Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia

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BlankNrf2 responses and the therapeutic selectivity of electrophilic compounds

in chronic lymphocytic leukemia

1.. P. Wua,

2.. Tomoko Hayashia,

3.. B. Cottama,

4.. Guangyi Jina,

5.. Shiyin Yaoa,

6.. C. N. Wua,

7.. D. Rosenbacha,

8.. Maripat Corrb,

9.. B. Schwaba, and

10.. Dennis A. Carsona,1

+ Author Affiliations

1.. as Cancer Center, University of California San Diego, La Jolla, CA

92093; and

2.. b University of California San Diego School of Medicine, La Jolla, CA

92093

1.. Contributed by Dennis A. Carson, March 10, 2010 (sent for review January

29, 2010)

Abstract

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–related 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; a-ß unsaturated carbonyls,

isothiocyanates, sulfhydryl reactive metals, flavones, and polyphenols. Our

results show that compounds containing a-ß 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–1. a-ß Unsaturated carbonyl–containing compounds were

selectively cytotoxic to CLL, and loss of the a-ß unsaturation abrogated Nrf2

activity and CLL toxicity. The a-ß 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.

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