LAS0811: from combinatorial chemistry to activation of antioxidant response element.
The antioxidant response element (ARE) and its transcription factor, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), are potential targets for cancer chemoprevention. We sought to screen small molecules synthesized with combinatorial chemistry for activation of ARE. By high-throughput screening of 9400 small molecules from 10 combinatorial chemical libraries using HepG2 cells with an ARE-driven reporter, we have identified a novel small molecule, 1,2-dimethoxy-4,5-dinitrobenzene (LAS0811), as an activator of the ARE. LAS0811 upregulated the activity of NAD(P)H:quinone oxidoreductase 1 (NQO1), a representative antioxidative enzyme regulated by ARE. It enhanced production of an endogenous reducing agent, glutathione (GSH). In addition, LAS0811 induced expression of heme oxygenase 1 (HO1), which is an ARE-regulated enzyme with anti-inflammatory activity. Furthermore, LAS0811 reduced cell death due to the cytotoxic stress of a strong oxidant, t-butyl hydroperoxide (t-BOOH). Mechanistically, LAS0811 upregulated the expression of Nrf2 and promoted its translocation into the nuclei leading to subsequent ARE activation. Taken together, LAS0811 is a novel activator of the ARE and its associated detoxifying genes and, thus, a potential agent for cancer chemoprevention.
Zhu
Ming
M
Division of Hematology/Oncology, Department of Internal Medicine, UC-Davis Cancer Center, University of California-Davis, 4501 X Street, Sacramento, CA 95817, USA.
Baek
Hyounggee
H
Liu
Ruiwu
R
Song
Aimin
A
Lam
Kit
K
Lau
Derick
D
D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000502:physiology*
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human