title: Protection against 2-chloroethyl ethyl sulfide (CEES)-induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway.
abstract: Sulfur mustard (SM or mustard gas) was first used as a chemical warfare agent almost 100years ago. Due to its toxic effects on the eyes, lungs, and skin, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. SM exposed skin develops fluid filled bullae resulting from potent cytotoxicity of cells lining the basement membrane of the epidermis. Currently, there are no antidotes for SM exposure; therefore, chemopreventive measures for first responders following an SM attack are needed. Glutathione (GSH) is known to have a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. Therefore, we screened 6 potential chemopreventive agents for ability to induce GSH synthesis and protect cultured human keratinocytes against the SM analog, 2-chloroethyl ethyl sulfide (CEES). Using NCTC2544 human keratinocytes, we found that both sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of the GSH synthesis gene, GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells and preserved their viability by ~3-fold following exposure to CEES. Our data also suggested that CDDO-Me may act additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES. These results suggest that CDDO-Me is a promising chemopreventive agent for SM toxicity in the skin.
authors: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors: Erika L
authors: EL
authors: Abel
authors: Jennifer D
authors: JD
authors: Bubel
authors: Melissa S
authors: MS
authors: Simper
authors: Leslie
authors: L
authors: Powell
authors: S Alex
authors: SA
authors: McClellan
authors: Michael
authors: M
authors: Andreeff
authors: Michael C
authors: MC
authors: MacLeod
authors: John
authors: J
authors: DiGiovanni
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002619:Chemical Warfare Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C031278:2-chloroethyl ethyl sulfide; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D005978:Glutathione; D009151:Mustard Gas