Comprehensive evaluation of a novel nuclear factor-kappaB inhibitor, quinoclamine, by transcriptomic analysis.

Abstract

BACKGROUND AND PURPOSE:

The transcription factor nuclear factor-kappaB (NF-kappaB) has been linked to the cell growth, apoptosis and cell cycle progression. NF-kappaB blockade induces apoptosis of cancer cells. Therefore, NF-kappaB is suggested as a potential therapeutic target for cancer. Here, we have evaluated the anti-cancer potential of a novel NF-kappaB inhibitor, quinoclamine (2-amino-3-chloro-1,4-naphthoquinone).

EXPERIMENTAL APPROACH:

In a large-scale screening test, we found that quinoclamine was a novel NF-kappaB inhibitor. The global transcriptional profiling of quinoclamine in HepG2 cells was therefore analysed by transcriptomic tools in this study.

KEY RESULTS:

Quinoclamine suppressed endogenous NF-kappaB activity in HepG2 cells through the inhibition of IkappaB-alpha phosphorylation and p65 translocation. Quinoclamine also inhibited induced NF-kappaB activities in lung and breast cancer cell lines. Quinoclamine-regulated genes interacted with NF-kappaB or its downstream genes by network analysis. Quinoclamine affected the expression levels of genes involved in cell cycle or apoptosis, suggesting that quinoclamine exhibited anti-cancer potential. Furthermore, quinoclamine down-regulated the expressions of UDP glucuronosyltransferase genes involved in phase II drug metabolism, suggesting that quinoclamine might interfere with drug metabolism by slowing down the excretion of drugs.

CONCLUSION AND IMPLICATIONS:

This study provides a comprehensive evaluation of quinoclamine by transcriptomic analysis. Our findings suggest that quinoclamine is a novel NF-kappaB inhibitor with anti-cancer potential.

• Authors: W-Y Cheng, J-C Lien, C-Y Hsiang, S-L Wu, C-C Li, H-Y Lo, J-C Chen, S-Y Chiang, J-A Liang, T-Y Ho
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 157 Issue 5 Pg. 746-56 (Jul 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19422389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Naphthoquinones
• RELA protein, human
• Transcription Factor RelA
• NF-KappaB Inhibitor alpha
• Glucuronosyltransferase
• 2-amino-3-chloro-1,4-naphthoquinone

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Gene Expression Profiling (methods)
• Gene Expression Regulation (drug effects)
• Gene Regulatory Networks
• Glucuronosyltransferase (genetics)
• Humans
• I-kappa B Proteins (metabolism)
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Naphthoquinones (pharmacology)
• Oligonucleotide Array Sequence Analysis
• Phosphorylation
• Protein Transport
• Transcription Factor RelA (metabolism)
• Transfection