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

Abstract

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.

Modeling of senescence-related chemoresistance in ovarian cancer using data analysis and patient-derived organoids

“…PPAR encompasses three isoforms: PPARa, PPARb/d, and PPARg-a nuclear receptor family pivotal in regulating and transcribing target genes, energy metabolism, cellular dynamics, inflammation, and carcinogenesis (42,43). The interplay between the PPAR pathway and chemoresistance has garnered attention across diverse cancers, including diffuse large B-cell lymphoma (DLBCL) (44), breast cancer (45), hepatocellular carcinoma (HCC) (46), non-small cell lung cancer (NSCLC) (47), and OC (48). In addition, activation of the PPAR gamma signaling pathway can balance the release of inflammatory and anti-inflammatory cytokines, orchestrating a pre-malignant microenvironment that promotes cell senescence, and alleviating tumor burdens (49).…”

ROS induced pyroptosis in inflammatory disease and cancer

“…Currently, studies in tumors have indicated that elevated levels of ROS can induce pyroptosis, which is beneficial in combating cancer. For example, the Nrf2/PPARα molecular axis in breast cancer overcomes chemotherapy resistance and leads to better clinical outcomes by promoting pyroptosis ( 98 ). Rongjun Zhang et al.…”

Pyroptosis Modulators: New Insights of Gasdermins in Health and Disease

“…A recent study has shown that such a combination of inhibitors induces alterations in the tumor immune microenvironment associated with an increased cancer cell death via pyroptosis [ 103 ]. In this line, newly synthetized phenylsulfonimide PPAR⍺ antagonists induced apoptosis and pyroptosis of MCF7 breast cancer cells via Nrf2 activation and promotion of oxidative stress [ 104 ].…”