Chemical genomics of cancer chemopreventive dithiolethiones.

Carcinogenesis
Quynh T TranThomas R Sutter

Abstract

3H-1,2-dithiole-3-thione (D3T) and its analogues 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT) and 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD) are chemopreventive agents that block or diminish early stages of carcinogenesis by inducing activities of detoxication enzymes. While OLT has been used in clinical trials, TBD has been shown to be more efficacious and possibly less toxic than OLT in animals. Here, we utilize a robust and high-resolution chemical genomics procedure to examine the pharmacological structure-activity relationships of these compounds in livers of male rats by microarray analyses. We identified 226 differentially expressed genes that were common to all treatments. Functional analysis identified the relation of these genes to glutathione metabolism and the nuclear factor, erythroid derived 2-related factor 2 pathway (Nrf2) that is known to regulate many of the protective actions of dithiolethiones. OLT and TBD were shown to have similar efficacies and both were weaker than D3T. In addition, we identified 40 genes whose responses were common to OLT and TBD, yet distinct from D3T. As inhibition of cytochrome P450 (CYP) has been associated with the effects of OLT on CYP expression, we determined the half ma...Continue Reading

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Citations

Sep 21, 2011·Chemical Reviews·Francisco J SchopferBruce A Freeman
Sep 4, 2010·Antioxidants & Redox Signaling·Subramaniam Ponnappan, Usha Ponnappan
Oct 26, 2010·Free Radical Biology & Medicine·Xiaoguang OuyangThomas R Sutter
Sep 8, 2009·Toxicology and Applied Pharmacology·Mi-Kyoung Kwak, Thomas W Kensler
Jul 25, 2006·Breast Cancer Research : BCR·Gabriela AlexePeter L Hammer
May 12, 2018·Future Medicinal Chemistry·Mohd Imran AnsariMohd Kamil Hussain
Oct 16, 2015·The Journal of Biological Chemistry·Angelika F WinkelDieter Schmoll

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Datasets Mentioned

BETA
GSE8882

Methods Mentioned

BETA
PCA
chips

Software Mentioned

JAVA
Ingenuity
CORE
Gene Ontology Enrichment Analysis Software Toolkit
Affymetrix Microarray Suite
SigmaPlot
TF
Perl
Cluster

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