Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/395
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Article Toward the Design of New Α-Carboline Derivatives Against Anaplastic Lymphoma Kinase (Alk): A Comprehensive in Silico Approach(Wiley-VCH Verlag GmbH, 2025-11) Sari, Ceyhun; Akcok, IsmailAfter the first description of anaplastic lymphoma kinase (ALK) in an anaplastic large cell lymphoma cell line as a nucleophosmin (NPM) fusion partner, ALK and its various fusion partners have been implicated in numerous cancers such as non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), neuroblastoma, and rhabdomyosarcoma. In the last decade, several compounds targeting ALK have been developed and approved by the Food and Drug Administration (FDA). Despite the advances of generations of ALK inhibitors, a recent study highlighted that around half of the ALK-positive NSCLC patients will go through disease progression in response to first-line alectinib, which is a second-generation ALK inhibitor. In this study, we aimed to propose a novel alpha-carboline compound targeting the ALK tyrosine kinase domain to be used against various types of cancer in which ALK fusion proteins may be involved. In this regard, we designed more than 200 alpha-carboline derivatives and investigated their binding properties against ALK tyrosine kinase by using in silico protocols consisting of molecular docking studies, molecular dynamics simulations, MM/PBSA binding free energy calculation, and essential dynamics analysis. Considering the obtained results, we developed two promising candidates, compounds 208 & 209 with -9.05 and -9.80 binding energies, respectively, which demonstrated improved binding profiles over the course of a 300 ns simulation.Article Citation - WoS: 1Citation - Scopus: 2Tomatidine, a Steroidal Alkaloid, Synergizes With Cisplatin to Inhibit Cell Viability and Induce Cell Death Selectively on FLT3-ITD+ Acute Myeloid Leukemia Cells(Humana Press inc, 2024-07-11) Ayvaz, Havva Berre; Yenigul, Munevver; Akcok, Emel Basak Gencer; Gencer Akçok, Emel BaşakBackgroundAcute Myeloid Leukemia (AML) is a hematological cancer that frequently presents with a range of side effects and drug resistance during anticancer drug treatment. The current study aims to achieve increased efficacy by combining lower doses of cisplatin with increasing concentrations of tomatidine in AML cells to increase efficacy.MethodsAnti-proliferative effects of single and combination of cisplatin and tomatidine were assessed via MTT cell viability assay. The Annexin V/Propidium Iodide Double Staining method was used to measure the apoptotic effects of combined tomatidine and cisplatin treatment. Then, Western Blot analysis was performed to measure Poly (ADP-ribose) polymerase (PARP) and Caspase-3 protein expression levels.ResultsCisplatin treatment with lower concentrations displayed high cytotoxic effects on AML cells, compared with tomatidine. The combination of the Inhibitory Concentration (IC) 20 value of cisplatin and increasing doses of tomatidine exhibited a significant decrease in cell viability relative to single treatments. The combination index analysis revealed a mild synergistic effect of cisplatin IC20 and varying tomatidine doses. The apoptosis induced when cisplatin was combined with 500 mu M tomatidine by almost 20%, while the percentage of apoptosis in combination with 1 mM tomatidine was measured by 50% for both cell lines. The upregulation of proapoptotic cleaved-PARP (3.2 and 1.08-fold for THP-1 and MOLM-13, respectively) and downregulation in Caspase-3 (0.23 and 0.13-fold for THP-1 and MOLM-13, respectively) was detected.ConclusionsTogether, the study indicated that when tomatidine combined with cisplatin on AML cell lines, a combinatorial anti-proliferative and apoptotic effect is observed. The combination of cisplatin with tomatidine may be a promising approach.Book Part Sustainable Strategies for Cancer Phytomedicine: Balancing Efficacy and the Environment Responsibility(Springer Nature, 2025) Sari, Sibel; Saylan, DemetCancer is a complex disease, with approximately six million new cases reported annually. Despite the numerous treatment strategies employed worldwide, the severity of cancer continues to increase. Conventional cancer treatments, such as surgery, radiotherapy, and chemotherapy, are standard practices, but their clinical success is constrained by toxic side effects leading to damage to healthy tissues, unavoidable off-target effects, and significant cancer recurrence resulting from incomplete surgical removal. Therefore, interest in alternative therapies sourced primarily from natural products is increasing. The popularity of phytomedicine in cancer treatment approaches is increasing because of its efficacy, affordability, accessibility, and minimal adverse effects. Additionally, green chemistry approaches can be used to synthesize a wide array of anticancer drugs with various chemical structures, enhancing their therapeutic efficacy while minimizing or eliminating side effects and toxicity. The enhanced efficacy of cancer medicines made from plants is achieved via molecular innovations that support precise targeting. Various drug delivery systems that aim to reduce environmental pollution while reducing waste can be optimized for better results in therapy through nanotechnology. The delivery of effective cancer therapies while preserving the environment for generations to come is the objective of this approach, which includes green chemistry, sustainable production, and molecular developments. © 2025 Elsevier B.V., All rights reserved.Article Citation - WoS: 3Citation - Scopus: 4Rapamycin and Niacin Combination Induces Apoptosis and Cell Cycle Arrest Through Autophagy Activation on Acute Myeloid Leukemia Cells(Springer, 2024-12-23) Subay, Lale Beril; Akcok, Emel Basak Gencer; Akcok, Ismail; Gencer Akçok, Emel BaşakBackgroundAcute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by disorders in stem cell differentiation and excessive proliferation resulting in clonal expansion of dysfunctional cells called myeloid blasts. The combination of chemotherapeutic agents with natural product-based molecules is promising in the treatment of AML. In this study, we aim to investigate the anti-cancer effect of Rapamycin and Niacin combination on THP-1 and NB4 AML cell lines.Methods and ResultsThe anti-proliferative effects of Rapamycin and Niacin were determined by MTT cell viability assay in a dose- and time-dependent manner. The combination indexes were calculated by isobologram analysis. Furthermore, apoptosis was investigated by Annexin-V/Propidium Iodide(PI) double staining and cell cycle distribution was measured by PI staining. The expression levels of autophagy-related proteins were detected by western blotting. The combination of Rapamycin and Niacin synergistically decreased cell viability of AML cell lines. The combination treatment induced the apoptotic cell population of THP-1 and NB4 by 4.9-fold and 7.3-fold, respectively. In THP-1 cells, the cell cycle was arrested at the G2/M phase by 10% whereas the NB4 cells were accumulated at the G0/G1 phase. The combination treatment decreased Akt and p-Akt expression. Besides, the ATG7 expression was reduced by combination treatment on THP-1 cells. Similarly, the ATG5 level was downregulated in NB4 cells. The level of LC3B-II/LC3B-I, which is an indicator of autophagy flux, was upregulated in THP-1 and NB4 cells.ConclusionAlthough further studies are required, the combination of Rapamycin and Niacin combats cell proliferation by inducing cellular apoptosis, cell cycle arrest and autophagy activation.Book Part Citation - Scopus: 1Measurement of Autophagic Activity in Cancer Cells With Flow Cytometric Analysis Using Cyto-Id Staining(Humana Press Inc., 2024) Şansaçar, Merve; Gencer Akçok, Emel BaşakAutophagy is an evolutionarily conserved process providing the energy that cells need to survive, especially in stress situations, through catabolic processes. Considering the dual role of autophagy in cancer cells depending on the cellular context, it is crucial to comprehend the effect of drug candidates put forward to prevent cancer through the autophagy pathway. The CYTO-ID® Autophagy Detection Kit allows a rapid, specific and quantitative measurement of autophagic activity at the cellular level using a 488 nm-excitable green fluorescent detection reagent via flow cytometer. In this chapter, we present the CYTO-ID® Autophagy Detection method with a stepwise protocol to monitor the autophagy flux after the application of any compound to suspension cancer cell lines with flow cytometric analysis. © 2025 Elsevier B.V., All rights reserved.Article Citation - WoS: 13Citation - Scopus: 13Ethacrynic Acid and Cinnamic Acid Combination Exhibits Selective Anticancer Effects on K562 Chronic Myeloid Leukemia Cells(Springer, 2022-05-18) Yenigul, Munevver; Akcok, Ismail; Gencer Akcok, Emel BasakBackground Despite the recent advances in chemotherapy, the outcomes and the success of these treatments still remain insufficient. Novel combination treatments and treatment strategies need to be developed in order to achieve more effective treatment. This study was designed to investigate the combined effect of ethacrynic acid and cinnamic acid on cancer cell lines. Methods The anti-proliferative effect of ethacrynic acid and cinnamic acid was investigated by MTT cell viability assay in three different cancer cell lines. Combination indexes were calculated using CompuSyn software. Apoptosis was assessed by flow cytometric Annexin V-FITC/PI double-staining. The effect of the inhibitors on cell cycle distribution was measured by propidium iodide staining. Results The combination treatment of ethacrynic acid and cinnamic acid decreased cell proliferation significantly, by 63%, 75% and 70% for K562, HepG2 and TFK-1 cells, respectively. A 5.5-fold increase in the apoptotic cell population was observed after combination treatment of K562 cells. The population of apoptotic cells increased by 9.3 and 0.4% in HepG2 and TFK-1 cells, respectively. Furthermore, cell cycle analysis shows significant cell cycle arrest in S and G2/M phase for K562 cells and non-significant accumulation in G0/G1 phase for TFK-1 and HepG2 cells. Conclusions Although there is a need for further investigation, our results suggest that the inhibitors used in this study cause a decrease in cellular proliferation, induce apoptosis and cause cell cycle arrest.Article Efficacy of Combinatorial Inhibition of Hedgehog and Autophagy Pathways on the Survival of AML Cell Lines(Academic Press inc Elsevier Science, 2025-08) Sansacar, Merve; Pepe, Nihan Aktas; Akcok, Emel Basak Gencer; El Khatib, Mona; Gencer Akçok, Emel BaşakAcute myeloid leukemia (AML) is a common hematopoietic disease that results from diverse genetic abnormalities. Dysregulation of important signaling pathways, including the PI3K/AKT/mTOR, Wnt and Hedgehog pathways, plays crucial roles in the development of AML. Hedgehog pathway (Hh) is a conserved signaling pathway that is crucial throughout embryogenesis. Hh plays an important role in the regulation of autophagy, known as the cellular recycling process of organelles and unwanted proteins. Many studies have noted that the modulation of autophagy could act as a survival mechanism in AML. Considering the pivotal role of autophagy and Hh signaling in AML, understanding the relationship between these pathways is important for overcoming leukemia. Therefore, we examined the efficacy of Hh inhibition by GLI-ANTagonist 61 (GANT61) in MOLM-13 and CMK cells via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenil-2H-tetrazolium bromide (MTT) cell viability assays. GANT61 resulted in decreased cell viability in both cell lines. Therefore, we focused on the outcome of autophagy modulation in AML cells. We observed that the autophagy inhibitors ammonium chloride (NH4CI), chloroquine (CQ), and nocodazole led to a significant reduction in the proliferation of both cell lines. Cotreatment with autophagy pathway inhibitors and GANT61 synergistically affected both AML cell lines. Moreover, dual targeting of these pathways resulted in arrest at the G0/G1 phase in MOLM-13 cells but not in CMK cells. Furthermore, the combination of nocodazole and GANT61 increased the expression level of LC3B-II in both cell lines. Compared with that in the untreated control cells, the GLI1 gene expression level in both cell lines was significantly lower after GANT61 and autophagy cotreatment. In conclusion, targeting Hh and autophagy could be a favorable option to combat AML.Article Anticancer Effect of Ethanolic Yellow Hawthorn Extract on Chronic Myeloid Leukemia Cells and Acute Myeloid Leukemia Cells(Ondokuz Mayis Universitesi, 2025) Arslan, Ayşe Nur; Akçok, IsmailCancer is a disease characterized by abnormal cell growth and invasion and metastasis of these cells to other tissues or organs of the body. Natural products have been used for centuries as drugs or in drug development, especially for the treatment of cancer. Besides, extracting natural products with several bioactive compounds has a promising effect on cancer treatment. In this study, we aimed to investigate the anticancer effect of the ethanolic extract of yellow hawthorn fruits on K562 (Chronic Myeloid Leukemia) and MOLM-13 (Acute Myeloid Leukemia) cell lines. The antiproliferative effect of the ethanolic extract of yellow hawthorn fruits was investigated in time-and dose-dependent manners. The Annexin-V/Propidium Iodide (PI) double staining was used to examine the apoptosis. Furthermore, cell cycle analysis is conducted by PI staining. The cell viability of K562 and MOLM-13 cell lines was significantly reduced by the ethanolic extract of yellow hawthorn fruits with IC50 values of 9144 µg/mL and 3515 µg/mL in 48-hour incubation time, respectively. Moreover, the results showed that the ethanolic extract of yellow hawthorn fruits caused an increased apoptosis by 12.7-and 8.87-fold changes in K562 and MOLM-13 cell lines compared to control groups, respectively. Ethanolic extract of yellow hawthorn fruit has reduced cell proliferation, induced apoptosis and arrested the cell cycle at G0/G1 phase by 71% in MOLM-13 and at G2/M phase by 80.3% and G0/G1 phase by 38.2 % in K562 cells. Further studies should be conducted to elucidate the mechanism of the effect of yellow hawthorn fruit on these cancer cells. © 2025 Elsevier B.V., All rights reserved.