Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer

Background: Tamoxifen and the citrus flavonoid tangeretin exhibit similar i nhibitory effects on the growth and invasive properties of human mammary ca ncer cells in vitro; furthermore, the two agents have displayed additive ef fects in vitro. In this study, we examined whether tangeretin would enhance tamoxifen's therapeutic benefit in vivo, Methods: Female nude mice (n = 80 ) were inoculated subcutaneously with human MCF-7/6 mammary adenocarcinoma cells. Groups of 20 mice were treated orally by adding the following substa nces to their drinking water: tamoxifen (3 x 10(-5) M), tangeretin (1 x 10( -4) M), tamoxifen plus tangeretin (3 x 10(-5) M plus 1 x 10(-4) M), or solv ent. Results and Conclusions: Oral treatment of mice with tamoxifen resulte d in a statistically significant inhibition of tumor growth compared with s olvent treatment (two-sided P = .001), Treatment with tangeretin did not in hibit tumor growth, and addition of this compound to drinking water with ta moxifen completely neutralized tamoxifen's inhibitory effect. The median su rvival time of tumor-bearing mice treated with tamoxifen plus tangeretin wa s reduced in comparison with that of mice treated with tamoxifen alone (14 versus 56 weeks; two-sided P = .002), Tangeretin (1 x 10(-6) M or higher) i nhibited the cytolytic effect of murine natural killer cells on MCF-7/6 cel ls in vitro, which may explain why tamoxifen-induced inhibition of tumor gr owth in mice is abolished when tangeretin is present in drinking water. Imp lications: We describe an in vivo model to study potential interference of dietary compounds, such as flavonoids, with tamoxifen, which could lead to reduced efficacy of adjuvant therapy. In our study, the tumor growth-inhibi ting effect of oral tamoxifen was reversed upon addition of tangeretin to t he diet. Our data argue against excessive consumption of tangeretin-added p roducts and supplements by patients with mammary cancer during tamoxifen tr eatment.