1,720,972 research outputs found
2‐(Methyl(phenyl)amino)‐N‐(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition
No full text: The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD+-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC50 values of 9.97, 5.74, and 8.92 μM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2
In silico approach reveals N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamides as promising selective SIRT2 inhibitors: the case of structural optimization of virtual screening-derived hits
No full textEpigenetic modifications play an essential role in tumor suppression and promotion. Among the diverse range of epigenetic regulators, SIRT2, a member of NAD+-dependent protein deacetylates, has emerged as a crucial regulator of cellular processes, including cell cycle progression, DNA repair, and metabolism, impacting tumor growth and survival. In the present work, a series of N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamide derivatives were identified following a structural optimization of previously reported virtual screening hits, accompanied by enhanced SIRT2 inhibitory potency. Among the compounds, ST44 and ST45 selectively inhibited SIRT2 with IC50 values of 6.50 and 7.24 mu M, respectively. The predicted binding modes of the two compounds revealed the success of the optimization run. Moreover, ST44 displayed antiproliferative effects on the MCF-7 human breast cancer cell line. Further, the contribution of SIRT2 inhibition in this effect of ST44 was supported by western blotting, affording an increased alpha-tubulin acetylation. Furthermore, molecular dynamics (MD) simulations and binding free energy calculations using molecular mechanics/generalized born surface area (MM-GBSA) method evaluated the accuracy of predicted binding poses and ligand affinities. The results revealed that ST44 exhibited a remarkable level of stability, with minimal deviations from its initial docking conformation. These findings represented a significant improvement over the virtual screening hits and may contribute substantially to our knowledge for further selective SIRT2 drug discovery
Clinicopathological and immunohistochemical evaluation of lonidamine-entrapped lipid-polymer hybrid nanoparticles in treatment of benign prostatic hyperplasia: An experimental rat model
No full textBakar-Ates, Filiz/0000-0003-2809-8946Benign prostatic hyperplasia (BPH) is a progressive proliferative disease, the incidence of which is constantly increasing due to aging of population. In this research, a hexokinase-II enzyme inhibiting agent, lonidamine - the use of which is limited in BPH treatment due to high hepatic toxicity observed after three months of treatment - was selected as an active agent, based on its mechanism of action in treating BPH. The aim of this study was to evaluate in vivo therapeutic efficacy and hepatic toxicity of lipid-polymer hybrid nanoparticles of lonidamine in a rat BPH model created in rat prostates. After local injections of hybrid nanoparticles of lonidamine were administered to the rat prostates, hyperplasic structures of prostates were evaluated in terms of prostatic index values, immunohistochemical evaluations, and histopathological findings. Liver blood enzyme values were also determined to specify hepatic toxicity. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) reaction and histopathological methods to determine intravital degenerative destruction in liver. Through this study, lonidamine-loaded hybrid nanoparticles were found to reduce the he-patic toxicity and increase therapeutic efficiency of lonidamine. Therefore, lonidamine-entrapped hybrid nanoparticles may provide a promising, and very safe, drug delivery strategy in the treatment of BPH.Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114S132]This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK), Grant No: 114S132
Etoposide in combination with erastin synergistically altered iron homeostasis and induced ferroptotic cell death through regulating IREB2/FPN1 expression in estrogen receptor positive-breast cancer cells
No full textAim: Ferroptosis is an iron-dependent cell death mechanism that substantially differs from apoptosis. Since its mechanism involves increased oxidative stress and rich iron content, cancer cells are particularly vulnerable to ferroptotic death compared to healthy tissues. In the present study, the effect of etoposide in combination with a ferroptotic agent, erastin, was investigated in breast cancer.Main methods: Cell viability was assessed by the MTT assay. Oxidative stress, lipid peroxidation and glutathione peroxidase activity were detected using the relevant kits. Intracellular iron levels were measured by HPLC. Ferroptosis markers were explored by western blotting.Key findings: Results demonstrated that although etoposide didn't induce a significant cell death up to 50 mu M in MCF-7 cells, with the addition of erastin, a significant synergistic activity was achieved at a dose as low as 1 mu M (p < 0.05), contrary to normal breast epithelial cells. This cytotoxic effect was blocked by ferrostatin-1, which is a specific inhibitor of ferroptosis. The combined treatment of etoposide and erastin synergistically induced oxidative stress and lipid peroxidation, while suppressing glutathione peroxidase activity. More importantly, the combination treatment synergistically increased iron accumulation, which was associated with altered expres-sion of IREB2/FPN1. Additionally, ferroptosis-regulating proteins ACSF2 and GPX4 were altered more potently by the combination treatment, compared to untreated cells and erastin treatment alone (p < 0.05).Significance: In conclusion, this is the first study that reports enhanced cytotoxicity of etoposide, in combination with erastin, in ER-positive breast cancer cells via activation of ferroptotic pathways, and offers a new perspective for future regimens
Decreased Spexin Levels in Patients with Type 1 and Type 2 Diabetes
No full textBackground/Aims: Spexin is a novel peptide which has a potential role as a biomarker of insulin resistance, diabetes, and obesity. Our aim was to measure spexin levels in lean type 1 diabetic patients and its relevance to glycemic parameters without the presence of obesity or insulin resistance. Subjects and Methods: This cross-sectional study included 29 type 1 and 30 type 2 diabetic patients and a control group of 23 healthy subjects with adjusted age, sex, and body mass index (BMI). Height and weight were measured using standard techniques. Glucose levels, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum cortisol levels, and spexin levels were measured in each patient. Results: The median fasting serum spexin levels were significantly lower in patients with type 1 and type 2 diabetes than in control subjects (p = 0.008 and p = 0.041, respectively). Spexin levels were not correlated with glycemic parameters, lipids, BMI, cortisol levels, and thyroid-stimulating hormone (p > 0.05). Only age turned out to be correlated with spexin levels in patients with type 1 diabetes when we analyzed the groups separately. Regression models, including age and diabetes duration, revealed no association between age and spexin levels. Regression models, including cortisol, BMI, and HbA1c, revealed no association with spexin levels within each group. Conclusion: The presence of type 1 diabetes is associated with lower spexin levels, independent of glucose, lipid parameters, and BMI. The expression of spexin in the pancreas apart from the current glycemic control of the patients may be the main determinant of spexin levels in type 1 diabetic patients. © 2018 The Author(s) Published by S. Karger AG, Basel.WosPubme
Cucurbitacin B and erastin co-treatment synergistically induced ferroptosis in breast cancer cells via altered iron-regulating proteins and lipid peroxidation
No full text<p>Ferroptosis is a unique type of cell death which co-exists with elevated iron, suppressed antioxidative function and increased lipid peroxidation. Recent studies have shown that cancer cells are particularly susceptible to the compounds with ferroptotic activities. Cucurbitacin B (CuB) is a triterpenoid with potent biological properties. It has been demonstrated to induce apoptosis and inhibit metastasis in cancer cells. However, the underlying mechanism of the compound is still not fully understood. In the present study, we investigated the ferroptotic effect of CuB in breast cancer cells and evaluated the impact of its combination with erastin, a ferroptosis inducer. In this regard, MTT assay was performed to analyze cell viability. Lipid peroxidation, oxidative stress and the cellular antioxidant capacity were determined with relevant kits. The expression of ferroptotic proteins were analyzed by western blotting. The results indicated that the combined treatment of CuB and erastin activated the ferroptotic pathways significantly in MCF-7 and MDA-MB-231 breast cancer cells. More importantly, the combination treatment altered the expression of iron-related proteins IREB2 and FPN1. In conclusion, this study demonstrated the ferroptotic potential of CuB in breast cancer cells for the first time, and revealed its impact on the expression of iron-regulating proteins.</p>
Investigation of molecular mechanisms underlying the antiproliferative effects of colchicine against PC3 prostate cancer cells
No full textThis 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
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
No full textBackground: 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.Cumhuriyet University Scientific Research Project (CUBAP) [ECZ-045]This study was supported by Cumhuriyet University Scientific Research Project (CUBAP, Project No: ECZ-045, Sivas, Turkey)
Synthesis, Biological, and Computational Evaluation of Novel 1,3,5‐Substituted Indolin‐2‐one Derivatives as Inhibitors of Src Tyrosine Kinase
No full textBakar-Ates, Filiz/0000-0003-2809-8946;Several substituted indolin-2-one derivatives were synthesized and evaluated for their activities against Src kinase. Several compounds showed activity against Src, with IC50 values in the low micromolar range. Among them, compound 2f showed the most significant activity with an IC50 value of 1.02M. Molecular docking studies have been performed for evaluation of the binding modes of compound 2f into the Src active site. The docking structure of compound 2f disclosed that the indole NH forms a hydrogen bond with the carbonyl of Met341. These results suggest that our novel compound 2f is a promising compound for the further development of indole-based drugs targeting Src kinase.Ankara UniversityAnkara University [BAP 09B333600235, 13H3336002]This Project received a funding support from Ankara University (BAP 09B333600235 and 13H3336002) Scientific Research Funds
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