Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer.
BACKGROUND
Tamoxifen and the citrus flavonoid tangeretin exhibit similar inhibitory effects on the growth and invasive properties of human mammary cancer cells in vitro; furthermore, the two agents have displayed additive effects 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 substances 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 solvent.


CONCLUSIONS
Oral treatment of mice with tamoxifen resulted in a statistically significant inhibition of tumor growth compared with solvent treatment (two-sided P = .001). Treatment with tangeretin did not inhibit tumor growth, and addition of this compound to drinking water with tamoxifen completely neutralized tamoxifen's inhibitory effect. The median survival time of tumor-bearing mice treated with tamoxifen plus tangeretin was 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) inhibited the cytolytic effect of murine natural killer cells on MCF-7/6 cells in vitro, which may explain why tamoxifen-induced inhibition of tumor growth in mice is abolished when tangeretin is present in drinking water.


CONCLUSIONS
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-inhibiting effect of oral tamoxifen was reversed upon addition of tangeretin to the diet. Our data argue against excessive consumption of tangeretin-added products and supplements by patients with mammary cancer during tamoxifen treatment.
Department of Radiotherapy, Nuclear Medicine and Experimental Cancerology, University Hospital, Gent, Belgium. marc1.bracke@rug.ac.be
M E
ME
Bracke
H T
HT
Depypere
T
T
Boterberg
V L
VL
Van Marck
K M
KM
Vennekens
E
E
Vanluchene
M
M
Nuytinck
R
R
Serreyn
M M
MM
Mareel
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D005260:Female; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D007694:Killer Cells, Natural / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D013629:Tamoxifen / Q000097:blood / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D047309:Flavones; D005419:Flavonoids; D010936:Plant Extracts; D013629:Tamoxifen; C059006:tangeretin