RESUMO
Sulfur mustard (SM) is an alkylating agent, which has been used as in chemical warfare in a number of conflicts. As the generation of reactive oxygen species (ROS), and adducts in DNA and proteins have been suggested as the mechanism underlying SMinduced cytotoxicity, the present study screened several antioxidant candidates, including tannic acid, deferoxamine mesylate, trolox, vitamin C, ellagic acid and caffeic acid (CA) to assess their potential as therapeutic agents for SMinduced cell death. Among several antioxidants, CA partially alleviated SMinduced cell death in a dosedependent manner. Although CA treatment decreased the phosphorylation of p38 mitogenactivated protein (MAP) kinase and p53, p38 MAP kinase inhibition by SB203580 did not affect SMinduced cell death. As CA has also been reported as a 15lipoxygenase (15LOX) inhibitor, the role of 15LOX in SMinduced cytotoxicity was also examined. Similar to the results observed with CA, treatment with PD146176, a specific 15LOX inhibitor, decreased SMinduced cytotoxicity, accompanied by decreases in the production of tumor necrosis factorα and 15hydroxyeicosatetraenoic acid. Furthermore, the present study investigated the protective effects of two natural 15LOX inhibitors, morin hydrate and quercetin, in SMinduced cytotoxicity. As expected, these inhibitors had similar protective effects against SMinduced cytotoxicity. These antioxidants also reduced the generation of ROS and nitrate/nitrite. Therefore, the results of the present study indicated that the natural products, CA, quercetin and morin hydrate, offer potential as adjuvant therapeutic agents for SMinduced toxicity, not only by reducing inflammation mediated by the p38 and LOX signaling pathways, but also by decreasing the generation of ROS and nitrate/nitrite.