutamate antiporter or Erk/Akt in murine B16F10 melanoma cells [ 49,50 ] can induce enhanced radiosensitivity. Research on developing effective combination treatments that enhance radiosensitivity of melanoma is ongoing.…”