Ibuprofen and Nimesulide Derivatives Selectively Induce Apoptosis in HER2-Positive Breast Cancer via Inhibition of the PLA2-COX-2-NF-κB Pathway

Abstract

Background Chronic inflammation contributes to breast cancer development through the phospholipase A(2) (PLA(2))-cyclooxygenase-2 (COX-2)-nuclear factor kappa B (NF-kappa B) cascade, which regulates prostaglandin synthesis, oxidative stress, and transcription of pro-inflammatory and anti-apoptotic genes. This pathway is particularly active in HER2-positive breast cancer, promoting proliferation, invasion, and resistance to apoptosis. Non-steroidal anti-inflammatory drugs such as ibuprofen and nimesulide target COX enzymes and have shown potential in suppressing inflammation-driven tumorigenesis. In this study, we evaluated the anticancer and anti-inflammatory activity of newly synthesized, structurally modified ibuprofen and nimesulide derivatives designed to modulate PLA(2)-COX-2-NF-kappa B axis. Methods and Results Cytotoxicity was assessed in HER2-positive breast cancer cells (AU565 and SKBR3) and compared with normal dermal fibroblasts (HDF) and breast epithelial cells (MCF-12A), using WST-1 assays. Apoptosis, cell cycle distribution, caspase-3/7 activation, and ROS generation were analyzed by imaging-based assays, flow cytometry, and fluorescence methods. Gene expression of PLA2G2A and PTGS2 was quantified by qRT-PCR, and NF-kappa B translocation was analyzed by immunocytochemistry. Two ibuprofen triazole derivative (D1) and ibuprofen thioether derivative (D7) and one nimesulide derivative (D8) significantly reduced cell viability in a dose-dependent manner without affecting normal cells. These derivatives induced G(0)/G(1) arrest, caspase-3/7 activation, ROS reduction, and increased late apoptosis. Downregulation of PLA2G2A and PTGS2 expression and inhibition of NF-kappa B translocation confirmed disruption of the PLA(2)-COX-2-NF-kappa B cascade. Conclusion These findings demonstrate that structurally optimized ibuprofen and nimesulide derivatives exert dual anti-inflammatory and anticancer effects in HER2-positive breast cancer by suppressing PLA(2)-COX-2-NF-kappa B pathway and promoting apoptotic cell death.