The thiocarbonyl analog of chrysin induces apoptosis and oxidative stress-mediated unfolded protein response in breast cancer cells.

Natural flavones such as chrysin and baicalein were characterized by a wide range of biological activities including, among others, antioxidant and anticancer action. Nevertheless, their use in biomedical applications is restricted due to limited bioavailability. In the present study, C4 thionation-based approach was considered to produce thiochrysin and thiobaicalein with improved anticancer activity. The thiocarbonyl analogs were tested against breast cancer cells with different receptor status (MCF-7 ER-positive, MDA-MB-231 TNBC, and SK-BR-3 HER2-positive) along with the corresponding normal cells MCF-10F. Thiochrysin, when used at the concentration of 1 μM, sensitized MCF-7 and SK-BR-3 cells to apoptotic cell death compared to the action of parent flavone chrysin that was associated with elevated production of superoxide. Thiochrysin-mediated oxidative stress in MCF-7 cells resulted in the activation of unfolded protein response (UPR) as judged by increased phosphorylated status of IRE1, elevated levels of ATF6 and ER-associated chaperone GRP78. Cytotoxic potential of thiochrysin was also documented using 3D breast cancer cell-based spheroid models. Thiochrysin was also active against doxorubicin-induced senescent and drug-resistant MCF-7 and SK-BR-3 cells. In contrast, anti-breast cancer action of thiobaicalein was less pronounced. In silico approaches such as molecular simulations and ADMET profiling were also used to predict thiochrysin action in in vivo situations. In conclusion, we postulate that C4 thionation may potentiate the anticancer action of selected flavones, here chrysin, based on oxidative stress-mediated apoptosis.