Nobiletin bioactivation in MDA-MB-468 breast cancer cells by cytochrome P450 CYP1 enzymes.

Nobiletin is a fully methoxylated flavone that has demonstrated anticancer activity via multiple modes of action. In the present study, the metabolism and further antiproliferative activity of nobiletin was evaluated in the CYP1 expressing human breast cancer cell line MDA-MB-468 and the normal breast cell line MCF10A. Nobiletin was metabolized in MDA-MB-468 cells to a single-demethylated derivative assigned NP1. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Nobiletin exhibited submicromolar IC50 (0.1 ± 0.04 μM) in MDA-MB-468 cells, whereas it was considerably less active in MCF10A cells (40 μM). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 300-fold increase was noted in the IC50 (30 ± 2.4 μM) of nobiletin. In the presence of the CYP1 inhibitor acacetin, the conversion of nobiletin to NP1 was significantly reduced in MDA-MB-468 cells. Furthermore, a significant increase was noted in the population of the cells at the G1 phase, following treatment with nobiletin (10 μM) for 24 h compared with the control cells treated with DMSO (0.1%) alone (55.9 ± 0.14 vs. 45.6 ± 1.96), whereas the cell cycle of MCF10A cells was not significantly altered under the same treatment conditions. Taken collectively, the results suggest that nobiletin is selectively bioactivated in MDA-MB-468 breast cancer cells via metabolism by the cytochrome P450 CYP1 family of enzymes.