Inhibition of Gap Junctional Intercellular Communication and Activation of Mitogen-Activated Protein Kinase by Tumor-Promoting Organic Peroxides and Protection by Resveratrol

• Published in: Nutrition and cancer 2007-01, Vol.57 (1), p.38-47
• Main Authors: Upham, B.L, Guzvic, M, Scott, J, Carbone, J.M, Blaha, L, Coe, C, Li, L.L, Rummel, A.M, Trosko, J.E
• Format: Article
• Language: English
• Subjects: acetylcysteine; Animals; anticarcinogenic activity; Anticarcinogenic Agents - pharmacology; antioxidants; Biological and medical sciences; Blotting, Western; carcinogens; cell communication; Cell Communication - drug effects; chemical constituents of plants; dose response; Dose-Response Relationship, Drug; Epidemiology; epithelial cells; Epithelial Cells - enzymology; free radicals; gap junctions; Gap Junctions - drug effects; glutathione; Glutathione - metabolism; Humans; inhibitors; intercellular junctions; lines; Liver - cytology; Medical sciences; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - metabolism; nutrition-genotype interaction; Other treatments; Oxidants - pharmacology; peroxides; Peroxides - pharmacology; Rats; Rats, Inbred F344; reaction inhibition; red wines; resveratrol; Stilbenes - pharmacology; Time Factors; Treatment. General aspects; Tumors; Vitaceae
• ISSN: 0163-5581; 1532-7914
• DOI: 10.1080/01635580701268188

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.