Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 289, Issue 1, Pages 48-57Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2015.09.001
Keywords
Fenhexamid; Cyprodinil; Ovarian cancer; Xenograft models; Cathepsin D
Categories
Funding
- Ministry of Food and Drug Safety of Korea [14182MFDS977]
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Fenhexamid and cyprodinil are antifungal agents (pesticides) used for agriculture, and are present at measurable amounts in fruits and vegetables. In the current study, the effects of fenhexamid and cyprodinil on cancer cell proliferation and metastasis were examined. Additionally, the protein expression levels of cyclin D1 and cyclin E as well as cathepsin D were analyzed in BC-1 ovarian cancer cells that express estrogen receptors (ERs). The cells were cultured with 0.1% dimethyl sulfoxide (DMSO; control), 17 beta-estradiol (E2; 10(-9) M), and fenhexamid or cyprodinil (10(-8)-10(-7) M). Results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MIT) assay showed that fenhexamid and cyprodinil increased BC-1 cell proliferation about 1.5 to 2 times similar to E2 (5 times) compared to the control. When the cells were co-treated with ICI 182,780 (10(-8) M), an ER antagonist, the proliferation of pesticide-treated BC-1 cells was decreased to the level of the control. A wound healing assay revealed that the pesticides reduced the disrupted area in the BC-1 cell monolayer similar to E2. Protein levels of cydin D1 and E as well as cathepsin D were increased by fenhexamid and cyprodinil. This effect was reversed by co-treatment with ICI 182,780. In a xenograft mouse model with transplanted BC-1 cells, cyprodinil significantly increased tumor mass formation about 2 times as did E2 (6 times) compared to the vehicle (0.1% DMSO) over an 80-day period. In contrast, fenhexamid did not promote ovarian tumor formation in this mouse model. Cyprodinil also induced cell proliferation along with the expression of proliferating cell nuclear antigen (PCNA) and cathepsin D in tumor tissues similar to E2. Taken together, these results imply that fenhexamid and cyprodinil may have disruptive effects on ER-expressing cancer by altering the cell cycle- and metastasis-related gene expression via an ER-dependent pathway. (C) 2015 Elsevier Inc. All rights reserved.
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