Caffeic acid, morin hydrate and quercetin partially attenuate sulfur mustard-induced cell death by inhibiting the lipoxygenase pathway

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 SM-induced 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 SM-induced cell death. Among several antioxidants, CA partially alleviated SM-induced cell death in a dose-dependent manner. Although CA treatment decreased the phosphorylation of p38 mitogen-activated protein (MAP) kinase and p53, p38 MAP kinase inhibition by SB203580 did not affect SM-induced cell death. As CA has also been reported as a 15-lipoxygenase (15-LOX) inhibitor, the role of 15-LOX in SM-induced cytotoxicity was also examined. Similar to the results observed with CA, treatment with PD146176, a specific 15-LOX inhibitor, decreased SM-induced cytotoxicity, accompanied by decreases in the production of tumor necrosis factor and 15-hydroxyeicosatetraenoic acid. Furthermore, the present study investigated the protective effects of two natural 15-LOX inhibitors, morin hydrate and quercetin, in SM-induced cytotoxicity. As expected, these inhibitors had similar protective effects against SM-induced 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 SM-induced 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.