Identification of dithiolethiones with better chemopreventive properties than oltipraz

Abstract

Oltipraz and related dithiolethiones are an important class of chemopreventive agents. Studies were undertaken to identify cancer chemopreventive dithiolethiones more active than oltipraz. Largely based upon enzyme induction activities in vitro, 17 dithiolethiones, including oltipraz, were analyzed for their ability to induce hepatic phase II enzyme activities in vivo. Of these compounds, 15 produced greater induction of NAD(P)H:quinone reductase and 11 yielded greater induction of glutathione S-transferase than oltipraz. All 17 dithiolethiones were then tested for their ability to inhibit acute hepatotoxicity by aflatoxin B1 (AFB1), which previously has been shown to be an intermediate predictor of chemopreventive activity. Rats were pretreated with dithiolethiones (0.3 mmol/kg body wt, three times a week per os) and challenged with two acutely toxic doses of AFB1 (0.5 mg/kg body wt, once daily for two successive days per os). Inhibition of hepatotoxicity was measured by changes in body weight gain during AFB1 challenge, reduction in levels of hepatic enzymes in serum and diminution of bile duct cell proliferation. Nine dithiolethiones spanning a range of responses in this toxicity screen were further tested for their ability to prevent AFB1-induced tumorigenicity, as assessed by a reduction in hepatic burden of putative preneoplastic foci. Six dithiolethiones were found to be considerably more effective than oltipraz in preventing AFB1-induced tumorigenesis. In general, dithiolethiones that were very effective in inhibition of acute hepatotoxicity were also found to be effective in prevention of hepatic tumorigenesis.

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes

“…As a point of reference, NQO1 enzyme activity is increased 4-fold in the liver of female mice treated with f2,200 Amol oltipraz/kg (40). D3T is a known chemopreventive agent that protects against tumorigenesis in the liver (41). Treatment by gavage with 300 Amol D3T/kg results in 3-fold induction of NQO1 activity in mouse liver (29).…”

1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)

“…At least two 1,2-dithiole-3-thiones have clinical applications, and this class of compounds has been extensively evaluated as anticarcinogens and antioxidants. Oltipraz (4-methyl-5-pyrazinyl-1,2-dithiole-3-thione) and related compounds have been used successfully to treat schistosomiasis and have been considered chemoprotective agents against a variety of cancers (33,40,44). Anetholedithione (5-[4-methoxyphenyl]-1,2-dithiole-3-thione) also has chemoprotective activity (46) and is used in many countries as a choleretic and to increase salivary flow (35).…”

Development of a Green Fluorescent Protein Microplate Assay for the Screening of Chemopreventive Agents

“…This new assay, as a cell-based functional assay, could provide a platform for identifying agents with potential chemoprevention and anticancer activity. A screening assay, such as ours, can also serve as an adjunct to the process that has recently been used (21)(22)(23) to create rationally designed structural analogs of known chemopreventive molecules. Each of these approaches holds great promise to generate ever new chemopreventive compounds that will find increased clinical utility.…”