Evaluation of anticancer activity of urotropine surface modified iron oxide nanoparticles using a panel of forty breast cancer cell lines.

Urotropine, an antibacterial agent to treat urinary tract bacterial infections, can be also considered as a repurposed drug with formaldehyde-mediated anticancer activity. Recently, we have synthesized urotropine surface modified iron oxide nanoparticles (URO@Fe3O4 NPs) with improved colloidal stability and limited cytotoxicity against human fibroblasts. In the present study, we have investigated URO@Fe3O4 NP-mediated responses in a panel of forty phenotypically different breast cancer cell lines along with three non-cancerous corresponding cell lines. URO@Fe3O4 NPs promoted oxidative stress and FOXO3a-based antioxidant response in breast cancer cells. Elevated levels of GPX4 and decreased levels of ACSL4 in URO@Fe3O4 NP-treated breast cancer cells protected against ferroptotic cell death. On the contrary, URO@Fe3O4 NPs impaired the activity of PERK, a part of unfolded protein response (UPR), especially when the glucose supply was limited, that was accompanied by genetic instability, and apoptotic and/or necrotic cell death in breast cancer cells. In conclusion, this is the first comprehensive analysis of anticancer effects of URO@Fe3O4 NPs against a panel of forty breast cancer cell lines with different receptor status and in glucose replete and deplete conditions. We suggest that presented results might be helpful for designing new nano-based anti-breast cancer strategies.