Abel, Erika L.;
McIvor, Elizabeth;
Bubel, Jennifer D.;
Simper, Melissa S.;
Powell, Leslie;
Fields, Tammy Y.;
Andreeff, Michael;
MacLeod, Michael C.;
DiGiovanni, John
Abstract 1339: Upregulation of the glutathione detoxification pathway protects against cytotoxicity induced by the alkylating agent, 2-chloroethyl ethyl sulfide (CEES)
Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Artikel
Titel:
Abstract 1339: Upregulation of the glutathione detoxification pathway protects against cytotoxicity induced by the alkylating agent, 2-chloroethyl ethyl sulfide (CEES)
Beteiligte:
Abel, Erika L.;
McIvor, Elizabeth;
Bubel, Jennifer D.;
Simper, Melissa S.;
Powell, Leslie;
Fields, Tammy Y.;
Andreeff, Michael;
MacLeod, Michael C.;
DiGiovanni, John
Erschienen:
American Association for Cancer Research (AACR), 2011
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Sulfur mustard (SM) is a vesicating agent that was first used in chemical warfare over 100 years ago. SM alkylates DNA and is mutagenic in various model systems. Epidemiological studies indicate that chronic exposure increases the risk of cancer in exposed tissues. Due to its incapacitating effects, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. Currently, there are no antidotes for SM-induced toxicity; therefore, chemopreventive and therapeutic measures are needed. Glutathione (GSH) exerts a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. The rate-limiting step in GSH synthesis is catalyzed by the glutamate cysteine ligase (GCL) holoenzyme, which is composed of a catalytic and a regulatory subunit (GCLC and GCLM, respectively). Cancer chemopreventive agents are known to modulate expression of GCL and GSH S-transferases (GSTs) via activation of the transcription factor, Nrf2, and may, therefore, have utility in inhibiting SM-induced damage in the skin. We have screened 6 chemopreventive agents for ability to induce GSH synthesis and protect cultured NCTC2544 human keratinocytes against the SM analogue, 2-chloroethyl ethyl sulfide (CEES). We found that sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells (118.0±11.6 nmol/mg protein versus 66.5±7.9 nmol/mg protein) and preserved their viability by ∼3-fold following exposure to CEES. CDDO-Me acted additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES by 6-fold (60% in cells treated with a combination of CDDO-Me and DTP vs 10% in cells treated with vehicle only). In vivo, topical application of either sulforaphane or CDDO-Me elevated epidermal GSH and GST levels in the skin of C57BL/6 mice. These results suggest that CDDO-Me and sulforaphane are promising chemopreventive agents for SM toxicity in the skin.</jats:p>
<jats:p>Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1339. doi:10.1158/1538-7445.AM2011-1339</jats:p>