title: Inhibition of gap junctional intercellular communication and activation of mitogen-activated protein kinase by tumor-promoting organic peroxides and protection by resveratrol.
abstract: Dicumyl peroxide (di-CuOOH) and benzoyl peroxide (BzOOH) act as tumor promoters in SENCAR mice, whereas di-tert-butylhydroperoxide does not. Tumor promotion requires the removal of growth suppression by inhibition of gap junctional intercellular communication (GJIC) and the induction of mitogenic intracellular pathways. We showed that di-CuOOH and BzOOH both reversibly inhibited GJIC and transiently activated mitogen-activated protein kinase, specifically, the extracellular receptor kinase at noncytotoxic conditions in WB-F344 rat liver epithelial cells, whereas the non-tumor-promoting di-tert-butylhydroperoxide did not inhibit GJIC or activate extracellular receptor kinase. di-CuOOH but not BzOOH inhibited GJIC through a phosphatidylcholine-specific phospholipase C-dependent mechanism. N-acetylcysteine (NAC) was needed to prevent a cytotoxic, glutathione-depleting effect of BzOOH, whereas di-CuOOH was noncytotoxic and did not alter glutathione levels at all doses and times tested. Pretreatment of WB-F344 cells with resveratrol, a polyphenolic antioxidant present in red wine, prevented at physiological doses the inhibition of GJIC by di-CuOOH but not from BzOOH and was effective in significantly preventing extracellular receptor kinase activation by both peroxides. NAC did not prevent any of the peroxide effects on either GJIC or extracellular receptor kinase, suggesting a specific antioxidant effect of resveratrol.
authors.affiliation: Department of Pediatrics & Human Development and the National Food Safety & Toxicology Center, Michigan State University, East Lansing 48824-1302, USA. brad.upham@ht.msu.edu
authors.forename: Brad L
authors.initials: BL
authors.lastname: Upham
authors.forename: Miodrag
authors.initials: M
authors.lastname: Guzvić
authors.forename: Jacob
authors.initials: J
authors.lastname: Scott
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Carbone
authors.forename: Ludek
authors.initials: L
authors.lastname: Blaha
authors.forename: Chad
authors.initials: C
authors.lastname: Coe
authors.forename: Lan Lan
authors.initials: LL
authors.lastname: Li
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Rummel
authors.forename: James E
authors.initials: JE
authors.lastname: Trosko
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002450:Cell Communication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000201:enzymology; D017629:Gap Junctions / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D010545:Peroxides / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D016588:Anticarcinogenic Agents; D016877:Oxidants; D010545:Peroxides; D013267:Stilbenes; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; D000077185:Resveratrol