Sulforaphane promotes the removal of doxorubicin-induced senescent epithelial and breast cancer cells and activates AhR/CYP1A1-based adaptive response in vitro.

Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, is characterized by antioxidant, anti-inflammatory, and anticancer properties by activating NRF2 pathway, suppressing NFκB pathway, and promoting apoptotic cell death signals and epigenetic changes, respectively. However, SFN-based action against drug-induced senescent cells has never been addressed. In the present study, three breast cancer cell lines with different receptor status, namely triple negative BT-549 and HCC38, and MDA-MB-361 (ER-positive, HER2-positive) along with normal epithelial MCF-10F cells were subjected to 5 μM SFN treatment at both proliferating and non-proliferating (doxorubicin-induced senescence) state. BT-549 proliferating cells were more prone to SFN stimulation than normal ones that was accompanied by oxidative stress-based apoptosis. In contrast, SFN was active in a similar manner against both drug-induced senescent normal and breast cancer cells that resulted in apoptosis-mediated elimination of non-proliferating cells. SFN also stimulated adaptive responses in doxorubicin-induced senescent cells as judged by the activation of aryl hydrocarbon receptor (AhR)/cytochrome P450 1A1 (CYP1A1) pathway and upregulation of heat shock protein 90 (HSP90). In silico analysis with molecular docking also predicted SFN interactions with selected proteins involved in drug detoxification and cell death that warrants further investigation. We postulate that SFN may have senotherapeutic potential, especially against apoptosis resistant chemotherapy-induced senescent normal and breast cancer cells.