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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\u2082\u2013COX-2\u2013NF-\u03baB axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>PLA2G2A<\/jats:italic>\n                      and\n                      <jats:italic>PTGS2<\/jats:italic>\n                      was quantified by qRT-PCR, and NF-\u03baB translocation was analyzed by immunocytochemistry. Two ibuprofen triazole derivative (\n                      <jats:bold>D1<\/jats:bold>\n                      ) and ibuprofen thioether derivative (\n                      <jats:bold>D7<\/jats:bold>\n                      ) and one nimesulide derivative (\n                      <jats:bold>D8<\/jats:bold>\n                      ) significantly reduced cell viability in a dose-dependent manner without affecting normal cells. These derivatives induced G\u2080\/G\u2081 arrest, caspase-3\/7 activation, ROS reduction, and increased late apoptosis. Downregulation of\n                      <jats:italic>PLA2G2A<\/jats:italic>\n                      and\n                      <jats:italic>PTGS2<\/jats:italic>\n                      expression and inhibition of NF-\u03baB translocation confirmed disruption of the PLA\u2082\u2013COX-2\u2013NF-\u03baB cascade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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\u2082\u2013COX-2\u2013NF-\u03baB pathway and promoting apoptotic cell death.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11033-026-11835-6","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:02:14Z","timestamp":1777028534000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ibuprofen and nimesulide derivatives selectively induce apoptosis in HER2-positive breast cancer via inhibition of the PLA\u2082\u2013COX-2\u2013NF-\u03baB pathway"],"prefix":"10.1007","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8506-2723","authenticated-orcid":false,"given":"Egemen","family":"\u00c7ak\u0131rl\u0131","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5664-1566","authenticated-orcid":false,"given":"\u0130pek","family":"Bedir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4181-7290","authenticated-orcid":false,"given":"Ya\u011fmur","family":"Biliz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3892-2775","authenticated-orcid":false,"given":"\u00d6zg\u00fcr","family":"Y\u0131lmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9405-8905","authenticated-orcid":false,"given":"\u015e. 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