{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:21:48Z","timestamp":1791156108344,"version":"4.1.0"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"16","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,4,20]]},"abstract":"<jats:p>Recent studies show that redox-active small molecules are selectively cytotoxic to chronic lymphocytic leukemia (CLL). Although elevated levels of reactive oxygen species in CLL cells have been implicated, the molecular mechanism underlying this selectivity is unclear. In other cell types, the nuclear factor erythroid 2\u2013related factor 2 (Nrf2) signaling pathway regulates the oxidative stress response. We found elevated Nrf2 signaling in untreated CLL cells compared with normal lymphocytes. Therefore, we tested 27 known electrophilic and antioxidant compounds with drug-like properties and determined their CLL-selective cytotoxicity and effect on Nrf2 signaling. The selected compounds were from five distinct structural classes; \u03b1-\u03b2 unsaturated carbonyls, isothiocyanates, sulfhydryl reactive metals, flavones, and polyphenols. Our results show that compounds containing \u03b1-\u03b2 unsaturated carbonyls, sulfhydryl reactive metals, and isothiocyanates are strong activators of Nrf2 in a reporter assay system and in primary human CLL based on increased expression of the Nrf2 target heme oxygenase\u20131. \u03b1-\u03b2 Unsaturated carbonyl\u2013containing compounds were selectively cytotoxic to CLL, and loss of the \u03b1-\u03b2 unsaturation abrogated Nrf2 activity and CLL toxicity. The \u03b1-\u03b2 unsaturated carbonyl containing compounds ethacrynic acid and parthenolide activated Nrf2 in normal peripheral blood mononuclear cells, but had a less potent effect in CLL cells. Furthermore, ethacrynic acid bound directly to the Nrf2-negative regulator Kelch-like ECH-associated protein 1 (Keap1) in CLL cells. These experiments document the presence of Nrf2 signaling in human CLL and suggest that altered Nrf2 responses may contribute to the observed selective cytotoxicity of electrophilic compounds in this disease.<\/jats:p>","DOI":"10.1073\/pnas.1002890107","type":"journal-article","created":{"date-parts":[[2010,4,5]],"date-time":"2010-04-05T20:35:31Z","timestamp":1270499731000},"page":"7479-7484","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":116,"title":["Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia"],"prefix":"10.1073","volume":"107","author":[{"given":"Raymond P.","family":"Wu","sequence":"first","affiliation":[{"name":"Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard B.","family":"Cottam","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyi","family":"Jin","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyin","family":"Yao","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego, La Jolla, CA 92093; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina C. 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