Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1-mediated metabolism to the product 4′ hydroxy tangeretin

Tangeretin is a polyniethoxylated 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 4' 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 (0.25 +/- 0.15 mu M) in MDA-MB-468 cells, whereas it was less active in MCF7 cells (39.3 +/- 1.5 mu M) and completely inactive in MCF10A cells (> 100 mu M). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 70-fold increase was noted in the IC50 (18 +/- 1.6 mu M) of tangeretin. In the presence of the CYP1 inhibitor acacetin, the conversion of tangeretin to 4 ' OH tangeretin was significantly reduced in MDA-MB-468 cells (2.55 +/- 0.19 mu M vs. 6.33 +/- 0.12 mu M). 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 4' hydroxy tangeretin.