Chemical genomics of cancer chemopreventive dithiolethiones

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 maximal inhibitory concentration (IC 50 ) values for inhibition of CYP1A2. The rank order of inhibitor potency was OLT ) TBD ) D3T, with IC 50 values estimated as 0.2, 12.8 and >100 mM, respectively. Functional analysis revealed that OLT and TBD, in addition to their effects on CYP, modulate liver lipid metabolism, especially fatty acids. Together, these findings provide new insight into the actions of clinically relevant and lead dithiolethione analogues.

Targeting NRF2 signaling for cancer chemoprevention

“…In particular, it was of interest that 24 subunits of the 26S proteasome were coordinately increased by D3T in the liver and 80% of these inducible proteasome subunits were only seen in wild-type mice. A recent report by Tran et al (Tran et al , 2009), could confirm that many of these NRF2-dependent genes, particularly detoxifying and antioxidant proteins, are increased in rat liver following D3T treatment. Furthermore, in their gene array analysis of a pharmacological structure-activity relationship, 226 differentially expressed genes are common to D3T and two of its analogs: oltipraz and 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD).…”

Complete Protection against Aflatoxin B1-Induced Liver Cancer with a Triterpenoid: DNA Adduct Dosimetry, Molecular Signature, and Genotoxicity Threshold

“…Total DNA content was determined spectrophotometrically using diphenylamine. Total RNA was isolated from frozen liver tissue (18). The levels of RNA for all genes were analyzed by qRT-PCR.…”

Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

“…PCK1 (phosphoenolpyruvate carboxykinase 1) is a key control point during the regulation of gluconeogenesis. It has been shown that PCK1 is involved in the processes of small molecule biochemistry, carbohydrate metabolism, molecular transport, and response to drugs including 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD), 3H-1,2-dithiole-3-thione (D3T), and its analogues 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT) [63]. MDH1 (malate dehydrogenase 1) in this pathway has been reported to be relevant with drug toxicity [64, 65].…”