Chemical genomics of cancer chemopreventive dithiolethiones

Quynh T. Tran, Lijing Xu, Vinhthuy Phan, Shirlean B. Goodwin, Mostafizur Rahman, Victor X. Jin, Carrie H. Sutter, Bill D. Roebuck, Thomas W. Kensler, E. Olusegun George, Thomas R. Sutter

Research output: Contribution to journalArticle

22 Scopus citations

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-3 H-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 (IC50) values for inhibition of CYP1A2. The rank order of inhibitor potency was OLT > TBD > D3T, with IC50 values estimated as 0.2, 12.8 and >100 μM, 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.

Original languageEnglish (US)
Pages (from-to)480-486
Number of pages7
JournalCarcinogenesis
Volume30
Issue number3
DOIs
StatePublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

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    Tran, Q. T., Xu, L., Phan, V., Goodwin, S. B., Rahman, M., Jin, V. X., Sutter, C. H., Roebuck, B. D., Kensler, T. W., George, E. O., & Sutter, T. R. (2009). Chemical genomics of cancer chemopreventive dithiolethiones. Carcinogenesis, 30(3), 480-486. https://doi.org/10.1093/carcin/bgn292