Autors: Bracke ME, Depypere HT, Boterberg T, Van Marck VL, Vennekens KM, Vanluchene E, Nuytinck M, Serreyn R and Mareel MM

Research Institute: Department of Radiotherapy, Nuclear Medicine and Experimental Cancerology, University Hospital, Gent (Belgium)

Publication: Journal of the National Cancer Institute. 1999 February 17;91(4):354-9

The citrus flavonoid tamoxifen is an anti-cancer drug that increases the survival of breast cancer patients. Tomaxifen resistance is a problem with certain patients and can be caused by insensitivity of cancer cells, altered drug metabolism or interference of other chemicals. Some flavonoids can interfere with tamoxifen treatment because of their direct estrogenic activity or their acceleration of tamoxifen breakdown in the liver. Previous in-vitro studies indicate that the flavonoid tangeretin suppresses tumour growth and invasion of human breast cancer cells and activities cell-to-cell adhesion, in a similar way as tamoxifen. The aim of this study was to investigate the combined treatment with tamoxifen and tangeretin on human breast cancer cells, which were grown in the skin of mice.

Treatment of the mice with tamoxifen alone resulted in an expected inhibition of tumor growth. However, the addition of tangeretin to the drinking water neutralized the inhibitory effect of tamoxifen en resulted in a shorter survival time. A similar test in vitro was not able to demonstrate this neutralizing effect of tangeretin. To the contrary, the combined treatment of tangeretin and tamoxifen showed an amplified growth inhibition.

The researchers tried to determine the exact mechanism of the tangeretin effect. Many flavonoids are known to interfere with the gastrointestinal absorption and to induce the production of drug metabolizing enzymes. They found that tangeretin does not influence the metabolism of tamoxifen because tamoxifen concentration in tissues of liver, tumours, fat and kidneys was not influenced by the intake of the flavonoid. They found that tangeretin inhibited the cytolysis of breast cancer cells by LAK cells (lymphokine-activated killer cell) and explained the tangeretin effect by its selective toxicity to the LAK cells.

The study concluded that oral intake of tangeretin by mice reduces the tumor-suppressing effects of tamoxifen because it reduces the number of natural killer cells, which play a major role in the rejection of tumours. However, the quantity of tangeretin used in this mice experiment was high (human equivalent of 280 mg per day) and cannot be ingested by the consumption of normal quantities of citrus juices. The researchers stressed that the consumption of citrus products has many health benefits, even to cancer patients and that it should not be concluded from this experiment that tangeretin is carcinogenic. They advised against the consumption of dietary supplements containing high levels of citrus flavonoids.