Browsing by Author "Ilhan S."
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Item Essential Oils from Vitex agnus castus L. Leaves Induces Caspase-Dependent Apoptosis of Human Multidrug-Resistant Lung Carcinoma Cells through Intrinsic and Extrinsic Pathways(Routledge, 2020) Ilhan S.Essential oil (EO) fractions of plants are complex mixtures of volatile compounds with broad-spectrum biological properties. In the current study, the EO content of Vitex agnus castus L. (VAC) leaves growing in the Aegean region of Turkey was extracted and identified. Then, VAC EOs were investigated for their potential antioxidant, cytotoxic and apoptotic effects in human H69AR multi-drug resistant cancer cells. EOs were isolated by hydrodistillation and chemical composition was determined by GC-MS. Cell viability was assessed via MTT and trypan blue assays. Antioxidant activity was evaluated by measuring the total antioxidant activity and free radical scavenging activity. Apoptosis was evaluated via DNA fragmentation and caspase 3/7 activity assays. Changes in the levels of apoptotic genes were determined by RT-qPCR. The results indicated strong antioxidant activity and cytotoxic effect on H69AR cancer cells but not on HEK-293 human normal cells indicating the tumor-specific effect. VAC EOs induced caspase 3/7 activation and apoptosis through triggering both extrinsic- and intrinsic-pathways by modulating Bcl-2, Bcl-XL, Bax, Bad, FADD, Caspase-8, Caspase-9, TRAIL R1/DR4 and TRAIL R2/DR5. This study revealed that VAC EOs may be a promising candidate in the development of novel therapeutic agents for multi-drug resistant lung cancer treatment. © 2020 Taylor & Francis Group, LLC.Item Profile of Apoptotic Proteins after Curcumin Treatment by Antibody Array in H69AR Lung Cancer Cells(Istanbul University Press, 2020) Ilhan S.Objective: The aim of the study was to investigate the changes in the expression levels of apoptosis-related proteins after treatment with curcumin (Cur) on multiple drug-resistant H69AR non-small cell lung cancer cells. Materials and Methods: Viability of H69AR cells after Cur exposure (5-100 μg/mL) was evaluated via MTT assay at 24, 48 and 72 h. Apoptosis was assessed via ELISA assay. Apoptosis related proteins of breast cancer cell lines were analyzed by a Human Apoptosis Antibody Array. Protein-protein interactions were analyzed and visualized by using the STRING database. Results: Cur inhibited cell viability and induced apoptosis in H69AR cells. The IC50 value of Cur in H69AR cells was 8.75 μg/ mL. The array results showed that the protein levels of pro-apoptotic proteins such as Bad, Bax, Caspase-3, TRAIL R1, TRAIL R2, FADD, Fas, SMAC/DIABLO, HMOX2 were significantly increased by 2.4-, 3.1-, 2.6-, 3.1-, 3.4-, 2.4-, 2.1-, 4.1- and 5.5-fold in H69AR cells (p<0.05). Moreover, the protein levels of the anti-apoptotic proteins such as Bcl-2, cIAP-1, CLU and HIF1A were significantly decreased by 4.1-, 3.2-, 2.2- and 2.0-fold, respectively in H69AR cells by Cur exposure (p<0.05). Conclusion: Findings of this study suggested that Cur induced apoptosis of human H69AR cells via mediating several proteins involved in both extrinsic and intrinsic apoptotic pathways. © European Journal of Biology. All rights reserved.Item 4-Propargyl-substituted 1H-pyrroles induce apoptosis and autophagy via extracellular signal-regulated signaling pathway in breast cancer(John Wiley and Sons Inc, 2021) Atmaca H.; Ilhan S.; Yilmaz E.S.; Zora M.Novel pyrrole derivatives (PDs) with propargyl units (1–7) were investigated for their anticancer activity on breast cancer cells. The MTT assay was used to assess the cell viability. Morphological changes in human breast cancer cells were visualized under a phase-contrast microscope. Apoptosis and autophagy were detected using the DNA fragmentation assay and staining by autophagic vacuoles, respectively. The levels of apoptosis- and autophagy-related proteins such as cytochrome c, Bcl-2, LC3-I/II were investigated by Western blot analysis. The effect of PDs on the ERK1/2 signaling pathway was investigated using specific inhibitors. All the tested PDs were found to be active in the range of 36.7 ± 0.2 to 459.7 ± 4.2 µM. Compounds 3 and 4 showed cytotoxic activity in breast cancer cells, but were found to be safer with lower cytotoxicity on human nontumorigenic epithelial breast cells. Compound 4 induced apoptosis, whereas compound 3 induced autophagy. Both compounds inhibited the ERK signaling pathway in breast cancer cells. The present study revealed that both synthesized PDs induced different programmed cell death types by inhibiting the ERK signaling pathway in two genotypically different breast cancer cells. Therefore, novel PDs might be promising anticancer agents for breast cancer therapy and further structural modifications of PDs may yield promising anticancer agents. © 2021 Deutsche Pharmazeutische GesellschaftItem Profiling of apoptosis-associated proteins in human prostate cancer cells in response to Montivipera bulgardaghica albizona venom by protein array(Taylor and Francis Ltd., 2021) Ilhan S.; Çiçek K.; Tok C.V.; Atmaca H.Here we studied the possible cytotoxic and apoptotic effects of Anatolian endemic mountain viper, Montivipera bulgardaghica albizona (M.b. albizona) venom on human PC-3 and DU-145 prostate cancer cell lines. M.b. albizona venom induced cytotoxicity and apoptosis of both prostate cancer cells in a concentration-dependent manner. Protein array results revealed that the levels of major components of the mitochondrion-initiated and the extrinsic death receptor-mediated pathways were significantly changed in prostate cancer cells by venom treatment. These data suggest that one or more of the purified components of the M.b. albizona venom may serve as an appropriate therapeutic agent for prostate cancer. Further bioactivity guided studies are required for the identification of bioactive compounds of M.b. albizona venom. © 2020 Informa UK Limited, trading as Taylor & Francis Group.Item Population structure and gene flow of the syntopic turtles Emys and Mauremys from coastal and inland regions of Anatolia (Turkey): results from mitochondrial and microsatellite data(Springer Science and Business Media B.V., 2021) Ilhan S.; Vamberger M.; Ayaz D.; Fritz U.Revealing the genetic basis of the existence of different species living together in different geographic regions provides clarification of this phylogeographic differentiation. In this study, we investigated the population genetics and evaluated the level of genetic variation of inland and coastal populations of Mauremys and Emys in Turkey. Tissue samples of 196 terrapins were studied which were collected from syntopic coastal (Gölbent-Söke/Aydın; M. rivulata and E. orbicularis) and inland populations (Bahçesaray/Aksaray; M. caspica and E. orbicularis). DNA was isolated using the InnuPREP DNA Mini Kit. Mitochondrial DNA sequences and allelic variation at 13 microsatellite loci for Mauremys and 12 microsatellite loci for Emys were examined. Three haplotypes were found for Emys orbicularis (Im, Ip and Iw) collected from the coastal region and two haplotypes for Emys orbicularis (Ig and Im) collected from inland. Two haplotypes were identified for M. caspica (Cmt8 and Cmt9) and three haplotypes were identified for M. rivulata (Rmt3, Rmt24 and Rmt26). Using microsatellites and the software STRUCTURE the most probable value for K was revealed as two 2 for both species. The FST value between M. rivulata and M. caspica was 0.39, and between the coastal and inland populations of E. orbicularis 0.09. It can be concluded that Emys populations tend to evolve by somehow preserving the allelic richness they have and Mauremys populations continue to differentiate so that new species emerge in the evolutionary process to reach the ideal allelic structure. © 2021, The Author(s), under exclusive licence to Springer Nature B.V.Item Trabectedin (ET-743) in prostate cancer: Endoplasmic reticulum stress-induced apoptotic effect(John Wiley and Sons Inc, 2022) Atmaca H.; Oğuz F.; Ilhan S.Trabectedin is a chemotherapy agent originating from a tunicate, Ecteinascidia turbinata. In this study, DNA-independent action mechanisms of trabectedin are investigated in prostate cancer (PCa) cells. Cell viability was assessed via XTT assay. Apoptosis was evaluated via flow cytometry. Tetramethylrodamine ethyl ester (TMRE) dye was utilized to determine mitochondrial membrane potential (MMP). Cell cycle distribution was investigated via flow cytometric analysis. Reactive oxygen species (ROS) were monitored using fluorescence CM-H2DCFDA dye. Changes in CHOP, p-eIF2α, GRP78 and p-PERK which are endoplasmic reticulum (ER) stress-involved proteins were investigated via western blot. Trabectedin induced cytotoxicity and cell cycle arrest at the G2/M phase. Trabectedin decreased MMP via ROS generation in PCa cells. ER stress-related proteins CHOP, p-eIF2α, GRP78 and p-PERK were also elevated by trabectedin treatment indicating the induction of ER stress-induced apoptosis. The results of this study show that trabectedin may be an effective chemotherapeutic for PCa. © 2022 Wiley-VCH GmbH.Item Endoplasmic Reticulum Stress-Induced Apoptotic Effects of Novel 1-Pyrroline (3,4-Dihydro-2H-pyrrole) Derivatives on Breast Cancer Cells(John Wiley and Sons Inc, 2022) Atmaca H.; Ilhan S.; Korkmaz E.; Zora M.Heterocyclic compounds have emerged as promising and appealing scaffolds for developing effective antitumor agents. Here, the effects of synthesized 24 different 1-pyrroline derivatives (PDs) containing substituted aryl sulfide moiety were investigated on human breast cancer cell lines. The viability of cells was assessed via MTT assay. Reactive oxygen species (ROS) generation was analyzed via fluorescent dye CM-H2DCFDA. Apoptotic cells were determined via flow cytometry. Endoplasmic reticulum (ER) stress-associated protein levels were analyzed via western blot analysis. Four of the PDs (PD-12, -14, -16 and -17) had great cytotoxic selectivity against breast cancer cells. Apoptotic cell death was induced by PDs via the generation of ROS. PDs significantly increased the GRP78, p-PEAK, p-eIF2α, and CHOP protein levels indicating ER stress in breast cancer cells. These results imply that newly synthesized PDs may be potential anticancer agents as they selectively inhibit breast cancer cells. © 2022 Wiley-VHCA AG, Zurich, Switzerland.Item Synthesis of silver nanoparticles using Alpinia officinarum rhizome extract induces apoptosis through down-regulating Bcl-2 in human cancer cells(Akademiai Kiado ZRt., 2022) Atmaca H.; Çamlı Pulat Ç.; Ilhan S.In this study, silver nanoparticles were synthesized using Alpinia officinarum rhizome extract via an eco-friendly green synthesis method. The silver nanoparticles (AO-AgNPs) were characterized by UV–Vis spectrometry, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and dynamic light scattering. Further, the cytotoxic and apoptotic effects of AO-AgNPs were investigated in human cancer cells with different tissue origins via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and flow cytometric analyses, respectively. The expression levels of anti-apoptotic Bcl-2 protein were evaluated via a real-time polymerase chain reaction. The synthesized AO-AgNPs induced a significant cytotoxic effect in all tested cancer cells but not in normal cells. AO-AgNPs induced the percentage of apoptotic cells and reduced the levels of anti-apoptotic Bcl-2 mRNA levels in cancer cells. These results demonstrate the potential application of AO-AgNPs in cancer treatment. © 2022, Akadémiai Kiadó Zrt.Item Drug Delivery Systems for Cancer Treatment: A Review of Marine-derived Polysaccharides(Bentham Science Publishers, 2022) Atmaca H.; Oguz F.; Ilhan S.Cancer is a disease characterized by uncontrolled cell proliferation and the spread of cells to other tissues and remains one of the worldwide problems waiting to be solved. There are various treatment strategies for cancer, such as chemotherapy, surgery, radiotherapy, and immunotherapy, although it varies according to its type and stage. Many chemotherapeutic agents have limited clinical use due to lack of efficacy, off-target toxicity, metabolic instability, or poor pharmacokinetics. One possible solution to this high rate of clinical failure is to design drug delivery systems that deliver drugs in a controlled and specific manner and are not toxic to normal cells. Marine systems contain biodiversity, including components and materials that can be used in biomedical applications and therapy. Biomaterials such as chitin, chitosan, alginate, carrageenan, fucoidan, hyaluronan, agarose, and ulvan obtained from marine organisms have found use in DDSs today. These polysaccharides are biocompatible, non-toxic, biodegradable, and cost-effective, making them ideal raw materials for increasingly complex DDSs with a potentially regulated release. In this review, the contributions of polysaccharides from the marine environment to the development of anticancer drugs in DDSs will be discussed. © 2022 Bentham Science Publishers.Item Newly Synthesized Benzimidazoles Inhibit Vascular Endothelial Growth Factor and Matrix Metalloproteinase-2 and-9 Levels in Prostate Cancer Cells(Bentham Science Publishers, 2022) Ilhan S.; Dilekci G.; Guner A.; Bektas H.Background: Investigating the effects of newly synthesized agents on various molecular mechanisms to understand their mechanism of action is an important step of pre-clinical screening. Benzimidazoles are composed of a unique fused benzene and imidazole ring and have attracted great attention due to their broad bioactivities, including antitumor. Objective: In the current study, we reported the synthesis of novel benzimidazole derivatives and investigated the pos-sible cytotoxic and anti-angiogenic effects on human prostate cancer and umbilical vein endothelial cells (HUVECs). Methods: MTT assay was used to assess cell viability. A scratch assay was conducted to monitor the migration of cells. mRNA expression levels of VEGF, MMP-2, and MMP-9 were evaluated using qPCR. Changes in protein levels were evaluated by western blotting. Results: Compound G1, having a chlorine moiety, showed a potent cytotoxic activity on both prostate cancer cells and HUVECs, and inhibited cell migration via decreasing the mRNA and protein levels of key angiogenesis-related molecules such as VEGF, MMP-2, and MMP-9. Conclusion: These results suggest that newly synthesized G1 may be a novel anti-angiogenic agent for prostate cancer treatment. © 2022 Bentham Science Publishers.Item Design and synthesis of benzimidazole derivatives as apoptosis-inducing agents by targeting Bcl-2 protein(Institute for Ionics, 2023) Ilhan S.; Çamli Pulat Ç.; Oguz F.; Bektaş H.; Menteşe E.; Atmaca H.Bcl-2, an anti-apoptotic protein, is a well-known and appealing cancer therapy target. Novel series of benzimidazole derivatives were synthesized and tested for their activity as Bcl-2 inhibitors on T98G glioblastoma, PC3 prostate, MCF-7 breast, and H69AR lung cancer cells. MTT assay was used to evaluate the cytotoxic effect. PI Annexin V Apoptosis Detection Kit was used to detect apoptosis. Expression levels of the Bcl-2 protein were examined by the Western blot analysis and qRT-PCR. All synthesized benzimidazole derivatives exhibited a cytotoxic effect on cancer cells with IC50 values in the range of 25.2–88.2 µg/mL. Among all derivatives, compounds C1 and D1 demonstrated a higher cytotoxic effect on cancer cells with IC50 values < 50 µg/mL, while a lower cytotoxic effect against human embryonic kidney cells with IC50 values of > 100 µg/mL. C1 and D1 caused a significant increase in the percentage of apoptotic cells in all types of cancer cell cells and both Bcl-2 mRNA and protein levels were significantly reduced. These results suggest that the novel benzimidazole derivatives may be candidates for apoptosis-inducing agents in cancer treatment by targeting anti-Bcl-2 proteins in cancer cells. Graphical abstract: [Figure not available: see fulltext.]. © 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.Item Venom peptides of crotalus atrox against sars-cov-2 spike protein and human ace2 receptor by molecular docking analysis(Sakarya University, 2023) Ilhan S.Venoms are composed of about 100 to 500 pharmacologically active compounds. Less than 0.01% of these compounds have been identified and a significant majority of them act on unknown receptors. Here, the potential Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) activities of selected Crotalus atrox venom peptides (CVPs) including Atrolysin D (AD), vascular apoptosis-inducing protein-1 (VAIP-1), Catrocollastatin (CC), and Calcium-Free Phospholipase A2 (CFP) were investigated via molecular docking analysis. CVPs were docked against human angiotensin-converting enzyme-2 (ACE-2) and 3- chymotrypsin-like protease (3CLpro) viral spike protein. All CVPs had low binding energies to both 3CLpro and ACE2, suggesting that they interacted strongly with the active sites of enzymes, compared to the reference drugs lopinavir and ritonavir. The binding energy of 3CLpro was -139.517 kcal/mol, -96.239 kcal/mol, -121.590 kcal/mol, -259.424 kcal/mol with AD, VAIP-1, CC, and CFP, respectively. CFP showed a very strong binding activity with 3CLpro, suggesting that it could be a very effective compound in inhibiting the SARS-CoV-2 virus. The binding energy of ACE2 was -101.165 kcal/mol, -73.064 kcal/mol, -106.918 kcal/mol, -82.830 kcal/mol with AD, VAIP-1, CC, and CFP, respectively. AD made a much stronger bond with ACE2 than reference drugs, showing that it could be used as a virusprotective component in humans. The results suggest a potential drug candidate for the development of therapeutics against Coronavirus disease 2019 (COVID-19). In vitro and in vivo experiments are needed to confirm these compounds' potential preventive and therapeutic effects. © 2020, Historical and Geographical Institute of Rio Grande do Sul. All rights reserved.Item Bioevaluation of Spiro N-Propargylic β-Enaminones as Anti-Breast Cancer Agents: In Vitro and Molecular Docking Studies(John Wiley and Sons Inc, 2023) Atmaca H.; Ilhan S.; Dundar B.A.; Zora M.The study aimed to investigate the in vitro inhibitory activities of spiro N-propargylic β-enaminones, SPEs 1-31, against BCa cells, to perform in silico molecular docking studies to understand the nature of the interaction between the compounds and the ERα, PR, EGFR, and Her2, and to determine the ADMET and drug-likeness properties. Cytotoxic activity was investigated via MTT assay. DNA fragmentation was evaluated via ELISA assay. Cell cycle distributions were investigated by flow cytometry. Expression levels of Bcl-2, Bax, p21 and Cyclin D1 were measured by qRT-PCR and western blot analysis. Molecular docking was done using Autodock/vina software. ADMET analysis was calculated using the ADMETlab 2.0 tool. SPEs 1, 22, and 28 showed selective cytotoxic activity against all BCa cells with SI values >2. SPEs induced apoptosis and caused significant changes in Bcl-2 and Bax levels. The cell cycle was arrested at the S phase and levels of p21 and Cyclin D1 were induced in all BCa cells. Molecular docking analysis revealed that SPE1, SPE22, and SPE28 showed high binding affinities with ERα, PR, EGFR, and Her2. ADMET analysis revealed that SPEs are drug-like compounds as they obey the five rules of Lipinsky and are not toxic. Therefore, these potential anticancer compounds should be further validated by in vivo studies for their appropriate function in human health with a safety profile, and a comprehensive drug interaction study should be performed. © 2023 Wiley-VHCA AG, Zurich, Switzerland.Item N-Propargylic β-enaminones in breast cancer cells: Cytotoxicity, apoptosis, and cell cycle analyses(John Wiley and Sons Inc, 2023) Ilhan S.; Atmaca H.; Yilmaz E.S.; Korkmaz E.; Zora M.Breast cancer is one of the most common cancers worldwide and the discovery of new cytotoxic agents is needed. Enaminones are regarded to be a significant structural motif that is found in a variety of pharmacologically active compounds however the number of studies investigating the anticancer activities of N-propargylic β-enaminones (NPEs) is limited. Herein we investigated the potential cytotoxic and apoptotic effects of 23 different NPEs (1-23) on human breast cancer cells. Cytotoxicity was evaluated via MTT assay. Apoptotic cell death and cell cycle distributions were investigated by flow cytometry. CM-H2DCFDA dye was used to evaluate cellular ROS levels. Expression levels of Bcl-2, Bax, p21, and Cyclin D1 were measured by quantitative real-time PCR. ADME properties were calculated using the ADMET 2.0 tool. NPEs 4, 9, 16, and 21 showed selective cytotoxic activity against breast cancer cells with SI values >2. NPEs induced apoptosis and caused significant changes in Bcl-2 and Bax mRNA levels. The cell cycle was arrested at the G0/G1 phase and levels of p21 and Cyclin D1 were upregulated in both breast cancer cells. ROS levels were significantly increased by NPEs, suggesting that the cytotoxic and apoptotic effects of NPEs were mediated by ROS. ADME analysis revealed that NPEs showed favorable distributions in both breast cancer cell lines, meaning good lipophilicity values, low unfractionated values, and high bioavailability. Therefore, these potential anticancer compounds should be further validated by in vivo studies for their appropriate function in human health with a safety profile, and a comprehensive drug interaction study should be performed. © 2023 Wiley Periodicals LLC.Item Efficient synthesis of novel 1,10 phenanthroline-substituted imidazolium salts: Exploring their anticancer applications(Elsevier Masson s.r.l., 2024) Çakır S.; Ilhan S.; Atmaca H.; Türkmen H.This study reports a new series of 1,10-phenanthroline-substituted imidazolium salts (1a–f), examining their design, synthesis, structure and anticancer activities. The structures of these salts (1a–f) were characterized using 1H, 13C NMR, elemental analysis, mass spectrometry and Fourier transform infrared (FT-IR) spectroscopies. The salts' cytotoxic activities were tested against cancer cell lines, specifically MCF-7, MDA-MB-231 and non-tumorigenic MCF-10A mammary cells. The study compared the impact of aliphatic and benzylic groups in the salts’ structure on their anticancer activity. Screening results revealed that compound 1c, in particular, showed promising inhibitory activity against the growth of MDA-MB-231 breast cancer cells, with an IC50 value of 12.8 ± 1.2 μM, indicating its potential as a chemotherapeutic agent. Cell apoptosis analysis demonstrated a tendency for compound 1c to induce early apoptosis in breast cancer cells. The stability/aquation of compound 1c was investigated using 1H NMR spectroscopy and its binding modes with DNA were explored via UV–Vis spectroscopy. Additionally, the study investigated the interaction residues and docking scores of compound 1c and the reference drug doxorubicin against Bax and Bcl-2 proteins using molecular docking. © Elsevier Masson SASItem Hericium erinaceus Extract Induces Apoptosis via PI3K/AKT and RAS/MAPK Signaling Pathways in Prostate Cancer Cells(John Wiley and Sons Inc, 2024) Atmaca H.; Çamli Pulat Ç.; Ilhan S.; Kalyoncu F.Prostate cancer (PCa) is increasing globally, surpassing lung cancer in incidence. Despite available treatment options, prostate cancer remains incurable. Hence, novel therapeutic strategies are urgently needed to treat PCa. Hericium erinaceus (HE), a medicinal mushroom, offers diverse therapeutic benefits. We examined HE's effects on PCa cells, preparing an ethanol extract and identifying its volatile compounds through GC-MS. MTT assay assessed cell viability, while specific inhibitors and western blotting explored HE's impact on PI3K/AKT and RAS/MAPK pathways. Flow cytometry and ELISA evaluated apoptosis induction. HE showed concentration- and time-dependent cytotoxicity on PCa cells with minimal effects on normal cells. Mechanistically, HE suppressed PI3K/AKT and RAS/MAPK pathways, reducing phosphorylated protein levels. Moreover, it induced PCa cell apoptosis. These findings suggest HE as a potential therapeutic for prostate cancer, shedding light on its cytotoxic and apoptotic effects for further investigation. © 2024 Wiley-VHCA AG, Zurich, Switzerland.Item Chitosan in cancer therapy: a dual role as a therapeutic agent and drug delivery system(Walter de Gruyter GmbH, 2024) Atmaca H.; Oguz F.; Ilhan S.Although chemotherapy is still the most preferred treatment for cancer, most chemotherapeutic agents target both cancer cells and healthy cells and cause serious side effects due to high toxicity. Improved drug delivery systems (DDSs), which enhance the efficacy of current chemotherapeutic drugs while reducing their toxicity, offer potential solutions to these challenges. Chitosan (CS) and its derivatives are biopolymers with biodegradable, biocompatible, and low-toxicity properties, and their structure allows for convenient chemical and mechanical modifications. In its role as a therapeutic agent, CS can impede the proliferation of tumor cells through the inhibition of angiogenesis and metastasis, as well as by triggering apoptosis. CS and its derivatives are also frequently preferred as DDSs due to their properties such as high drug-carrying capacity, polycationic structure, long-term circulation, and direct targeting of cancer cells. Various therapeutic agents linked to CS and its derivatives demonstrate potent anticancer effects with advantages such as reduced side effects compared to the original drugs, owing to factors like targeted distribution within cancer tissues and sustained release. This review emphasizes the utilization of CS and its derivatives, both as therapeutic agents and as carriers for established chemotherapeutic drugs. © 2024 Walter de Gruyter GmbH, Berlin/Boston.Item Evaluation of Novel Spiro-pyrrolopyridazine Derivatives as Anticancer Compounds: In Vitro Selective Cytotoxicity, Induction of Apoptosis, EGFR Inhibitory Activity, and Molecular Docking Analysis(American Chemical Society, 2024) Atmaca H.; Ilhan S.; Çamli Pulat C.; Dundar B.A.; 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 μM, respectively. Notably, SPP10 demonstrates selective cytotoxicity against cancer cells with a low impact on nontumorigenic cells (IC50 value: 26.8 ± 0.4 μM). 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. © 2024 The Authors. Published by American Chemical Society.Item Synthesis and Characterization of Piano-Stool Ruthenium(II)-Arene Complexes of Isatin Schiff Bases: Cytotoxicity and DNA Intercalation(American Chemical Society, 2024) Karabıyık H.; Karaer Tunçay A.; Ilhan S.; Atmaca H.; Türkmen H.A series of aryl-isatin Schiff base derivatives (3a-d) and their piano-stool ruthenium complexes (4a-d) were synthesized and characterized via 1H and 13C NMR and Fourier transform infrared (FTIR) spectroscopy. In addition, the purity of all of the compounds (3a-c and 4a-d) was determined via elemental analysis. Complex 4d was analyzed using X-ray crystallography. An in vitro antiproliferative study of the compounds (3a-c and 4a-d) against human hepatocellular carcinoma (HEPG2), human breast cancer (MCF-7), human prostate cancer (PC-3), and human embryonic kidney (HEK-293) cells exhibited their considerable antiproliferative activity. 4d exhibited effective cytotoxicity against HEPG2 and MCF-7. It displayed higher cytotoxicity than the reference metallo-drug cisplatin. Moreover, the stability of 4d was studied via 1H NMR spectroscopy, and the binding model between 4d and DNA was investigated via ultraviolet-visible spectroscopy. The lipophilicity of the synthesized complexes was determined using an extraction method. © 2024 The Authors. Published by American Chemical SocietyItem Effects of acute exposure to environmentally realistic tebuconazole concentrations on stress responses of kidney and digestive gland of Lymnaea stagnalis(Elsevier B.V., 2024) Somuncu S.; Atmaca H.; Ilhan S.This study aimed to investigate the effects of 24 and 72 h exposure to environmentally relevant concentrations of tebuconazole (TEB) (10, 100 and 500 µg/L) fungicide on the freshwater snail Lymnaea stagnalis. The focus was induction of oxidative stress, alteration of gene expressions and histopathological changes in the kidney and digestive gland. TEB treatment induced a time- and concentration-dependent increase in intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, while the total antioxidant capacity (TAC) was decreased. The activities of glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT) also increased in a time- and concentration-dependent manner in both tissues. TEB exposure significantly increased the mRNA levels of CAT, GPx, GR, heat shock proteins HSP40 and HSP70. Histological analysis revealed nephrocyte degeneration and disrupted digestive cells. The study concludes that acute exposure to TEB induces oxidative stress, alters antioxidant defense mechanisms, and leads to histopathological changes in L. stagnalis. © 2023 Elsevier B.V.