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    Ibuprofen and nimesulide derivatives selectively induce apoptosis in HER2-positive breast cancer via inhibition of the PLA₂–COX-2–NF-κB pathway
    (Springer Nature Link, 2026) Çakırlı, Egemen; Bedir, İpek; Biliz, Yağmur; Yılmaz, Özgür; Küçükgüzel, Şükriye Güniz; Telci, Dilek
    Background Chronic inflammation contributes to breast cancer development through the phospholipase A₂ (PLA₂)–cyclo oxygenase-2 (COX-2)–nuclear factor κB (NF-κB) 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 can cer, 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 PLA₂–COX-2–NF-κB 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 fluo rescence methods. Gene expression of PLA2G2A and PTGS2 was quantified by qRT-PCR, and NF-κB 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 G₀/G₁ arrest, caspase-3/7 activation, ROS reduction, and increased late apoptosis. Downregula tion of PLA2G2A and PTGS2 expression and inhibition of NF-κB translocation confirmed disruption of the PLA₂–COX-2– NF-κB 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 PLA₂–COX-2–NF-κB pathway and promoting apoptotic cell death.
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    Organotin-catalyzed synthesis, characterization, anticancer and antioxidant activities, and molecular modeling studies of nimesulide ureas as potential metap (type II) inhibitors
    (American Chemical Society, 2026) Biliz, Yağmur; Yılmaz, Özgür; Kuloğlu, Elif; Bedir, İpek; Çakırlı, Egemen; Arslan, Şevval; Telci, Dilek; Çevik, Özge; Yelekçi, Kemal; Koza, Gani; Küçükgüzel, Güniz
    In this study, a new series of nimesulide-derived ureas (3a−j) was designed and synthesized to investigate structural modifications of nimesulide and to evaluate their biological activity. The compounds were obtained in high yields (68−88%) under organotin-catalyzed conditions, and their structures were unequivocally established using comprehensive spectroscopic techniques, including 1 H NMR, 13C NMR, FTIR, and HRMS. Following structural confirmation, the antioxidant properties of the synthesized derivatives were evaluated using the 2,2-diphenyl-1- picrylhydrazyl (DPPH) radical scavenging assay, where compounds 3e, 3f, and 3i displayed notable radical-quenching activity. The nimesulide derivative 3i exhibited notable cytotoxicity across multiple breast cancer models, including the triple-negative MDAMB-231 and 4T1 cell lines, as well as the luminal MCF-7 subtype. Consistent with its enhanced potency, 3i triggered a robust shift from cell viability to programmed cell death, characterized predominantly by a dramatic accumulation of late-apoptotic populations following 72 h of treatment. This apoptotic signature was especially pronounced in Triple-Negative Breast Cancer (TNBC) cells, in which viable cell fractions were nearly eliminated. These findings suggest that structural modification of the nimesulide derivative can substantially improve its in vitro anticancer efficacy. Taken together, the observed cytotoxic and apoptosis-inducing effects suggest that compound 3i may represent a potential NSAID-based anticancer candidate. In line with its pronounced cytotoxic and proapoptotic profile, compound 3i also demonstrated strong inhibition of the MetAP2 enzyme, further reinforcing its potential as a multifunctional nimesulide-based anticancer agent. To obtain insight into the binding pose and binding energy of all synthesized compounds (3a−j) were docked into the active site of the MetAP2 enzyme. The computational inhibition constant values were correlated with the experimental values. To test the dynamic behavior of MetAP2-inhibitor complexes, a molecular dynamics (MD) simulation was also carried out for a 200 ns duration. MD revealed that the drugs bind to the active site of the MetAP2 enzyme, as indicated by stable RMSD and RMSF plots. In conclusion, in silico results and in vitro studies suggest that the nimesulide derivatives may be novel, potential NSAID-based anticancer drug candidates for treating breast, prostate, gastric, and glioblastoma.