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    DNA damage response inhibitors in cholangiocarcinoma: current progress and perspectives
    (PubMed, 2022) Anichini, Giulia; Ulukaya, Engin; Marra, Fabio; Raggi, Chiara; Geyik, Öykü Gönül
    Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and its incidence is dramatically increasing. The lack of understanding of the biology of this tumor has slowed down the identification of novel targets and the development of effective treatments. Based on next generation sequencing profiling, alterations in DNA damage response (DDR)-related genes are paving the way for DDR-targeting strategies in CCA. Based on the notion of synthetic lethality, several DDR-inhibitors (DDRi) have been developed with the aim of accumulating enough DNA damage to induce cell death in tumor cells. Observing that DDRi alone could be insufficient for clinical use in CCA patients, the combination of DNA-damaging regimens with targeted approaches has started to be considered, as evidenced by many emerging clinical trials. Hence, novel therapeutic strategies combining DDRi with patient-specific targeted drugs could be the next level for treating cholangiocarcinoma.
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    ?-hydroxybutyrate Does Not Influence Viability and Clonogenicity of A549 Lung Cancer Cells
    (2023) Malcanlı, Senanur; Geyik, Öykü Gönül; Özkaya, Ali Burak
    Background/Purpose: The metabolic shift from catabolism of carbohydrates to lipids results in production of ketone bodies leading to a state called ketosis. Ketosis via ketone supplement or ketogenic diet has been proposed as a non-toxic therapeutic option for a broad range of malignancies. Although the clinical impact of ketogenic diet is well-documented, the effect of ketone bodies on cancer cell biology is not clear for some cancers including non-small-cell lung cancer (NSCLC). In this study, we aimed to demonstrate the effects of the most prominent ketone body, ?-hydroxybutyrate, on a NSCLC cell line, A549. Methods: A549 cell line was utilized as the in vitro model in this study. The effects of different ?-hydroxybutyrate concentrations on cell viability were measured via sulphorodamine-B (SRB) viability assay. Long term effects of ketosis were evaluated via colony formation assay. Finally, the effect of ?-hydroxybutyrate on cell migration was determined via scratch assay. Results: Our results suggest that introduction of ?-hydroxybutyrate in physiologically relevant concentrations into the cell culture media does not influence cell viability, clonogenicity or migration. Conclusion: ?-hydroxybutyrate has been previously demonstrated to induce, inhibit or does not influence the viability of different cell lines but there is no report regarding its effects on NSCLC cells. Here we report that physiologically relevant concentrations of ?-hydroxybutyrate have no effect on viability, clonogenicity and migration of A549 cells.
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    Prolonged Β-Hydroxybutyrate-Mediated Ketosis Enhances Ponatinib Response of K562 Chronic Myeloid Leukaemia Cells
    (Dokuz Eylul University, 31 Ocak 2025) Özkaya, Ali Burak; Malcanlı, Senanur; Geyik, Öykü Gönül
    Purpose: Ketosis is a metabolic state characterized by production of ketone bodies, including acetoacetate, β-hydroxybutyrate (BHB), and acetone, in response to reduced blood glucose levels. BHB stands out as the principal ketone body in nutritional ketosis which has diverse therapeutic implications for metabolic, nondegenerative and neoplastic disorders. In current study we investigated the impact of ketosis on chronic myeloid leukaemia (CML) cell viability and drug response. Materials and Methods: We investigated the impact of BHB-mediated ketosis on the viability of K562 cells, an in vitro model of CML, and explored the influence of BHB on the sensitivity of these cells to ponatinib, a multi-targeted tyrosine kinase inhibitor used in CML treatment. We used MTT assay to measure cell viability and Hoechst/PI assay to measure cell death. Results: Our findings reveal that BHB concentrations ranging from 1 mM to 5 mM, which fall within the physiological range of ketosis, elicit a minimal yet concentration-dependent reduction in cell viability. We also observed that while a 24-hour pre-treatment with BHB did not enhance the response of K562 cells to ponatinib, prolonged ketosis (4 days) improved response of cells to the drug by decreasing final cell viability from 25.15% to 13.12%. The primary mode of viability inhibition by ponatinib was cell death which was further intensified by exposure to prolonged ketosis. Conclusion: Ketosis induced by ketogenic diet of ketone body supplementation is considered as safe and effective adjuvant cancer therapy options and here, we report its potential effectiveness in the context of CML.