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2-Phenylethyne-1-Sulfonamide Derivatives as New Drugs Candidates for Heat Shock Protein 70 and Doublecortin-like Kinase
(DergiPark, 2021) Ergul, Mustafa; Sayin, Koray; Ataseven, Hilmi
Under physiological conditions HSP70 plays crucial roles in protein homeostasis. This protein is overexpressed in many types of cancer cells and increased levels of HSP70 is closely associated with tumorigenesis and poor clinical outcomes. The present study was designed to evaluate in silico assessment of newly designed 30 different 2-Phenylethyne-1-Sulfonamide derivatives potential heat shock protein 70 inhibitors. The mentioned structures were optimized at B3LYP/6-31+G(d, p) level in water and active sites of them are determined. Then, molecular docking calculations were done between the related structures and 4PO2 and 5JZN. It is found that compound (5), (12) and (20) were found as the better ones than those of compound (1) and (2). Drug likeness studies were performed via pharmacological ADME (absorption, distribution, metabolism, and excretion) properties estimation and the drug properties of (5) and (12) were found as the better than those of compound (1), (2) and (20). © 2021. All Rights Reserved.
A Novel 6,8,9-Trisubstituted Purine Analogue Drives Breast Cancer Luminal A Subtype MCF-7 to Apoptosis and Senescence through Hsp70 Inhibition
(Bentham Science Publ Ltd, 2023) Kul, Pinar; Tuncbilek, Meral; Ergul, Mustafa; Tunoglu, Ezgi Nurdan Yenilmez; Tutar, Yusuf
Background: Cancer cells restrain apoptotic and senescence pathways through intracellular heat shock protein 70 (Hsp 70). These cells aid stimulus-independent growth, and their higher metabolism rate requires Hsps. Hsps compensate abnormally increased substrate protein folding rate of cancer cells. Objective: Misfolding of substrate proteins especially signaling substrate proteins, may not function properly. Therefore, Hsp70 folds these substrate proteins into their native-fully functional states, and this mode of action helps cancer cell survival. Methods: Targeting Hsps is promising cancer therapy, and in this study, 6,8,9-trisubstituted purine derivatives were designed and synthesized to inhibit Hsp70 and drive cancer cells to apoptosis. Further, oncogenic stimuli through inhibitors can induce an irreversible senescent state and senescence is a barrier to transformation. Results: Hsp70 helps cancer cells to bypass the cellular senescence program, however, binding of N-6-(4-isopropylaniline) analogue (7) depletes Hsp70 function as evidenced by aggregation assay and Hsp70 depletion induces senescence pathway. Conclusion: The purine-based inhibitor-compound 7 effectively inhibits MCF-7 cell line. Moreover, the therapeutic potential with regard to the senescence-associated secretory phenotype has complementary action. Dual action of the inhibitor not only drives the cells to apoptosis but also force the cells to be in the senescence state and provides promising results specially for luminal A type breast cancer therapy.
A specific inhibitor of polo-like kinase 1, GSK461364A, suppresses proliferation of Raji Burkitt's lymphoma cells through mediating cell cycle arrest, DNA damage, and apoptosis
(Elsevier Ireland Ltd, 2020) Ergul, Mustafa; Bakar-Ates, Filiz
Polo-like kinase 1 (PLK1) is a prominent mediatory player during the cell cycle, mitosis, and cytokinesis in eukaryotic cells. Besides its physiological roles, PLK1 expression is upregulated in a wide range of human malignant tumors and its overexpression worsens prognosis, therefore, specific inhibition of PLK1 in tumor cells is a fascinating approach for the development of novel chemotherapeutics. The present study elucidated the potential cytotoxic effects of a PLK1 inhibitor, GSK461364A, in five cancer cell lines including Raji, K562, PC3, MCF-7, MDA-MB-231, along with noncancerous L929 cells by XTT assay. The cells were treated for 24 h with GSK461364A at different concentrations ranged between 0.5 and 40 mu M and significant cytotoxicity was observed in all treated groups with the IC50 values between 2.36 and 4.08 mu M. GSK461364A was also found to be safer with lower cytotoxicity against L929 cells and the IC50 value was found to be greater than 40 mu M. Raji cells were identified as the most sensitive cell line against GSK461364A with the lowest IC50 values, hence it was selected for further studies to evaluate the underlying mechanism of cytotoxic activity. The treatment of Raji cells with GSK461364A caused a cell cycle arrest at the G2/M phase, also altered TOS, which is an indicator of oxidative stress, and DNA damage response, significantly. The Annexin V binding assay revealed that GSK461364A treatment significantly increased in the percentage of early and late apoptotic cells. Fluorescence imaging also showed that GSK461364A treatment significantly induced apoptosis of Raji cells. The apoptotic effect of the compound has also been confirmed by increased expressions of Bax and cleaved caspase 3 and along with the decreased expression of BCL-2. The results demonstrated that GSK461364A induced anticancer effects which was mainly promoted by cell cycle arrest, oxidative stress, DNA damage, and finally apoptosis in Burkitt's lymphoma cells. Taken together, the present results emphasized that GSK461364A could be a useful therapeutic agent in patients with Burkitt's lymphoma. However, further studies are required to consolidate the anticancer activity of this promising compound.
All-in-One Nanohybrids Combining Sonodynamic Photodynamic and Photothermal Therapies
(Amer Chemical Soc, 2024) Taydas, Dilsad; Ozler, Muhammed Emre; Ergul, Mustafa; Inan, Zeynep Deniz Sahin; Sozmen, Fazli
A wide variety of methods are being developed to ultimately defeat cancer; while some of these strategies have shown highly positive results, there are serious obstacles to overcome to completely eradicate this disease. So, it is crucial to construct multifunctional nanostructures possessing intelligent capabilities that can be utilized to treat cancer. A possible strategy for producing these multifunctional nanostructures is to combine various cancer treatment techniques. Based on this point of view, we successfully synthesized multifunctional HCuS@Cu2S@Au-P(NIPAM-co-AAm)-PpIX nanohybrids. The peculiarities of these thermosensitive polymer-modified and protoporphyrin IX (PpIX)-loaded hollow nanohybrids are that they combine photodynamic therapy (PDT), sonodynamic therapy (SDT), and photothermal therapy (PTT) with an intelligent design. As an all-in-one nanohybrids, HCuS@Cu2S@Au-P(NIPAM-co-AAm)-PpIX nanohybrids were employed in the SDT-PDT-PTT combination therapy, which proved to have a synergistic therapeutic effect for in vitro tumor treatments against breast tumors.
Critical Residues in Hsp70 Nucleotide Binding Domain for Challenges in Drug Design
(Bentham Science Publ Ltd, 2022) Ergul, Mustafa; Aktan, Fugen; Tutar, Yusuf
Background: The association of a drug with its target protein correlates to its medicinal activity and the microenvironment plays a key role in this association. The key challenge is to iden-tify mutations which unlikely to respond to designed drugs. Objective: Hsp70 is an anti-apoptotic factor and tumor cells overexpress Hsp70 to survive against anti-cancer agents. The impact of pathogenic mutations on Hsp70 is unknown. Elucidation of these alterations is essential to understand the molecular switch mechanism. Thus, critical spots on Hsp70 Nucleotide Binding Domain (NBD) are important since mutation-driven sensitivity may be useful in designing innovative inhibitors. Methods: ATP, AMP-PNP (non-hydrolyzable analog of ATP) along with commercially available compounds VER-155008 (ATP analog and competitive inhibitor) and MKT-077 (allosteric inhibi-tor of ADP bound form) were docked to Hsp70 NBD structurein silico to identify critical amino acids of inhibition mechanism. Site-directed mutagenesis of the determined critical residues along with ATP hydrolysis and luciferase refolding was performed. Wild-type and mutant Hsp70s were compared to determine the effect on protein functions in the presence or absence of inhibitors. Results: This study identified three mutants that have a loss of function for Hsp70, which may alter the drug inhibition activity as oncogenic cells have multiple mutations. Conclusion: Two commercial inhibitors employed here that mimic ATP and ADP states, respec-tively, are not affected by these mutational perturbations and displayed effective interference for Hsp70 functions. Designing inhibitors by considering these critical residues may improve drug de-sign and increase drug efficiency.
Design, synthesis, and anticancer activity of novel 4-thiazolidinone-phenylaminopyrimidine hybrids
(Springer, 2021) Ture, Asli; Ergul, Mustafa; Ergul, Merve; Altun, Ahmet; Kucukguzel, Ilkay
4-Thiazolidinones and phenylaminopyrimidines are known as anticancer agents. Imatinib is the pioneer phenylaminopyrimidine derivative kinase inhibitor, which is used for the treatment of chronic myeloid leukemia. With a hybrid approach, a novel series of 5-benzylidene-2-arylimino-4-thiazolidinone derivatives containing phenylaminopyrimidine core were designed, synthesized, and tested for their anticancer activity on K562 (chronic myeloid leukemia), PC3 (prostat cancer), and SHSY-5Y (neuroblastoma) cells. Since superior anticancer activity was observed on K562 cells, further biological studies of selected compounds (8, 15, and 34) were performed on K562 cells. For the synthesis of designed compounds, thiourea compounds were converted to 2-imino-1,3-thiazolidin-4-ones with alpha-chloroacetic acid in the presence of sodium acetate. 5-Benzylidene-2-imino-1,3-thiazolidin-4-one derivatives were obtained by Knoevenagel condensation of 2-imino-1,3-thiazolidin-4-ones with related aldehydes. Compounds 8, 15, and 34 were evaluated for cell viability, apoptosis studies, cell cycle experiments, and DNA damage assays. IC50 values of compounds 8, 15, and 34 were found as 5.26 +/- 1.03, 3.52 +/- 0.91, and 8.16 +/- 1.27 mu M, respectively, in K562 cells. Preferably, these compounds showed less toxicity towards L929 cells compared to imatinib. Furthermore, compounds 8 and 15 significantly induced early and late apoptosis in a time-dependent manner. Compounds 15 and 34 induced cell cycle arrest at G0/G1 phase and compound 8 caused cell cycle arrest at G2/M phase. Based on DNA damage assay, compounds 8 and 15 were found to be more genotoxic than imatinib towards K562 cells. To put more molecular insight, possible Abl inhibition mechanisms of most active compounds were predicted by molecular docking studies. In conclusion, a novel series of 5-benzylidene-2-arylimino-4-thiazolidinone derivatives and their promising anticancer activities were reported herein. [GRAPHICS] .
Determination of biological activity of Tragopogon porrifolius and Polygonum cognatum consumed intensively by people in Sivas
(Elsevier, 2020) Eruygur, Nuraniye; Ucar, Esra; Atas, Mehmet; Ergul, Merve; Ergul, Mustafa; Sozmen, Fazli
Objective: This study was aimed to investigate the in vitro antioxidant, antimicrobial, cytotoxicity, and enzyme inhibition activities of Tragopogon porrifolius and Polygonum cognatum which are naturally grown and consumed intensively by people in Sivas, Turkey. Methods: Plant materials were extracted with aqueous ethanol by maceration method. The components of the extracts were determined using the Gas Chromatography Mass Spectrometry. Antimicrobial, cytotoxic and enzyme inhibition activities of the extracts were investigated by micro dilution, XTT assay and 96-micro-well plate methods, respectively. The antioxidant activity evaluated using the DPPH radical scavenging, thiobarbituric acid and reducing power methods. The total phenol and total flavonoid content was also examined. Results: GC-MS analysis revealed the presence of 31 compounds inP. cognatum extract and 29 compounds in T. porrifolius extract. According to the results, T. porrifolius extract showed high level of antioxidant activity in comparison to P. Cognatum extract. T. porrifolius exhibited higher alpha-glucosidase inhibitory activity, and both extract showed strong alpha-amylase inhibition activity compared to reference drug acarbose. T. porrifolius and P. cognatum ethanolic extracts exhibited antimicrobial activity in the concentration range of 0.039-2.5 mg/ml. Both extracts also exhibited significant anticancer effect on MDA-MB-231 breast cancer cells. The IC50 values of T. porrifolius and P. cognatum extracts in MDA-MB-231 cells were determined as 0.0625 mg/mL and 0.053 mg/mL, respectively. Conclusion: Our findings demonstrated that T. porrifolius and P. cognatum ethanolic extracts have promising effect on antioxidant, antimicrobial and cytotoxic activity as well as enzyme inhibition activity, and hence further studies required to identify specific compounds responsible for these activities.
Determination of inhibitory activities of enzymes, related to Alzheimer's disease and diabetes mellitus of plane tree (Platanus orientalis L.) extracts and their antioxidant, antimicrobial and anticancer activities
(C M B ASSOC, 2018) Ucar, Esra; Eruygur, Nuraniye; Atas, Mehmet; Ergul, Merve; Ergul, Mustafa; Sozmen, Fazli
Plane tree (Platanus orientalis L.) leaves have been employed for centuries in various countries due to their pharmacological value. Therefore, determination of the biological activity of the leaves is of interest. The aim of the study was to evaluate the inhibitory effects against Alzheimer's disease-related enzymes Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE), diabetes mellitus related enzymes alpha-glucosidase and alpha-amylase. The antioxidant, anticancer, and antimicrobial activities of the leaves were also studied. According to the results, both water and methanol extracts of P. orientalis demonstrated more alpha-glucosidase and alpha-amylase inhibition activity than the antidiabetic drug-acarbose at the same concentration level. In addition, extracts showed good inhibition activity against AChE and BuChE. Significant results were obtained regarding antioxidant, anticancer, and antimicrobial activities. These results are very promising especially for the improvement of pharmaceutical formulations to treat various diseases such as age-related diseases, cancer, diabetes etc. and it is necessary to conduct further experiments.
Evaluation of Various Biological Activities of Endemic Sideritis libanotica Extracts
(Horticulture and Forestry Society from Transylvania, 2019) Atas, Mehmet; Eruygur, Nuraniye; Sozmen, Fazli; Ergul, Mustafa; Ergul, Merve; Akpulat, Huseyin Askin; Ucar, Esra
In recent years, using of plants to develop combine therapies for treatment of certain diseases such as cancer, Alzheimer's disease, and diabetes mellitus is extremely plausible approach. Perhaps, the definitive treatment of some of these diseases is hidden in the complex content of a plant in nature. Thus, in the present study, we decided to determine the biological activities of methanol and water extracts of the endemic Sideritis libanotica. To the best of our knowledge, the present study is the first investigation on antioxidant, enzyme inhibitory activity, antimicrobial activity, and in vitro cytotoxicity of S. libanotica. According to results, while the methanol extract shows better anti-cholinesterase, ?-glucosidase, and ?-amylase inhibition activity and cytotoxicity than the water extract, the tyrosinase inhibitory activity of the water extract was found to be better than the methanol extract. This study provides valuable information on how the biological activity of endemic S. libanotica changes in different solvent extractions such as water and methanol. © 2019, Horticulture and Forestry Society from Transylvania. All rights reserved.
GSK461364A suppresses proliferation of gastric cancer cells and induces apoptosis
(Pergamon-Elsevier Science Ltd, 2023) Ataseven, Dilara; Tastemur, Seyma; Yulak, Fatih; Karabulut, Sebahattin; Ergul, Mustafa
Polo-like kinase 1 (PLK1) is crucial in regulating cell division and has been shown to have an oncogenic function in several cancers. Since PLK1 overexpression is closely related to tumorigenesis and has been correlated with poor clinical outcomes, specific inhibition of PLK1 in cancer cells is a promising approach for developing new anticancer drugs. In this context, the aim of the present study was to evaluated the potential cytotoxic effects of GSK461364A, a competitive inhibitor for PLK1, in gastric cancer cell line SNU-1 cells and explored its cytotoxic mechanism. The cells were exposed to GSK461364A at different concentrations ranging from 1 to 40 mu M for 24 h, and it showed considerable cytotoxicity with an IC50 value of 4.34 mu M. The treatment of SNU-1 cells with GSK461364A results in cell cycle arrest at the G2/M phase, decreased mitochondrial membrane potential, and increased apoptosis as indicated by Annexin V binding assay. In addition, GSK461364A treatment significantly increased the total oxidant (TOS) level, a signal of oxidative stress, and increased cleaved PARP and 8-oxo-dG levels as an indicator of DNA damage. ELISA experiments evaluating Bax, BCL-2, and cleaved caspase 3 also confirmed the apoptotic effect of GSK461364A. Current findings suggest that GSK461364A may be a chemotherapeutic agent in patients with gastric cancer. Nevertheless, more research is needed to evaluate GSK461364A as a cancer treatment drug.
Important Anti-Cancer Applications of Protein Based Nanoparticles
(BENTHAM SCIENCE PUBL LTD, 2013) Ergul, Mustafa; Ergul, Merve; Tutar, Yusuf
Cancer is one of the most important health problems in the world and the treatment approaches are still challenging and generally not at desirable levels. Conventional anti-cancer agents may cause systemic toxicity, have poor solubility, and lack of selectivity. In order to overcome these hurdles, nanoparticle based therapeutics have been widely employed to enhance therapeutic efficacies and reduce systemic toxicity of pharmaceutical agents. In recent years, nanoparticulate carrier systems (NPCs) in medicine have attracted considerable scientific attention and interest in the worldwide because of their unique properties in the diagnosis and therapy of many diseases including cancer. One of the therapeutic strategies of NPCs is protein based nanoparticles. Human serum albumin (HSA) and bovine serum albumin (BSA) are the most frequently used materials for this purpose due to their remarkable advantages. In this review article, we focused on protein based nanoparticles and summarized their important applications including anti-cancer drug delivery, photodynamic therapy, and gene delivery.
In Vitro Evaluation of the Chemical Composition and Various Biological Activities of Ficus carica Leaf Extracts
(Turkish Pharmacists Assoc, 2019) Ergul, Mustafa; Ergul, Merve; Eruygur, Nuraniye; Atas, Mehmet; Ucar, Esra
Objectives: The present study aimed to investigate the inhibitory activities of enzymes related to diabetes mellitus and Alzheimer's disease of the methanol and water extracts of Ficus carica leaf extracts. The bioactive compounds and anticancer, antioxidant, and antimicrobial effects of the extracts were also investigated. Materials and Methods: The bioactive compounds in the extracts were determined by gas chromatography-mass spectrometry. The antioxidant activity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulphonic acid) (ABTS) radical scavenging, total phenol and flavonoid content, ferric reducing power, and iron chelating method. The anticancer, anticholinesterase, and antimicrobial effects were investigated using the XTT assay, Ellman method, and microdilution, respectively. Results: Our results showed that between the water and methanol extracts there was a difference in terms of chemical composition. The antioxidant results suggested that both extracts have strong antioxidant activity. Similarly, both extracts showed strong alpha-glucosidase and alpha-amylase inhibition activity, while the water extract had higher inhibition activity than the methanol extract against acetylcholinesterase and butyrylcholinesterase. The methanol extract of F. carica exhibited significant anticancer activity on MDA-MB-231 cells and showed moderate antimicrobial activities against Escherichia coli and Staphylococcus aureus. Conclusion: Our results suggest that F. carica leaves could be a valuable source for developing a promising therapeutic agent in cancer, diabetes, and Alzheimer's disease.
Investigation of molecular mechanisms underlying the antiproliferative effects of colchicine against PC3 prostate cancer cells
(Pergamon-Elsevier Science Ltd, 2021) Ergul, Mustafa; Bakar-Ates, Filiz
This work examined the cytotoxic effects of colchicine on PC3 cells and elucidated the possible underlying mechanisms of its cytotoxicity. The cells were exposed to colchicine at different concentrations ranging from 1 to 100 ng/mL for 24 h, and it showed considerable cytotoxicity with an IC50 value of 22.99 ng/mL. Mechanistic studies also exhibited that colchicine treatment results in cell cycle arrest at the G2/M phase as well as decreased mitochondrial membrane potential and increased early and late apoptotic cells. The apoptotic and DNAdamaging effects of colchicine have also been verified by fluorescence imaging and ELISA experiments, and they revealed that while colchicine treatment significantly modulated expression as increases in Bax, cleaved caspase 3, cleaved PARP, and 8-hydroxy-desoxyguanosine levels and as a decrease of BCL-2 protein expression. Besides, colchicine treatment significantly increased the total oxidant (TOS) level, which is a signal of oxidative stress and potential cause of DNA damage. Finally, the results of quantitative real-time PCR experiments demonstrated that colchicine treatment concentration-dependently suppressed MMP-9 mRNA expression. Overall, colchicine provides meaningful cytotoxicity on PC3 cells due to induced oxidative stress, reduced mitochondrial membrane potential, increased DNA damage, and finally increased apoptosis in PC3 cells. Nevertheless, further research needs to be conducted to assess the potential of colchicine as an anticancer drug for the treatment of prostate cancer.
Mechanism of anticancer effect of ETP-45658, a PI3K/AKT/mTOR pathway inhibitor on HT-29 Cells
(Humana Press Inc, 2023) Yulak, Fatih; Filiz, Ahmet Kemal; Joha, Ziad; Ergul, Mustafa
The PI3K pathway plays a crucial role in tumor cell proliferation across various cancers, including colon cancer, making it a promising treatment target. This study aims to investigate the antiproliferative activity of ETP-45658, a PI3K/AKT/mTOR pathway inhibitor, on colon cancer and elucidate the underlying mechanisms. HT-29 colon cancer cells were treated with varying doses of ETP 45658 and its cytotoxic effect assessed using the XTT cell viability assay.ELISA was also used to measure TAS, TOS, Bax, BCL-2, cleaved caspase 3, cleaved PARP, and 8-oxo-dG levels. Flow cytometry was performed to investigate apoptosis, cell cycle, caspase 3/7 activity, and mitochondrial membrane potential. Additionally, following the administration of DAPI (4,6-diamidino-2-phenylindole) dye, the cells were visualized using an immunofluorescence microscope. It was observed that ETP-45658 exerted a dose-dependent and statistically significant antiproliferative effect on HT-29 colon cancer cells. Further investigations using the IC50 dose showed that ETP-45658 decreased TAS levels and increased TOS levels and revealed that it upregulated apoptotic proteins while downregulating anti-apoptotic proteins. Our findings also showed that it increased Annexin V binding, arrested the cell cycle at G0/G1 phase, induced caspase 3/7 activity, impaired mitochondrial membrane potential, and ultimately triggered apoptosis in HT-29 cells. ETP-45658 shows promise against colon cancer by inducing cell death, and oxidative stress, and arresting the cell cycle. Targeting the PI3K/AKT/mTOR pathway with ETP-45658 offers exciting potential for colon cancer treatment.
Novel indole hydrazide derivatives: Synthesis and their antiproliferative activities through inducing apoptosis and DNA damage
(Wiley-V C H Verlag Gmbh, 2020) Kilic-Kurt, Zuhal; Acar, Cemre; Ergul, Mustafa; Bakar-Ates, Filiz; Altuntas, Tunca G.
A series of novel indole hydrazide derivatives was synthesized and evaluated for their anticancer activities. Compound 12 exhibited the highest antiproliferative activity against the MCF-7 cell line, with an IC50 value of 3.01 mu M. Treatment of MCF-7 cells with compound 12 led to cell cycle arrest at the G0/G1 phase and also displayed a significant annexin V binding pattern, indicating that compound 12 is effective in apoptotic cell death. The Western blot analysis showed that compound 12 increased the expression of proapoptotic Bax and decreased the levels of the antiapoptotic Bcl-2 protein. It was also observed that MCF-7 cells treated with compound 12 showed reduced levels of procaspase-3 and -9 proteins. Moreover, compound 12 treatment induced a significant DNA damage in MCF-7 cells by increasing H2AX and ATM phosphorylation.
Perturbation of HSP Network in MCF-7 Breast Cancer Cell Line Triggers Inducible HSP70 Expression and Leads to Tumor Suppression
(Bentham Science Publ Ltd, 2020) Ergul, Mustafa; Aktan, Fugen; Yildiz, Mehmet T.; Tutar, Yusuf
Background: Heat shock protein 70 (HSP70) is constitutively expressed in normal cells but aberrantly expressed in several types of tumor cells, helping their survival in extreme conditions. Thus, specific inhibition of HSP70 in tumor cells is a promising strategy in the treatment of cancer. HSP70 has a variety, of isoforms in the cellular organelles and form different functions by co-ordinating and cooperating with co chaperones. Cancer cells overexpress HSPs during cell growth and proliferation and HSP network provides resistance against apoptosis. The present study aimed to evaluate quantitative changes in HSPs- and cancer-associated gene expressions and their interactions in the presence of 2-phenylethyenesulfonamide (PES) in MCF-7 cells. Methods: AntiproliCerative activity of PES was evaluated using the wXTT assay. Inducible HSP70 (HSP70i) levels in the PES-treated cells were determined using the ELISA kit. PCR Array was performed to assess the IISPs- and cancer-pathway focused gene expression profiling. Gene network analysis was performed using the X2K, yLd (N1.3.18.1) programs, and web-based gene list enrichment analysis tool Enrichr. Results: The results demonstrated that PES exposure increased the amount of both HSP70i gene and protein expression surprisingly. However, the expression of HSP70 isoforms as well as other co-chaperones, and 17 cancer-associated genes decreased remarkably as expected. Additionally, interaction network analysis revealed a different mechanism; PES induction of HSP70i employs a cell cycle negative regulator, RBI, which is a tumor suppressor gene. Conclusion: PES treatment inhibited MCF-7 cell proliferation and changed several HSPs- and cancer-related gene expressions along with their interactions through a unique mechanism although it causes an interesting increase at HSP70i gene and protein expressions. RBI gene expression may play an important role in this effect as revealed by the interaction network analysis.
RO3280: A Novel PLK1 Inhibitor, Suppressed the Proliferation of MCF-7 Breast Cancer Cells Through the Induction of Cell Cycle Arrest at G2/M Point
(Bentham Science Publ Ltd, 2019) Ergul, Mustafa; Bakar-Ates, Filiz
Background: As a member of serine/threonine-protein kinase, Polo-like kinase 1 (PLK1) plays crucial roles during mitosis and also contributes to DNA damage response and repair. PLK1 is aberrantly expressed in many types of tumor cells and increased levels of PLK1 are closely related to tumorigenesis and poor clinical outcomes. Therefore, PLK1 is accepted as one of the potential targets for the discovery of novel anticancer agents. The objective of this study was to assess the cytotoxic effects of a novel PLK1 inhibitor, RO3280, against MCF-7, human breast cancer cells; HepG2, human hepatocellular carcinoma cells; and PC3, human prostate cancer cells, as well as non-cancerous L929 fibroblast cells. Methods: Antiproliferative activity of RO3280 was examined using the XTT assay. Flow cytometry assay was performed to evaluate cell cycle distribution, apoptosis, multicaspase activity, mitochondria' membrane potential, and DNA damage response. Apoptosis with fluorescence imaging studies was also examined. Results: According to the results of .XTT assay, although RO3280 displayed potent cytotoxicity in all treated cancer cells, the most sensitive cell line was identified as MCF-7 cells that were selected for further studies. The compound induced a cell cycle arrest in MCF-7 cells at G2/M phase and significantly induced apoptosis, multicaspase activity, DNA damage response, and decreased mitochondria' membrane potential of MCF-7 cells. Conclusion: Overall, RO3280 induces anticancer effects promoted mainly by DNA damage, cell cycle arrest, and apoptosis in breast cancer cells. Further studies are needed to assess its usability as an anticancer agent with specific cancer types.
Tannic acid protects neuroblastoma cells against hydrogen peroxide - triggered oxidative stress by suppressing oxidative stress and apoptosis
(Elsevier, 2024) Yulak, Fatih; Ergul, Mustafa
Recent investigations indicate that tannic acid is associated with a decrease in oxidative damage. Growing evidence supports the protective effects of tannic acid on the central nervous system (CNS). However, uncertainties persist regarding its influence on hydrogen peroxide (H2O2)-triggered oxidative impairment in nerve cells and its interaction with apoptosis. Hence, the objective of this work was to examine the neuroprotective impact of tannic acid on SH-SY5Y cell impairment following H2O2-induced oxidative stress, particularly concerning apoptotic pathways. The control group received no treatment, while the H2O2 group underwent treatment with 0.5 mM H2O2 for a duration of 24 h. The tannic acid group received treatment with different concentrations of tannic acid for a duration of 24 h. Meanwhile, the tannic acid + H2O2 group underwent pre-treatment with tannic acid for one hour and was subsequently subjected to 0.5 mM H2O2 for one day. Within the tannic acid + H2O2 group, the cell viability in SH-SY5Y cells was notably enhanced by tannic acid at concentrations of 2.5, 5, and 10 mu M. It also resulted in a considerable rise in TAS (Total Antioxidant Status) levels and a concurrent decline in TOS (Total Oxidant Status) levels, serving as indicators of reduced oxidative stress. Additionally, tannic acid treatment resulted in decreased levels of apoptotic markers (Bax, cleaved PARP, and cleaved caspase 3) and oxidative DNA damage marker (8-oxo-dG), while increasing the anti-apoptotic marker Bcl-2. The findings from flow cytometry also revealed a significant reduction in the apoptosis rate following pretreatment with tannic acid. In summary, tannic acid demonstrates protective effects on SH-SY5Y cells in the face of H2O2-triggered oxidative damage by suppressing both oxidative stress and apoptosis. Nevertheless, additional research is warranted to assess the neuroprotective potential of tannic acid.
The effect of magnesium sulfate on memory and anxiety-like behavior in a rat model: an investigation of its neuronal molecular mechanisms
(Taylor & Francis Ltd, 2024) Cetin, Ali; Ozdemir, Ercan; Golgeli, Asuman; Taskiran, Ahmet Sevki; Karabulut, Sebahattin; Ergul, Mustafa; Gumus, Erkan
BackgroundAnxiety is an adaptive response to potentially threatening conditions. Excessive and uncontrolled anxiety responses become nonadaptive and cause anxiety disorders. To better understand the anxiety-modulating effects of Mg sulfate, behavioral test batteries in the assessment of anxiety and learning and memory functions were performed simultaneously over a time period. This study also examines the effects of Mg sulfate compared to diazepam, an anxiolytic drug with amnestic effects on anxiety-like behavior, as well as possible oxidative-nitrosative stress and hippocampal changes in male rats exposed to predator odor.MethodsYoung adult Sprague-Dawley male rats were used. The rats were assessed using a comprehensive neurobehavioral test battery consisting of novel object recognition, open field, and successive alleys tasks. Anxiety was induced by cat odor, and diazepam and Mg were used as study drugs. Of the frontal cortex and hippocampus, the state of total oxidant and antioxidant and NO levels and histological examination of hippocampal CA1, CA2, CA3, and DG regions were performed.ResultsDiazepam- and Mg-treated rats showed an improvement in anxiety-related behavior to predator odors. Furthermore, Mg treatment alleviated some of the increasing oxidative stress in the frontal cortex and hippocampus of rats, while diazepam treatment in particular enhanced hippocampal oxidant and antioxidant activity. In addition, brain NO increase induced by animal odor exposure or diazepam treatment was ameliorated by Mg administration.ConclusionsOverall, our work suggests that Mg had a partial anxiolytic effect on anxiety-like behaviors, although not as much as diazepam, and this effect varied depending on the dose. Mg treatment might counteract increased oxidative stress and elevated NO levels in the brain.
The Effects of Proton Pump Inhibitors (Pantoprazole) on Pentylenetetrazole-Induced Epileptic Seizures in Rats and Neurotoxicity in the SH-SY5Y Human Neuroblastoma Cell Line
(Springer/Plenum Publishers, 2021) Taskiran, Ahmet Sevki; Ergul, Mustafa; Gunes, Handan; Ozturk, Aysegul; Sahin, Bilal; Ozdemir, Ercan
Recent studies have shown that proton pump inhibitors have positive effects on the nervous system. However, its effect on epileptic seizure and neuronal damage are still unclear. In this study, it was aimed to investigate the effect of pantoprazole on pentylenetetrazole-induced epileptic seizures in rats and neurotoxicity in the SH-SY5Y cell line. Animals were divided into three groups: control, saline (1 mL/kg serum physiologic), and pantoprazole (10 mg/kg). Pentylenetetrazole (45 mg/kg) was given to induce a seizure and a passive avoidance test trial was carried out to evaluate memory function. 8-hydroxy-2 '-deoxyguanosine (8-OHdG), caspase-3, and brain-derived neurotrophic factor (BDNF) levels were measured in the brain by commercial kits. SH-SY5Y cells were treated with saline or pantoprazole for one hour, and then pentylenetetrazole (30 mu m) was added to the medium to induce neurotoxicity. After 24 h, cell viability, total antioxidant, total oxidant status, and apoptosis were measured in SH-SY5Y cells. It was found that pantoprazole treatment postponed epileptic seizure onset, protected memory, reduced 8-OHdG, caspase-3, and also increased BDNF in the brain. In addition, it blocked pentylenetetrazole toxicity, apoptosis, increased antioxidant, and decreased oxidant status in SH-SY5Y cells. Pantoprazole significantly improved seizure, oxidative stress, and apoptosis. Thus, pantoprazole could be used as a supportive therapeutic agent in epilepsy.

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