Abstract
Women diagnosed with breast cancer frequently seek complementary and alternative (CAM) treatment options that can help to cope with their disease and the side effects of conventional cancer therapy. Especially in Europe, breast cancer patients use herbal products containing mistletoe (Viscum album L.). The oldest and one of the most prescribed conventional drugs for the treatment of estrogen receptor positive breast cancer is tamoxifen. Aside from positive clinical experience with the combination of tamoxifen and mistletoe, little is known about possible herb-drug interactions (HDIs) between the two products. In the present in vitro study, we investigated the effect of standardized commercial mistletoe preparations on the activity of endoxifen, the major active metabolite of tamoxifen. The estrogen receptor positive human breast carcinoma cell line MCF-7 was treated with (E/Z)-endoxifen hydrochloride in the presence and absence of a defined estradiol concentration. Each concentration of the drug was combined with fermented Viscum album L. extracts (VAE) at clinically relevant doses, and proliferation, apoptosis and cell cycle were analyzed. In parallel, possible inhibition of CYP3A4/5 and CYP2D6 was investigated using 50-donor mixed gender pooled human liver microsomes (HLMs). VAE did not inhibit endoxifen induced cytostasis and cytotoxicity. At higher concentrations, VAE showed an additive inhibitory effect. VAE preparations did not cause inhibition of CYP3A4/5 and CYP2D6 catalyzed tamoxifen metabolism. The in vitro results suggest that mistletoe preparations can be used in combination with tamoxifen without the risk of HDIs.
Highlights
Women diagnosed with breast cancer frequently seek complementary and alternative (CAM) treatment options that can help to cope with their disease and the side effects of conventional cancer therapy
Proliferation Given that estradiol has a mitogenic effect on hormone receptor positive tumor cells and may interfere with the effects of the investigated drugs, we performed the experiments in both estrogen-depleted conditions and in the presence of a defined estradiol concentration
In cells cultured in the presence or absence of estradiol, proliferation was significantly inhibited by VAE from host tree Malus domestic (VAEM) concentrations ≥10 μg/mL (p < 0.05). 100 μg/mL VAEM reduced the proliferation of cells cultured in presence of estradiol to 20% and in cells cultured without estradiol to 15% (p < 0.001) (Fig. 1a)
Summary
Women diagnosed with breast cancer frequently seek complementary and alternative (CAM) treatment options that can help to cope with their disease and the side effects of conventional cancer therapy. The oldest and one of the most prescribed conventional drugs for the treatment of estrogen receptor positive breast cancer is tamoxifen. Aside from positive clinical experience with the combination of tamoxifen and mistletoe, little is known about possible herb-drug interactions (HDIs) between the two products. In the present in vitro study, we investigated the effect of standardized commercial mistletoe preparations on the activity of endoxifen, the major active metabolite of tamoxifen. Tamoxifen is a prodrug with a relatively low affinity for estrogen receptors. Endoxifen competes with estrogen and binds to ERs with an almost 100-fold higher affinity than tamoxifen [5]. It shows proand anti-estrogenic activity by its binding to ERα and/or
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