LAS0811: From combinatorial chemistry to activation of antioxidant response element

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article number420194
JournalJournal of Biomedicine and Biotechnology
Volume2009
DOIs
StatePublished - 2009

Fingerprint

Antioxidant Response Elements
Chemical activation
Chemoprevention
Molecules
NF-E2 Transcription Factor
Dinitrobenzenes
Small Molecule Libraries
tert-Butylhydroperoxide
Heme Oxygenase-1
Reducing Agents
Hep G2 Cells
Cell death
Enzymes
Oxidants
NAD
Glutathione
Neoplasms
Screening
Oxidoreductases
Cell Death

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Genetics
  • Molecular Biology
  • Health, Toxicology and Mutagenesis
  • Medicine(all)

Cite this

LAS0811 : From combinatorial chemistry to activation of antioxidant response element. / Lau, Derick H; Zhu, Ming; Baek, Hyounggee; Liu, Ruiwu; Song, Aimin; Lam, Kit.

In: Journal of Biomedicine and Biotechnology, Vol. 2009, 420194, 2009.

Research output: Contribution to journalArticle

@article{d0d3d945e37442a192e1007b0a956fb3,
title = "LAS0811: From combinatorial chemistry to activation of antioxidant response element",
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.",
author = "Lau, {Derick H} and Ming Zhu and Hyounggee Baek and Ruiwu Liu and Aimin Song and Kit Lam",
year = "2009",
doi = "10.1155/2009/420194",
language = "English (US)",
volume = "2009",
journal = "BioMed Research International",
issn = "2314-6133",
publisher = "Hindawi Publishing Corporation",

}

TY - JOUR

T1 - LAS0811

T2 - From combinatorial chemistry to activation of antioxidant response element

AU - Lau, Derick H

AU - Zhu, Ming

AU - Baek, Hyounggee

AU - Liu, Ruiwu

AU - Song, Aimin

AU - Lam, Kit

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70350031282&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350031282&partnerID=8YFLogxK

U2 - 10.1155/2009/420194

DO - 10.1155/2009/420194

M3 - Article

C2 - 19794825

AN - SCOPUS:70350031282

VL - 2009

JO - BioMed Research International

JF - BioMed Research International

SN - 2314-6133

M1 - 420194

ER -