WoS İndeksli Yayınlar Koleksiyonu

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

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Author: search.filters.author.Atlihan, IremSubject: search.filters.subject.Breast Cancer

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  • 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.
  • Article
    Citation - WoS: 7
    Effect of Flurbiprofen Derivative (sgk597) on Cell Proliferation and Apoptosis of Breast Cancer Cell Lines
    (Istanbul Univ, Fac Pharmacy, 2022) Atlihan, Irem; Sevinc, Sevgi Kocyigit; Orun, Oya; Yilmaz, Ozgur; Kucukguzel, S. Guniz; Tiber, Pinar Mega
    Background and Aims: The incidence of breast cancer is increasing day by day, especially in women. The search for new drugs against breast cancer is the focus of attention in research. Breast cancer and prostate cancer have remarkable biological similarities. Therefore, the 4-(4-chlorophenyl)-3-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-5-((4-fluorobenzyl)thio)-4H-1,2,4-triazole (SGK597) compound that is suppressing cell proliferation in prostate cancer, was studied in MCF-7 breast can-cer and MCF-10A mammary epithelial cell lines. Methods: The WST-8 method was used to determine cell viability and cytotoxicity of SGK597 in MCF-7 and MCF10-A cell lines. The JC-1 test was applied to determine changes in mitochondrial membrane potential. The protein expression levels of Bax, Bcl-2, and c-PARP associated with apoptosis were determined using Western blot analysis.Results: After 24 and 48 hours of incubation of SGK597, the IC50 values were 28.74 pM and 17.28 pM for MCF-7; 65.9 pM and 50.5 pM for MCF-10A, respectively. Mitochondrial membrane potential showed a tendency toward depolarization in MCF-7 cells as a result of increasing concentration of SGK597, while the same tendency was not seen for MCF-10A. As a result of western blot experiments, no increase in the Bax/Bcl-2 ratio and c-PARP expression level was observed, indicating no apoptosis.Conclusion: It was observed that the compound SGK597 suppressed MCF-7 cell proliferation. These results indicate that SGK597 may be a candidate compound for use as an anticancer agent. Keywords: Apoptosis, breast cancer, flurbiprofen, thioether, triazole