The mycotoxin zearalenone and its metabolite α-zearalenol impair anticancer activity of doxorubicin in estrogen receptor-positive breast cancer cells

Our environment, especially our diet, exposes us to numerous bioactive compounds that have the potential to interact with anticancer therapies. Although understanding these exposome-drug interactions is crucial for optimizing anticancer therapy, limited knowledge exists on the interference of contaminants, especially mycotoxins, with anticancer drugs. One of the most prevalent mycotoxins in food and feed is zearalenone (ZEN), which demonstrated estrogenic activity that is even stronger in its metabolite α-zearalenol (α-ZEL). Consequently, in this study, we investigated whether these mycoestrogens affect estrogen-dependent breast cancer therapy with doxorubicin, a standard treatment option. The effects of mycoestrogens on doxorubicin were investigated in MCF7 estrogen receptor-positive breast cancer cells. Cell viability assays revealed that both ZEN (between 1 and 10 µM) and α-ZEL (>0.01 µM) reduced the anticancer activity of doxorubicin. This decrease in doxorubicin activity by α-ZEL, and to a lesser degree ZEN, was due to a decrease in cell death (up to 30 % reduction of annexin V signal by both, 50 % more protein expression of the apoptosis-related proteins B-cell lymphoma 2 and 25 % less Bcl-2-associated X protein by 0.1 µM α-ZEL) and stimulation of the cell cycle progression (up to 6 % more cells in S phase and 5 % less in G2/M phase, and changes in protein expression of cell cycle-related proteins cyclin D1, p16, p21 and p53 by α-ZEL). Application of an estrogen receptor α inhibitor linked the ability of α-ZEL to interfere with cell viability and apoptosis to its activation of the receptor. Consequently, contamination of our diet with mycoestrogens might not only impact cancer growth but also impair the effectiveness of anticancer therapy in patients with estrogen-dependent cancer, warranting greater attention in its management.