Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33,342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG0/G1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy.

Toxicology and applied pharmacology. 2016 Jun 07 [Epub ahead of print]

Kuo-Liang Wei, Fei-Yun Chen, Chih-Yi Lin, Guan-Lun Gao, Wen-Ya Kao, Chi-Hui Yeh, Chang-Rong Chen, Hao-Chun Huang, Wei-Ren Tsai, Koa-Jen Jong, Wan-Jung Li, Jyan-Gwo Joseph Su

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, 61363, Taiwan, ROC,; College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan, ROC., Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C., Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C., Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C; Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C., Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C., Department of Environmental Engineering, College of Engineering, Da-Yeh University, Dacun, Changhua, 51591, Taiwan, ROC., Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C., Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, 61363, Taiwan, ROC., Division of Applied Toxicology, Taiwan, Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Executive Yuan, Taichung, 41358, Taiwan, ROC., Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C., Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C., Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan, R, .O.C. Electronic address: .