Asset Details
Do you wish to reserve the book?
Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia
Do you wish to request the book?
Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia
2010
Overview
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; α-β unsaturated carbonyls, isothiocyanates, sulfhydryl reactive metals, flavones, and polyphenols. Our results show that compounds containing α-β 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. α-β Unsaturated carbonyl-containing compounds were selectively cytotoxic to CLL, and loss of the α-β unsaturation abrogated Nrf2 activity and CLL toxicity. The α-β unsaturated carbonyl containing compounds ethacrynic acid and parthenolide activated Nrf2 in normal peripheral blood mono-nuclear 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.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Antineoplastic Agents - pharmacology
/ Cells
/ Chronic lymphocytic leukemia
/ flavones
/ Gene Expression Regulation, Leukemic
/ heme oxygenase (biliverdin-producing)
/ Heme Oxygenase-1 - biosynthesis
/ Humans
/ Leukemia
/ Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
/ Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
/ Leukocytes, Mononuclear - metabolism
/ metals
/ NF-E2-Related Factor 2 - biosynthesis
/ Thiols
