LAS0811: From Combinatorial Chemistry to Activation of Antioxidant Response Element

Ming Zhu,Aimin Song,Kit Lam,Derick Lau,Hyounggee Baek,Ruiwu Liu

doi:10.1155/2009/420194

Abstract

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.

Highlights

Chemoprevention is a promising strategy to prevent cancer by employing small molecules to enhance production of phase II detoxifying enzymes which are capable of scavenging carcinogens [1]
Upon screening 10 combinatorial chemical libraries consisting of 9400 small molecules (Figure 1), we have identified, from library L9, one novel compound, 1,2-dimethoxy-4,5dinitrobenzene (LAS0811), which consistently induced antioxidant response element (ARE) activation higher than the prototype activator of ARE, tBHQ
Many analogs of each library weakly activated ARE

Summary

Introduction

Chemoprevention is a promising strategy to prevent cancer by employing small molecules to enhance production of phase II detoxifying enzymes which are capable of scavenging carcinogens [1]. A number of structurally unrelated molecules, such as anethole dithiolethiones, curcumin, isothiocyanates, caffeic acid, phenethyl esters, flavonoids, and triterpenoids, have been shown to activate ARE and subsequent induction of the phase II detoxifying enzymes [2, 3]. The ARE is a cis-acting element located in the promoter region of a number of genes encoding phase II detoxifying enzymes and antioxidative proteins [7, 8]. These enzymes and proteins include NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), γ-glutamatecysteine ligase (GCL), heme oxygenase 1 (HO1), thioredoxin reductase-1, and thioredoxin

Methods

Results

Conclusion