Browsing by Author "Pulat, CC"

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    Liquidambar orientalisMill. gum extract induces autophagy via PI3K/Akt/mTOR signaling pathway in prostate cancer cells
    Atmaca, H; Pulat, CC; Cittan, M
    Liquidambar orientalisMill . (LOM), is an endemic species having a local distribution in the southwestern coastal district of Turkey. Styrax liquidus gum (SLG), is a gum-like resinous which exudates in response to injury of the trunk of LOM. The aim of the study was to investigate the cytotoxic effects and the molecular mechanisms of the ethanolic SLG extract in human prostate cancer cells. GC-MS analysis was performed to identify the volatile compound composition. Cytotoxicity was determined by XTT analysis. Apoptosis and necrosis were evaluated via ELISA assay. Autophagic cell death was detected via monodansylcadaverine (MDC) staining and by measuring the levels of LC3I and LC3II. The protein levels of p-PI3K, p-Akt and p-mTOR were evaluated by western blot analysis. In the present study, it is shown that the SLG extract containing a considerable amount of ravidomycin derivate induced autophagic cell death in prostate cancer cells via inhibiting the PI3K/Akt/mTOR pathway.
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    Evaluation of Novel Spiro-pyrrolopyridazine Derivatives as Anticancer Compounds: In Vitro Selective Cytotoxicity, Induction of Apoptosis, EGFR Inhibitory Activity, and Molecular Docking Analysis
    Atmaca, H; Ilhan, S; Pulat, CC; Dundar, BA; Zora, M
    Cancer, characterized by uncontrolled cell proliferation, remains a global health challenge. Despite advancements in cancer treatment, drug resistance and adverse effects on normal cells remain challenging. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase protein, is crucial in controlling cell proliferation and is implicated in various cancers. Here, the cytotoxic and apoptotic potential of 21 newly synthesized spiro-pyrrolopyridazine (SPP) derivatives was investigated on breast (MCF-7), lung (H69AR), and prostate (PC-3) cancer cells. XTT assay was used for cytotoxicity assessment. Flow cytometry and western blot (WB) analyses were conducted for apoptosis detection. Additionally, the EGFR inhibitory potential of these derivatives was evaluated via a homogeneous time-resolved fluorescence (HTRF) assay, and WB and molecular docking studies were conducted to analyze the binding affinities of SPP10 with EGFR. SPPs, especially SPP10, exhibit significant cytotoxicity across MCF-7, H69AR, and PC-3 cancer cells with IC50 values of 2.31 +/- 0.3, 3.16 +/- 0.8, and 4.2 +/- 0.2 mu M, respectively. Notably, SPP10 demonstrates selective cytotoxicity against cancer cells with a low impact on nontumorigenic cells (IC50 value: 26.8 +/- 0.4 mu M). Flow cytometric analysis demonstrated the potent induction of apoptotic cell death by SPP10 in all of the tested cancer cells. Western blot analysis revealed the involvement of key apoptotic proteins, with SPP10 notably inhibiting antiapoptotic Bcl-2 while inducing pro-apoptotic Bax and cytochrome c. SPP10 exhibited significant EGFR kinase inhibitory activity, surpassing the efficacy of the reference drug erlotinib. Molecular docking studies support these findings, revealing strong binding affinities of SPP10 with both wild-type and mutated EGFR. The study underscores the significance of heterocyclic compounds, particularly spiro-class heterocyclic molecules, in advancing cancer research. Overall, SPP10 emerges as a promising candidate for further investigations in cancer treatment, combining potent cytotoxicity, apoptotic induction, and targeted EGFR inhibition.
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    Novel benzimidazole derivatives: Synthesis, in vitro cytotoxicity, apoptosis and cell cycle studies
    Atmaca, H; Ilhan, S; Batir, MB; Pulat, CC; Güner, A; Bektas, H
    The aim of the study was to synthesize a new series of benzimidazole derivatives and to investigate the underlying molecular mechanisms of the potential cell cycle inhibition and apoptotic effects against a panel of selected human cancer cell lines along with HEK-293 human embryonic kidney cells. MTT assay was used to evaluate cytotoxic effects. MuseT Cell Analyzer was used to assess cell cycle progression. Annexin-V/PI staining assay was used for detecting apoptosis. All the synthesized compounds showed a significant cytotoxic effect against cancer cells with the IC50 values between 9.2 and 166.1 mu g/mL. Among the tested derivatives, compound 5 showed significant cytotoxic activity against MCF-7, DU-145 and H69AR cancer cells with the IC50 values of 17.8 +/- 0.24, 10.2 +/- 1.4 and 49.9 +/- 0.22 mu g/mL respectively. The compounds 5 was also tested on HEK-293 human embryonic kidney cells and found to be safer with lesser cytotoxicity. The results revealed that compound 5 significantly increased cell population in the G2/M-phase which is modulated by a p53 independent mechanism. Compound 5 caused an increase in the percentage of late apoptotic cells in all tested cancer cells in a concentration-dependent manner. Among all synthesized derivatives, compound 5 the bromo-derivative, showed the highest cytotoxic potential, induced G2/M cell cycle arrest and apoptotic cell death in genotypically different human cancer cells. These results suggest that compound 5 might be a promising agent for cancer therapy and further structural modifications of benzimidazole derivatives may create promising anticancer agents.