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‑α 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.
Department of Immunology, School of Medicine, Keimyung University, Daegu 406‑799, Republic of Korea.
Shin
S
Kim
Department of Research, The Armed Forces Medical Research Institute, Daejeon 305‑878, Republic of Korea.
Kwang-Joon
KJ
Jeong
Department of Research, The Armed Forces Medical Research Institute, Daejeon 305‑878, Republic of Korea.
Sung Kweon
SK
Cho
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
Joo-Won
JW
Park
Department of Research, The Armed Forces Medical Research Institute, Daejeon 305‑878, Republic of Korea.
Woo-Jae
WJ
Park
D000975:Antioxidants / Q000008:administration & dosage; D002109:Caffeic Acids / Q000008:administration & dosage*; D016923:Cell Death / Q000187:drug effects*; D018736:DNA Adducts / Q000187:drug effects; D005419:Flavonoids / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage; D015603:Keratinocytes / Q000187:drug effects; D008084:Lipoxygenase / Q000096:biosynthesis / Q000235:genetics*; D009151:Mustard Gas / Q000633:toxicity; D010766:Phosphorylation; D011725:Pyridines / Q000008:administration & dosage; D011794:Quercetin / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D047309:Flavones
D000975:Antioxidants; D002109:Caffeic Acids; D018736:DNA Adducts; D005419:Flavonoids; D007093:Imidazoles; D008084:Lipoxygenase; D009151:Mustard Gas; D011725:Pyridines; D011794:Quercetin; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; C008548:morin; D047309:Flavones; C093642:SB 203580; C040048:caffeic acid