Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8553899 | Toxicology in Vitro | 2018 | 41 Pages |
Abstract
Tangeretin is a polymethoxylated flavone with multifaceted anticancer activity. In the present study, the metabolism of tangeretin was evaluated in the CYP1 expressing human breast cancer cell lines MCF7 and MDA-MB-468 and in the normal breast cell line MCF10A. Tangeretin was converted to 4â² OH tangeretin by recombinant CYP1 enzymes and by CYP1 enzymes expressed in MCF7 and MDA-MB-468 cells. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Tangeretin exhibited submicromolar IC50 (0.25â¯Â±â¯0.15â¯Î¼M) in MDA-MB-468 cells, whereas it was less active in MCF7 cells (39.3â¯Â±â¯1.5â¯Î¼M) and completely inactive in MCF10A cells (>100â¯Î¼M). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 70-fold increase was noted in the IC50 (18â¯Â±â¯1.6â¯Î¼M) of tangeretin. In the presence of the CYP1 inhibitor acacetin, the conversion of tangeretin to 4â² OH tangeretin was significantly reduced in MDA-MB-468 cells (2.55â¯Â±â¯0.19â¯Î¼M vs. 6.33â¯Â±â¯0.12â¯Î¼M). The mechanism of antiproliferative action involved cell cycle arrest at the G1 phase for MCF7 and MDA-MB-468 cells. Tangeretin was further shown to induce CYP1 enzyme activity and CYP1A1/CYP1B1 protein expression in MCF7 and MDA-MB-468 cells. These results suggest that tangeretin inhibits the proliferation of breast cancer cells via CYP1A1/CYP1B1-mediated metabolism to the product 4â² hydroxy tangeretin.
Keywords
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Authors
Somchaiya Surichan, Randolph R. Arroo, Aristidis M. Tsatsakis, Vasilis P. Androutsopoulos,