Browsing by Author "Bedir, Ipek"

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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, 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.
Citation - WoS: 2
Citation - Scopus: 1
Synthesis and Investigation of Cytotoxic Effects of Compounds Derived From Flurbiprofen
(Elsevier, 2023) Gokoglan, Ecem; Dere, Damla; Bedir, Ipek; Yelekci, Kemal; Telci, Dilek; Kucukguzel, S. Guniz
New flurbiprofen derivatives containing 1,2,4-triazoline-5-thione (4) and thioethers (5a-r) were synthesized in this study. The structures of synthesized compounds were characterized by spectral methods (FT-IR, 1H NMR, 13C NMR) and 19F NMR (only compound 5l), besides elemental analysis. In addition, molecular binding of these compounds to the human methionine aminopeptidase 2 enzyme was performed using AutoDock 4.2, the software product of the research, computationally. All synthesized compounds were evaluated for cytotoxic effect against MDA-MB231 triple-negative breast cancer cell line by using WST-1 Cell Viability and Proliferation assay. Doxorubicin is in the anthracycline class and is an antineoplastic agent. It is used to provide regression in common neoplastic conditions such as breast carcinoma. Due to the cardiovascular side effects of doxorubicin, a combination study was conducted with the (& PLUSMN;)(R,S)-3-{1-[2-fluoro-(1,1 & PRIME;-biphenyl)-4-yl]ethyl}-4-methyl-5-{[2(trifluoromethyl)benzyl]thio}-4H-1,2,4-triazole (5l) with promising cytotoxic effects. As a result of the combination, it was shown as 7% MDA-MB231 cell viability. Therefore, based on the evaluations, a better cytotoxic effect was achieved with the 5l combination depending on the low dose of doxorubicin.