title: Novel dithiolethione-modified nonsteroidal anti-inflammatory drugs in human hepatoma HepG2 and colon LS180 cells.
abstract: OBJECTIVE
  Nonsteroidal anti-inflammatory drugs (NSAID) are promising chemopreventive agents against colon and other cancers. However, the molecular basis mediated by NSAIDs for chemoprevention has not been fully elucidated. Environmental carcinogens induce DNA mutation and cellular transformation; therefore, we examined the effect of NSAIDs on carcinogenesis mediated by the aryl hydrocarbon receptor signaling pathway. In this study, we investigated the activities of a new class of NSAIDs containing dithiolethione moieties (S-NSAID) on both arms of carcinogenesis.
  
  
  METHODS
  We investigated the effects of the S-NSAIDs, S-diclofenac and S-sulindac, on carcinogen activation and detoxification mechanisms in human hepatoma HepG2 and human colonic adenocarcinoma LS180 cells.
  
  
  RESULTS
  We found that S-diclofenac and S-sulindac inhibited the activity and expression of the carcinogen activating enzymes, cytochromes P-450 (CYP) CYP1A1, CYP1B1, and CYP1A2. Inhibition was mediated by transcriptional regulation of the aryl hydrocarbon receptor (AhR) pathway. The S-NSAIDs down-regulated carcinogen-induced expression of CYP1A1 heterogeneous nuclear RNA, a measure of transcription rate. Both compounds blocked carcinogen-activated AhR from binding to the xenobiotic responsive element as shown by chromatin immunoprecipitation. S-diclofenac and S-sulindac inhibited carcinogen-induced CYP enzyme activity through direct inhibition as well as through decreased transcriptional activation of the AhR. S-sulindac induced expression of several carcinogen detoxification enzymes of the glutathione cycle including glutathione S-transferase A2, glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione reductase.
  
  
  CONCLUSIONS
  These results indicate that S-diclofenac and S-sulindac may serve as effective chemoprevention agents by favorably balancing the equation of carcinogen activation and detoxification mechanisms.
authors.affiliation: Basic Research Program, Science Applications International Corporation-Frederick, Inc., and Laboratory of Metabolism, National Cancer Institute-Frederick, Frederick, Maryland, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Bass
authors.forename: Pawel
authors.initials: P
authors.lastname: Sienkiewicz
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Macdonald
authors.forename: Robert Y S
authors.initials: RY
authors.lastname: Cheng
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: Grace Chao
authors.initials: GC
authors.lastname: Yeh
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013871:Thiones / Q000494:pharmacology*
chemical_list: C520611:2-((2,6-dichlorophenyl)amino)benzeneacetic acid 4-(3H-1,2-dithiol-3-thione-5-yl)phenyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C539817:S-sulindac; D013871:Thiones; D004008:Diclofenac; D013467:Sulindac; D019363:Cytochrome P-450 CYP1A1