WoS İndeksli Yayınlar Koleksiyonu

Permanent URI for this collectionhttps://hdl.handle.net/20.500.14627/6

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  • Article
    Ibuprofen and Nimesulide Derivatives Selectively Induce Apoptosis in HER2-Positive Breast Cancer via Inhibition of the PLA2-COX-2-NF-κB Pathway
    (Springer, 2026) Bedir, Ipek; Cakirli, Egemen; Kucukguzel, S. Guniz; Yilmaz, Ozgur; Biliz, Yagmur; Telci, Dilek
    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.
  • Article
    Investigation of Novel Nimesulide Derivatives Against Breast Cancer
    (Academic Press Inc Elsevier Science, 2025) Birgul, Kaan; Atlihan, Irem; Dere, Damla; Yelekci, Kemal; Tiber, Pinar Mega; Orun, Oya; Kucukguzel, S. Guniz
    This study focused on the synthesis of novel nimesulide semicarbazone derivatives and the evaluation of their cytotoxic potential against luminal-A (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines. Additionally, their effects on mitochondrial membrane potential (MMP), apoptosis, and mitogen-activated protein kinase (MAPK) pathway modulation were investigated. Breast cancer remains the most prevalent malignancy among women, with luminal-A and triple-negative subtypes posing significant therapeutic challenges due to drug resistance and the lack of effective targeted treatments. The MAPK pathway plays a crucial role in breast cancer progression, making its inhibition a promising therapeutic approach. Non-steroidal anti-inflammatory drugs (NSAIDs), particularly nimesulide, have demonstrated anticancer potential beyond their well-established anti-inflammatory properties. Accordingly, the semicarbazone moiety was incorporated into the molecular scaffold to enhance the antiproliferative efficacy of nimesulide derivatives, as it has been reported to exhibit cytotoxic and apoptosis-inducing effects across various cancer cell lines. A series of nimesulide semicarbazone derivatives (5a-m) were synthesized through multi-step reactions and characterized using elemental analysis, FT-IR, 1H NMR, 13C NMR and Mass spectroscopy (5e). In silico studies were performed to predict their binding affinities to MAPK12. The cytotoxic effects of the synthesized compounds were assessed by determining IC50 values in MCF-7 and MDA-MB-231 cell lines (CCK8 test). Compounds exhibiting strong cytotoxic activity were further examined for their impact on MMP depolarization (JC-1 assay), apoptosis induction (Annexin V-FITC/PI staining), and MAPK pathway modulation (Western blotting of p-ERK and ERK protein). Molecular docking results indicated that the synthesized compounds exhibited favorable interactions with MAPK12, with compound 5e showing one of the highest binding affinity (-9.29 kcal/mol, Ki = 0.154 mu M). Cytotoxicity assays revealed that compound 5e had the lowest IC50 values (11.77 +/- 0.26 mu M in MCF-7; 20.72 +/- 0.25 mu M in MDA-MB-231), demonstrating significantly higher cytotoxicity than nimesulide. JC-1 assays confirmed that compound 5e induced MMP depolarization at higher concentrations, suggesting apoptosis activation. Flow cytometry analysis further validated a substantial increase in apoptotic cell populations following treatment with compound 5e. Western blot results showed a dose-dependent decrease in p-ERK levels in both MCF-7 and MDA-MB-231 cells, confirming MAPK pathway inhibition. These findings support that nimesulide-based semicarbazones, particularly compound 5e, exhibit potent antiproliferative and pro-apoptotic activity via MAPK pathway modulation, offering a promising avenue for the development of targeted breast cancer therapies.