clostridium-perfringens-delta-toxin and 1-2-dithiol-3-thione

Dithiolethiones are a family of promising cancer chemopreventive agents, and induction of phase 2 enzymes is key to their chemopreventive activities. Two dithiolethiones have been evaluated in humans for cancer prevention. While some chemopreventive activities were detected in several human studies, potential side effects are a concern. Herein, we report structure-activity relationships of 25 dithiolethiones. Several compounds show exceedingly potent and bladder specific activity in phase 2 enzyme induction. Structural features responsible for such activity, as well as those inhibiting the activity, are discussed. Moreover, the compounds activate and depend on Nrf2 for their inductive activities. Nrf2 is a major transcriptional stimulator of cytoprotective genes and is critical for cancer prevention. Thus, several new dithiolethiones that are highly promising for bladder cancer prevention have been identified. Because the compounds act specifically in the bladder, the likelihood of potential systemic toxicity may be low.

Topics: Animals; Anticarcinogenic Agents; Cell Line, Tumor; Enzyme Induction; Female; Gene Knockdown Techniques; Glutathione Transferase; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Organ Specificity; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiones; Thiophenes; Urinary Bladder; Urinary Bladder Neoplasms

Identifying agents that block tumor initiation is a goal of cancer prevention. The ability of a chemically varied group of agents to induce various drug metabolizing genes in livers of rats was examined. Sprague-Dawley rats were treated for 7 days with various agents in the diet or by gavage. The agents examined, which might be expected to respond via specific nuclear receptors (CAR, AhR) as well as antioxidant response elements (AREs), included Phase I/II inducers [5,6-benzoflavone (BF, 5000mg/kg diet), diallyl sulfide (DAS, 500mg/kg BW/day), ethoxyquin (EXO, 300mg/kg BW/day) and phenobarbital (PB, 500mg/kg diet)] or pure Phase II inducers [1,2-dithiol-3-thione (DTT, 500mg/kg diet), and cyclopentadithiolthione (CPDTT, 175mg/kg BW/day)]. Liver RNA expression was analyzed employing oligonucleotide microarrays. The agents yielded unique expression profiles. In genes with known AREs, the induction ratios (Levels Treated/Levels Controls) were: quinone oxidoreductase (BF, 8:1; DTT, 3.2:1; CPDTT, 3:1; DAS, 1.8:1; Exo, 1.7:1), glutatione transferase Pi (DTT, 36:1; CPDTT, 34:1; EXO, 8:1; DAS, 5:1; BF, 2.5:1), and aldehyde keto reductase 7A3 (AFAR) (DTT and CPDTT, 14:1; DAS, 6:1; EXO, 4:1; PB, 1.5:1). When the search included a wider variety of Phase II drug metabolizing enzymes, no clear pattern was observed. Agent induced gene expression and preventive activity in published carcinogen induced tumor models showed limited correlation; questioning whether measuring the induction of one or two genes (e.g., quinone reductase) is a surrogate for overall Phase II inducing (antioxidant) and potential anti-tumor activity.

Topics: Allyl Compounds; Animals; Anticarcinogenic Agents; Antioxidants; beta-Naphthoflavone; Enzyme Induction; Ethoxyquin; Female; Gene Expression Regulation; Glutathione Transferase; Liver; NAD(P)H Dehydrogenase (Quinone); Oligonucleotide Array Sequence Analysis; Phenobarbital; Rats; Rats, Sprague-Dawley; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfhydryl Compounds; Sulfides; Thiones; Thiophenes