Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells.

The NF-E2-related factor 2 transcription factor (Nrf2) orchestrates the basal and stress-inducible activation of a vast array of antioxidant genes. A high amount of reactive oxygen species (ROS) promotes carcinogenesis in cells with defective redox-sensitive signaling factors such as Nrf2. In breast cancer (BC), emerging evidence indicates that increased Nrf2 activity enhances cell metastatic potential. An interconnection between peroxisome proliferator-activated receptors (PPARs) and Nrf2 pathways in cancer has been shown. In this light, newly synthesized PPARα antagonists, namely IB42, IB44, and IB66, were tested in the BC cell line MCF7 in parallel with GW6471 as the reference compound. Our results show that the most promising compound of this phenylsulfonimide series (IB66) is able to decrease MCF7 proliferation by blocking cells at the G2/M checkpoint. The underlying mechanism has been investigated, disclosing a caspase 3/Akt-dependent apoptotic/pyroptotic pathway induced by the increased generation of oxidative stress. Moreover, the involvement of Nrf2 and COX2 in IB66-treated MCF7 cell response has been highlighted. The reported data lay the groundwork for the development of alternative targeted therapy involving the Nrf2/PPARα molecular axis, able to overcome BC cell chemoresistance and cause better clinical outcomes, promoting other forms of programmed cell death, such as pyroptosis.