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 33342 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.
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.
Kuo-Liang
KL
Wei
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC.
Fei-Yun
FY
Chen
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC.
Chih-Yi
CY
Lin
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC; Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC.
Guan-Lun
GL
Gao
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC.
Wen-Ya
WY
Kao
Department of Environmental Engineering, College of Engineering, Da-Yeh University, Dacun, Changhua 51591, Taiwan, ROC.
Chi-Hui
CH
Yeh
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC.
Chang-Rong
CR
Chen
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, ROC.
Hao-Chun
HC
Huang
Division of Applied Toxicology, Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Executive Yuan, Taichung 41358, Taiwan, ROC.
Wei-Ren
WR
Tsai
Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC.
Koa-Jen
KJ
Jong
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC.
Wan-Jung
WJ
Li
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC. Electronic address: jgjsu@mail.ncyu.edu.tw.
Jyan-Gwo Joseph
JG
Su
D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity*; D002219:Carbamates / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D005659:Fungicides, Industrial / Q000633:toxicity*; D006801:Humans; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
D001562:Benzimidazoles; D002219:Carbamates; D005659:Fungicides, Industrial; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; C006698:carbendazim
Aryl hydrocarbon receptor; Carbendazim; Cytochrome P450