Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death.

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Wei KL, Chen FY, Lin CY, Gao GL, Kao WY, Yeh CH, Chen CR, Huang HC, Tsai WR, Jong KJ, Li WJ, Su JG

Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death.

Toxicol Appl Pharmacol. 2016 Sep 1;306:86-97. doi: 10.1016/j.taap.2016.06.004. Epub 2016 Jun 7.

PubMed ID

27286660 [ View in PubMed

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Abstract

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 beta-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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
beta-Naphthoflavone	Aryl hydrocarbon receptor	Protein	Humans	Unknown	Agonist	Details
Carbendazim	Aryl hydrocarbon receptor	Protein	Humans	Yes	Agonist	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Carbendazim	Investigational	CYP1A1	1543	upregulated	carbendazim results in increased expression of CYP1A1 mRNA	15q24.1