Chemopreventive Agents Attenuate Rapid Inhibition of Gap Junctional Intercellular Communication Induced by Environmental Toxicants.
Altered gap junctional intercellular communication (GJIC) has been associated with chemical carcinogenesis, where both chemical tumor promoters and chemopreventive agents (CPAs) are known to conversely modulate GJIC. The aim of this study was to investigate whether attenuation of chemically inhibited GJIC represents a common outcome induced by different CPAs, which could be effectively evaluated using in vitro methods. Rat liver epithelial cells WB-F344 were pretreated with a CPA for either 30 min or 24 h, and then exposed to GJIC-inhibiting concentration of a selected tumor promoter or environmental toxicant [12-O-tetradecanoylphorbol-13-acetate (TPA), lindane, fluoranthene, 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), perfluorooctanoic acid (PFOA), or pentachlorophenol]. Out of nine CPAs tested, quercetin and silibinin elicited the most pronounced effects, preventing the dysregulation of GJIC by all the GJIC inhibitors, but DDT. Metformin and curcumin attenuated the effects of three GJIC inhibitors, whereas the other CPAs prevented the effects of two (diallyl sulfide, emodin) or one (indole-3-carbinol, thymoquinone) GJIC inhibitor. Significant attenuation of chemically induced inhibition of GJIC was observed in 27 (50%) out of 54 possible combinations of nine CPAs and six GJIC inhibitors. Our data demonstrate that in vitro evaluation of GJIC can be used as an effective screening tool for identification of chemicals with potential chemopreventive activity.
a Department of Experimental Phycology and Ecotoxicology , Institute of Botany of the ASCR , Brno , Czech Republic.|b RECETOX - Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University , Brno , Czech Republic.
Pavel
P
Babica
a Department of Experimental Phycology and Ecotoxicology , Institute of Botany of the ASCR , Brno , Czech Republic.|b RECETOX - Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University , Brno , Czech Republic.
Lucie
L
Čtveráčková
a Department of Experimental Phycology and Ecotoxicology , Institute of Botany of the ASCR , Brno , Czech Republic.|b RECETOX - Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University , Brno , Czech Republic.
Zuzana
Z
Lenčešová
c Department of Pediatrics and Human Development & Institute for Integrative Toxicology, Michigan State University , Michigan , USA.
James E
JE
Trosko
c Department of Pediatrics and Human Development & Institute for Integrative Toxicology, Michigan State University , Michigan , USA.
Brad L
BL
Upham
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002210:Caprylates / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002450:Cell Communication / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D003634:DDT / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects; D005449:Fluorenes / Q000633:toxicity; D005466:Fluorocarbons / Q000633:toxicity; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000633:toxicity; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D016588:Anticarcinogenic Agents; D002210:Caprylates; D002273:Carcinogens; D005449:Fluorenes; D005466:Fluorocarbons; C007738:fluoranthene; D001556:Hexachlorocyclohexane; D008687:Metformin; C023036:perfluorooctanoic acid; D003634:DDT; D003474:Curcumin; D013755:Tetradecanoylphorbol Acetate