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Öğe Abiraterone Acetate, in Combination with Apigenin, Attenuates the Survival of Human Castration-Sensitive Prostate Cancer Cells(Bentham Science Publ Ltd, 2022) Genc, Fatih; Atabey, Ugur Simal; Serttas, Riza; Erdogan, SuatBackground: Abiraterone acetate (AA) is a selective inhibitor of CYP17 alpha-hydroxylase, which is crucial for androgen biosynthesis. Apigenin (Api) is a natural plant-derived flavonoid with potent antiproliferative and anti-migration effects. Objectives: We aimed to investigate the possible role of Api in combination with the androgen receptor inhibitor AA in the treatment of androgen-sensitive human prostate cancer LNCaP cells. Methods: The cells were either exposed to 10 mu M AA, 25 mu M Api, or in combination for 48 hours, then the viability rate was determined by the MTT test, whilst apoptosis and cell cycle phases were assessed by image-based cytometry. The expression of selected mRNA and proteins were evaluated by RT-qPCR and Western blot, respectively. Results: The combination of AA and Api significantly inhibited LNCaP as well as androgen-insensitive PC3 cell survival in a manner more marked than observed with either single treatment. Co-administration of Api with AA triggered apoptosis. This effect was demonstrated by Hoechst staining, and up-regulation of Bax, cytochrome c, caspase -3, and -8 and down-regulation of Bcl-2 expression confirmed the effect. AA and Api each individually arrested the cell cycle in the G1 phase, with dual applications, leading to no further increase in the effect produced. The expression of NF-kappa B p105/p50 and the phosphorylation of AKT markedly decreased after apigenin treatment, with combination treatment leading to a favourable effect in terms of further augmenting the reduction. Conclusion: The co-administration of Api with AA strongly enhanced the efficacy of AA therapy in the treatment of prostate cancer cells. These data suggested that the combination of AA and Api would be a potential chemotherapeutic strategy against prostate cancer.Öğe ANTINEOPLASTIC MULTI-DRUG CHEMOTHERAPY TO SENSITIZE TUMORS TRIGGERS MULTI-DRUG RESISTANCE AND INHIBITS EFFICIENCY OF MAINTENANCE TREATMENT IN GLIOBLASTOMA CELLS(Excli Journal Managing Office, 2022) Doganlar, Oguzhan; Doganlar, Zeynep Banu; Erdogan, Suat; Delen, EmreCombinations of the well-known antineoplastic agents 5-fluorouracil (5-Fu), cisplatin, and paclitaxel are employed to increase radiotherapy/immunotherapy efficacy against persistent and resistant tumors. However, data remains needed on the hormetic, chronic, and long-term side effects of these aggressive combination chemotherapies. Here we investigated cellular and molecular responses associated with these combined agents, and their potential to induce multi-drug resistance against the temozolomide (TMZ) and etoposide (EP) used in glioblastoma mainte-nance treatment. We analyzed resistance and survival signals in U87 MG cells using molecular probes, fluorescent staining, qRT-PCR, and immunoblot. Repeated treatment with combined 5-Fu, cisplatin, and paclitaxel induced cross-resistance against TMZ and EP. Resistant cells exhibited elevated gene/protein expression of MRP1/ABCC1, ABCC2, BRCP/ABCG2, and GST. Moreover, they managed oxidative stress, cell cycle, apopto-sis, and autophagy signaling to ensure survival. In these groups TMZ and etoposide efficiency dramatically re-duced. Our result suggests that combined high-dose treatments of classical antineoplastic agents to sensitize tu-mors may trigger multi-drug resistance and inhibit maintenance treatment. When deciding on antineoplastic com-bination therapy for persistent/resistant glioblastoma, we recommend analyzing the long-term hormetic and chronic effects on cross-resistance and multi-drug resistance in primary cell cultures from patients.Öğe Beneficial effects of nontoxic ozone on H2O2-induced stress and inflammation(Canadian Science Publishing, 2016) Kucukgul, Altug; Erdogan, Suat; Gonenci, Ramazan; Ozan, GoncaIn this study, the anti-oxidant and anti-inflammatory efficacy of ozone oxidative preconditioning (OOP) were investigated on hydrogen peroxide (H2O2)-induced human lung alveolar cells. In MTT and trypan blue viability tests, while 100 mu mol/L H2O2 caused a 17.3% and 21.9% decrease in the number of living cells, respectively, ozone at 20 mu mol/L regenerated cell proliferation and prevented 9.6% and 11.0% of cell loss, respectively. In addition, H2O2 decreased the transcription levels of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) 5.43-, 2.89-, and 5.33-fold, respectively, while it increased Bax, NF-kappa beta, TNF-alpha, and iNOS expression 1.57-, 1.32-, 1.40-, and 1.41-fold, respectively. Ozone pretreatment, however, increased CAT, GPx, and SOD transcription levels 7.08-, 5.17-, and 6.49-fold and decreased Bax, NF-kappa beta, TNF-alpha, and iNOS transcriptions by 1.25-, 0.76-, 3.63-, and 7.91-fold, respectively. Moreover, intracellular glutathione (GSH) level and SOD activity were decreased by 46.2% and 45.0% in the H2O2 treatment group, and OOP recovered 58.5% and 20.1% of the decreases caused by H2O2. H2O2 also increased nitrite levels 7.84-fold, and OOP reduced this increase by half. Consequently, OOP demonstrated potent anti-oxidant and anti-inflammatory effects on in vitro model of oxidative stress-induced lung injury.Öğe Beraprost sodium, a prostacyclin (PGI) analogue, ameliorates lipopolysaccharide-induced cellular injury in lung alveolar epithelial cells(Tubitak Scientific & Technological Research Council Turkey, 2015) Vicil, Sinan; Erdogan, SuatBackground/aim: Human alveolar epithelial cells play a critical role in the pathogenesis of lung diseases. The objective of this study is to determine the contribution of beraprost sodium, a prostaglandin I-2 (PGI(2)) analogue, to inflammatory and oxidative events in response to lipopolysaccharide (LPS) in airway epithelial cells. Materials and methods: Human pulmonary alveolar epithelial cells (A549) were pretreated with 10 mu M beraprost sodium 30 min before stimulation with 1 mu g/mL LPS for 24 h. The cellular viability assessments were evaluated by quantitative MTT test. Catalase activity and glutathione and lipid peroxidation levels were determined using spectrophotometric techniques. mRNA expression analyses were performed by real-time qRT-PCR. Results: The endotoxin induced a dose-dependent increase in proliferation of the cells, which was suppressed by the beraprost sodium treatment. LPS increased the expressions of TNF-alpha and IL-1 beta genes by 8- and 2.5-fold, respectively. It also induced lipid peroxidation and depleted cellular antioxidant capacity. Pretreatments of the cells with beraprost sodium significantly reversed the inflammation and suppressed oxidative stress. Conclusion: These findings suggest that beraprost sodium will provide a pivotal molecular basis for the design of new therapeutic strategies to cure endotoxin-induced lung injury, although additional comprehensive studies are still required.Öğe Caffeic acid phenethyl ester protects lung alveolar epithelial cells from cigarette smoke-induced damage(Tubitak Scientific & Technological Research Council Turkey, 2015) Barlas, Firat Baris; Erdogan, SuatBackground/aim: To evaluate the influence of caffeic acid phenethyl ester (CAPE) on cigarette smoke (CS)-induced cell damage, oxidative stress, and inflammation in human alveolar epithelial cells. Materials and methods: A549 alveolar epithelial cells were divided into control, CS exposure, CAPE, and CS+CAPE treatment groups. Undiluted CS-exposed medium (100%) and three dilutions (50%, 25%, and 10%) of CS-exposed media were applied to cultured A549 cells, which were analyzed after 3 h of incubation. Viability was measured by MTT assay, the gene expressions were evaluated by real-time PCR, and spectrophotometric techniques were used for biochemical assessments. Results: While CS exposure markedly reduced cellular viability by 32% after 3 h of incubation, 2.5 mu M CAPE treatments prevented CS-induced cell death by 40% in the cells. CS exposure triggered lipid peroxidation and depleted antioxidant capacity through inhibiting catalase activity and depleting glutathione levels. Moreover, CS increased nitric oxide production via upregulation of iNOS expression. CAPE treatment significantly restored antioxidant capacity and prevented lipid peroxidation. Cigarette smoke exposure induced inflammation by significantly upregulating TNF-alpha, IL-1 beta, and COX-2 mRNA expressions (3-, 2- and 25-fold, respectively). CAPE treatment of A549 cells significantly reversed the inflammation. Conclusion: CAPE may potentially represent a new therapeutic option in the prevention of CS-induced lung damages.Öğe Cytotoxic and Antimigratory Activity of Retrochalcones from Glycyrrhiza echinata L. on Human Cancer Cells(Wiley-V C H Verlag Gmbh, 2023) Cevik, Dicle; Erdogan, Suat; Serttas, Riza; Kan, Yuksel; Kirmizibekmez, HasanCytotoxic activity-guided fractionation studies on Glycyrrhiza echinata roots led to the isolation of eight compounds (1-8). Chemical structures of the isolates were identified by NMR and MS analysis. Among the tested molecules, retrochalcones namely echinatin (3) (IC50=23.45-41.83 mu M), licochalcone B (4) (IC50=36.04-39.53 mu M) and tetrahydroxylmethoxychalcone (5) (IC50=7.09-80.81 mu M) were the most active ones against PC3, MCF7 and HepG2 cells. Moreover, 5 exhibited selectivity on prostate cancer cells (SI: 5.19). Hoechst staining and Annexin V/PI binding assays as well as cell cycle analysis on the compounds 3 (23 mu M) and 5 (5 and 7 mu M) demonstrated that these retrochalcones induced apoptosis and significantly suppressed cell cycle in G(1) and G(2)/M phases. Furthermore, 3 and 5 showed antimigratory effects on PC3 cells by wound healing assay. The results indicated that tested retrochalcones most particularly 5 could be potential anticancer drug candidates that prevent proliferation and migration of cancer cells.Öğe Esculetin Inhibits the Survival of Human Prostate Cancer Cells by Inducing Apoptosis and Arresting the Cell Cycle(Korean Soc Cancer Prevention, 2018) Turkekul, Kader; Colpan, R. Dilsu; Baykul, Talha; Ozdemir, Mehmet D.; Erdogan, SuatBackground: Prostate cancer (PCa) is one of the most important causes of death in men and thus new therapeutic approaches are needed. In this study, antiproliferative and anti-migration properties of a coumarin derivative esculetin were evaluated. Methods: Human PCa cell lines PC3, DU145, and LNCaP were treated with various concentrations of esculetin for 24 to 72 hours, and cell viability was determined by the MTT test. Cell cycle and apoptosis were analyzed by using cell-based cytometer. Gene expression levels were assessed by reverse transcription and quantitative real-time PCR, cell migration was determined by the wound healing assay. The protein expression was measured by Western blotting. Results: Esculetin inhibited cell proliferation in a dose- and time-dependent manner. Cell migration was inhibited by esculetin treatment. Administration of esculetin significantly reduced the cells survival, induced apoptosis and caused the G1 phase cell cycle arrest shown by image-based cytometer. The induced expression of cytochrome c, p53, p21 and p27, and down-regulated CDK2 and CDK4 may be the underlying molecular mechanisms of esculetin effect. Esculetin suppressed phosphorylation of Akt and enhanced protein expression of tumor-suppressor phosphatase and tensin homologue. Conclusions: Our findings showed that the coumarin derivative esculetin could be used in the management of PCa. However, further in vivo research is needed.Öğe Esculetin Protects Human Retinal Pigment Epithelial Cells from Lipopolysaccharide-induced Inflammation and Cell Death(Taylor & Francis Inc, 2018) Ozal, S. Altan; Turkekul, Kader; Gurlu, Vuslat; Guclu, Hande; Erdogan, SuatPurpose: Age-related macular degeneration (AMD) is the most common cause of visual loss. The dry AMD is characterized by retinal pigment epithelium (RPE) death and changes in AMD lead to severe loss of vision. Coumarin-derived esculetin has a number of therapeutic and pharmacological effects such as anti-inflammatory and antioxidant with various mechanisms. The purpose of this study was to investigate the effects of esculetin treatment on lipopolysaccharide (LPS)-induced inflammation, oxidative stress, and cell survival.Material and methods: Human RPE cells (ARPE-19) were incubated for 24-72h with 5g/ml LPS to induce inflammation and oxidative stress. Esculetin (5 M) was used to protect the cells from LPS-induced damage. The cell viability was evaluated by quantitative 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. Interleukin 6 (IL-6), IL-12, and vascular endothelial growth factor (VEGF) levels were determined by enzyme-linked immunosorbent assay (ELISA). IL-1, tumor necrosis factor receptor (TNFR), TNF-related apoptosis-inducing ligand (TRAIL), catalase, glutathione peroxidase (GPx), superoxide dismutase 1 (CuZnSOD) and SOD2 (MnSOD) mRNA expressions were analyzed by RT-quantitative polymerase chain reaction. Apoptosis was monitored by cell-based cytometer. NF-kappa B (NF-B) p65/RelA levels were determined by ELISA, and NF-B protein expression and extracellular signal-regulated kinase (ERK1/2) phosphorylation were evaluated by Western blot analysis.Results: Esculetin treatment significantly suppressed LPS-induced cell death mediated by apoptosis and necrosis in a concentration-dependent manner. While LPS caused significant inflammation with cytokine increase in cells, esculetin reduced the expression of LPS-induced cytokines, VEGF, TNFR, and TRAIL. Furthermore, exposure to LPS increased the expression of GPx and mitochondrial MnSOD, leading to oxidative stress in the cells. Esculetin treatment attenuated phosphorylation of ERK1/2 and NF-B expression mediated by LPS.Conclusions: These results suggest that esculetin may be an alternative treatment option for endotoxin-induced inflammation and oxidative stress, which therefore may inhibit the development of LPS-mediated AMD.Öğe Eupatilin attenuates TGF-?2-induced proliferation and epithelial-mesenchymal transition of retinal pigment epithelial cells(Taylor & Francis Ltd, 2021) Cinar, Ayca Kupeli; Ozal, S. Altan; Serttas, Riza; Erdogan, SuatPurpose The main characteristic of proliferative vitreoretinopathy (PVR) is migration, adhesion, and epithelial-mesenchymal transition (EMT) of retinal pigment epithelial cells (RPE). Eupatilin is a naturally occurring flavone that has the potential to inhibit cell proliferation and EMT. However, its efficacy on the PVR model induced by transforming growth factor-2 (TGF-beta 2) is unknown. In this study, the potential effect of eupatilin on proliferation and EMT in the treatment of RPE was investigated. Methods Serum starved human RPE cells (ARPE-19) were treated with 10 ng/ml TGF-beta 2 alone or co-treated with 25 mu M eupatilin for 48 h. Quantitative real-time PCR and Western blot analysis were used to assess targets at the mRNA and protein expression level, respectively. Apoptosis and cell cycle progression was assessed by image-based cytometry. The effect of treatment on cell migration was evaluated by wound healing assay. Results Eupatilin inhibited TGF-beta 2-induced RPE cell proliferation via regulating the cell cycle and inducing apoptosis. TGF-beta 2 upregulated mRNA expression of mesenchymal markers fibronectin and vimentin was significantly downregulated by the treatment, while the epithelial markers E-cadherin and occludin expression was upregulated. The therapy significantly suppressed TGF-beta 2 encouraged cell migration through downregulating the expression of transcription factors Twist, Snail, and ZEB1 induced by TGF-beta 2. Furthermore, eupatilin significantly inhibited the expression of MMP-1, -7, and -9, and suppressed NF-kappa B signalling. Conclusion These results suggest that eupatilin could inhibit the proliferation and transformation into fibroblast-like cells of RPE cells; thus the agent may be a potential therapeutic value in treating PVR.Öğe Eupatilin Inhibits the Proliferation and Migration of Prostate Cancer Cells through Modulation of PTEN and NF-?B Signaling(Bentham Science Publ Ltd, 2021) Serttas, Riza; Koroglu, Cagla; Erdogan, SuatBackground: Despite advances in the treatment of prostate cancer, side effects and the risks of developing drug resistance require new therapeutic agents. Eupatilin is a secondary metabolite of Artemisia asiatica and has shown potential anti-tumor activity in some cancers, but its potential in prostate cancer treatment has not yet been evaluated. Objective: The aim of the study was to investigate the effectiveness of eupatilin on prostate cancer cell proliferation and migration. Methods: Human prostate cancer PC3 and LNCaP cells were exposed to eupatilin and its efficacy on cell survival was determined by the MTT test. Apoptosis and cell cycle phases were evaluated by an image-based cytometer. Cell migration and invasion were evaluated by wound healing and matrigel migration assays; the expression of mRNA and protein was assessed by RT-qPCR and Western blot, respectively. Results: Eupatilin timeand dose-dependently reduced the viability of prostate cancer cells. Exposure of PC3 cells to 12.5 mu M-50 mu M eupatilin resulted in apoptosis by upregulating the expression of caspase 3, Bax and cytochrome c. Annexin V assessment also confirmed that eupatilin causes apoptosis. The treatment significantly upregulated the mRNA expression of p53, p21, and p27, causing cell cycle arrest in the G(1) phase. Administration of eupatilin inhibited migration and invasion of the cells by downregulating the expression of Twist, Slug and MMP-2,-7. In addition, the agent increased protein expression of tumor suppressor PTEN, while transcription factor NF-kappa B expression was reduced. Conclusion: Eupatilin strongly prevents the proliferation of prostate cancer cells, and suppresses migration and invasion. Due to its therapeutic potential, the clinical use of eupatilin in prostate cancer should also be supported by in vivo studies.Öğe The flavonoid apigenin reduces prostate cancer CD44+ stem cell survival and migration through PI3K/Akt/NF-?B signaling(Pergamon-Elsevier Science Ltd, 2016) Erdogan, Suat; Doganlar, Oguzhan; Doganlar, Zeynep B.; Serttas, Riza; Turkekul, Kader; Dibirdik, Ilker; Bilir, AyhanAims: Cancer stem cells (CSCs) are involved in drug resistance, metastasis and recurrence of cancers. The efficacy of apigenin on cell survival, apoptosis, migration and stemness properties were analyzed in CSCs. Main methods: Prostate CSCs (CD44(+)) were isolated from human prostate cancer (PCa) PC3 cells using a magnetic-activated cell sorting system. PC3 and CSCs were treated with various concentrations of apigenin, docetaxel and their combinations for 48 h. Key findings: Apigenin dose dependently inhibited CSCs and PC3 cell survival, and this was accompanied with a significant increase of p21 and p27. Apigenin induced apoptosis via an extrinsic caspase-dependent pathway by upregulating the mRNA expressions of caspases-8,-3 and TNF-alpha, but failed to regulate the intrinsic pathway as determined by the Bax, cytochrome c (Cyt-c) and APAF-1 in CSCs. In contrary to CSCs, apigenin induced intrinsic apoptosis pathway as evidenced by the induction of Bax, Cyt-c and caspase-3 while caspase-8, TNF-alpha and Bcl-2 levels remained unchanged in PC3 cells. The flavonoid strongly suppressed the migration rate of CSCs compared to untreated cells. Significant downregulation of matrix metallopeptidases-2,-9, Snail and Slug exhibits the ability of apigenin treatment to suppress invasion. The expressions of NF-kappa B p105/p50, PI3K, Akt and the phosphorylation of pAkt were decreased after apigenin treatment. Moreover, apigenin treatment significantly reduced pluripotency marker Oct3/4 protein expression which might be associated with the down-regulation of PI3K/Akt/NF-kappa B signaling. Significance: Our data indicated that, apigenin could be a useful compound to prevent proliferation and migration of cancer cells as well as CSCs. (C) 2016 Elsevier Inc. All rights reserved.Öğe Inhibition of Cigarette Smoke Induced-inflammation and Oxidative Damage by Caffeic Acid Phenethyl Ester in A549 Cells(Asian Journal Pharmaceutics, 2016) Kucukgul, Altug; Erdogan, SuatIntroduction: The main objective of this study was to evaluate the effect of antioxidative and antiapoptotic effects and underlying molecular mechanisms of caffeic acid phenethyl ester (CAPE) on human lung epithelial cells exposed to cigarette smoke (CS). Materials and Methods: Human alveolar epithelial A549 cells were exposed to CS and treated with various concentrations of CAPE for 24 h, and their effective concentrations were identified by cell viability assay (MTT). Antioxidant and anti-inflammatory effect of CAPE on nuclear erythroid related factor-2 (Nrf2) and nuclear factor-kappa beta (NF-kappa beta) protein levels were analyzed by Western blotting. Furthermore, caspase 8 gene expression level was analyzed by reverse transcription-quantitative polymerase chain reaction. Results: Low concentration CAPE pretreatment rescued 52% of CS-exposed A549 cells from death. CS upregulated gene expression level of caspase 8 by 4.28 fold. However, 2.5 mu M CAPE pretreatment increased caspase 8 level by 52%. CS exposure also elevated NF-kappa beta (p65) protein level by 70%, however, CAPE pretreatment significantly reversed this activation. While CS exposure decreased Nrf2 protein levels by 48% as compared with the control group, CAPE pretreatment increased Nrf2 protein level two folds approximately according to CS group. Discussion: CAPE markedly decreased inflammatory transcription factor NF-kB and increased antioxidant response element Nrf2 protein expression levels in CS-exposed human alveolar cells. According to the data obtained from this study, CAPE could be used as a strategic alternative to support treatment of inflammatory and oxidative stress-induced lung diseases.Öğe Inhibition of Midkine Suppresses Prostate Cancer CD133+ Stem Cell Growth and Migration(Elsevier Science Inc, 2017) Erdogan, Suat; Doganlar, Zeynep B.; Doganlar, Oguzhan; Turkekul, Kader; Serttas, RizaBackground: Midkine (MDK) is a tumor-promoting factor that is often overexpressed in various human carcinomas, and the role of MDK has not yet been fully investigated in prostate cancer stem cells. Materials and Methods: Prostate cancer CD133(+) stem cells (PCSCs) were isolated from human castration-resistant PC3 cells. PCSCs were treated with different concentrations of MDK inhibitor, iMDK, for 24-72 hours. The IC50 values were determined by the MTT test. Endogenous MDK messenger RNA expression was knocked down by small interfering RNA. Quantitative reverse transcription polymerase chain reaction, Western blot analyses and image-based cytometry were used to investigate apoptosis and cell cycle progression as well as their underlying molecular mechanisms. Cell migration was evaluated by the wound healing test. Results: iMDK caused dose- and time-dependent inhibition of PCSC survival. Similar growth inhibition was also obtained by small interfering RNA mediated knockdown of endogenous MDK expression. iMDK was shown to preferentially induce cell cycle arrest at the S and G2/M phases. Suppressed PCSC growth was also accompanied by increases in p53 and the cell cycle inhibitor p21 genes. Combinatorial treatment of iMDK with docetaxel significantly inhibited cell proliferation versus either of the agents used alone. Inhibition of MDK expression strongly suppressed the migration of PCSCs compared to untreated and docetaxel-treated cells. iMDK and the knockdown of MDK decreased p-Akt and significantly upregulated the expression of PI3K/phosphatase/tensin homolog. Conclusions: Our data indicate that MDK plays a crucial role in controlling PCSC proliferation and migration. Therefore, suppression of endogenous expression of MDK would, in combination with traditional chemotherapy drugs, be a potential treatment for PCSCs.Öğe Inhibition of Ribonucleotide Reductase Induces Endoplasmic Reticulum Stress and Apoptosis, Leading to the Death of Docetaxel-resistant Prostate Cancer Cells(Bentham Science Publ Ltd, 2023) Serttas, Riza; Erdogan, SuatBackground The development of chemotherapy resistance in prostate cancer (PCa) patients poses a significant obstacle to disease progression. Ribonucleotide reductase is a crucial enzyme for cell division and tumor growth. Triapine, an inhibitor of ribonucleotide reductase, has shown strong anti-tumor activity in various types of cancers. However, the effect of triapine on docetaxel-resistant (DR) human PCa cells has not been explored previously.Aim This study aimed to examine the potential anti-proliferative effects of triapine in PC3-DR (docetaxel-resistant) cells.Methods Cell viability was determined by the MTT test, and apoptosis and cell cycle progression were analyzed by image-based cytometer. mRNA and protein expression were assessed by RT-qPCR and western blot, respectively.Results Triapine administration significantly reduced PC3 and PC3-DR cells' survival, while the cytotoxic effect was higher in PC3-DR cells. Cell death resulting from inhibition of ribonucleotide reductase was mediated by endoplasmic reticulum stress, induction of apoptosis, and cell cycle arrest. The findings were supported by the upregulation of caspases, Bax, Bak, P21, P27, P53, TNF-alpha, FAS, and FASL, and downregulation of Bcl2, Bcl-XL, cyclin-dependent kinase 2 (CDK2), CDK4, cyclins, and heat shock proteins expression. According to the data, the reduction of ABC transporter proteins and NF-kappa B expression may play a role in triapine-mediated cytotoxicity in docetaxel-resistant cells.Conclusion Based on our findings, triapine emerges as a promising chemotherapeutic approach for combating docetaxel-resistant prostate cancer.Öğe Inhibition of telomerase potentiates enzalutamide efficiency of androgen-sensitive human prostate cancer cells(Imprimatur Publications, 2017) Gecgel, Karaca Kaan; Muduroglu, Mustafa; Erdogan, SuatPurpose: Androgen deprivation therapy (ADT) is one of the main strategies to treat prostate cancer (PCa) at various stages of its development. Androgen receptor (AR) antagonists such as enzalutamide are mainstay treatments for castration-sensitive prostate cancer. Though, a majority of patients initially respond to ADT, most will eventually progress to castrate-resistant, due to the development of different mutations on the AR. PCa cells express high telomerase activity, and there is a correlation between the total activity of telomerase and the Gleason score. Therefore, we hypothesized that the combination of enzalutamide plus a telomerase inhibitor could be more effective than enzalutamide alone in decreasing cell survival. Methods: In this study MTT test, RT-qPCR and image-based cytometry were used to investigate cell viability, apoptosis and cell cycle progression of androgen-responsive human prostate cancer LNCaP cells. The cells were treated with 5 mu M enzalutamide and 40 mu M telomerase inhibitor BIBR 1532, or with their combinations for 72 hrs. Results: Enzalutamide and BIBR 1532 alone inhibited cell proliferation in a dose-dependent manner. The combinations of the two agents could synergistically induce apoptotic and necrotic cell death. Either inhibition of telomerase by BIBR 1532 or AR blockages by enzalutamide decreased prostate-specific antigen (PSA) and the catalytic component of telomerase, hTERT, expression. Conclusion: These results suggest that telomerase inhibition therapy may contribute to the efficacy of enzalutamide in the androgen-sensitive PCa model.Öğe Low concentration of oleic acid exacerbates LPS-induced cell death and inflammation in human alveolar epithelial cells(Taylor & Francis Inc, 2017) Kucukgul, Altug; Erdogan, SuatPurpose: The current study aimed to investigate in vitro effects of oleic acid on lipopolysaccharide (LPS)-induced acute lung injury in the human lung epithelial cells (A549). Materials and Methods: The cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests. Selected gene expression levels were analyzed by Real-Time Quantitative-Polymerase Chain Reaction (RT-qPCR). Results: 24hours of LPS (100ng/mL) exposure decreased the cells' viability by 44.6% compared to untreated control. Low concentration (2.5nM) of oleic acid slightly suppressed the cell survival by 9.1% analyzed 24hours after incubation. However, oleic acid pretreatment before LPS exposure significantly increased cell survival loss to 63.9%. LPS exposure decreased the expressions of catalase (CAT) and glutathione peroxidase (GPx) mRNA levels by 2.8 and 2.5 fold, respectively. Moreover, pretreatment of the cells with oleic acid strengthened LPS-decreased expressions of CAT and GPx genes by 3.5 and 6.7 fold, respectively. The mRNA expressions of superoxide dismutase (SOD), induced nitric oxide synthase (iNOS), interleukin-1 beta, IL-12, COX-2, caspase-3 and caspase-8 were increased by 2.4, 2.2, 2.2, 2.3, 3.0, 2.6, and 2.5 fold, respectively, by LPS, and oleic acid pretreatment significantly potentiated the effect of LPS. Conclusion: Oleic acid worsens LPS-induced cell death by potentiating oxidative stress and inflammation in A549 lung epithelial cells.Öğe Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway(Elsevier France-Editions Scientifiques Medicales Elsevier, 2018) Erdogan, Suat; Turkekul, Kader; Dibirdik, Ilker; Doganlar, Oguzhan; Doganlar, Zeynep B.; Bilir, Ayhan; Oktem, GulperiAims: To examine the functions of growth factor midkine (MK) and a flavonoid quercetin on survival, apoptosis and migration of prostate cancer (PCa) stem cells (CSCs). Main methods: CD44(+)/CD133(+) and CD44(+) stem cells were isolated from PC3 and LNCaP cells, respectively by magnetic-activated cell sorting system. 3D cell culture was used to evaluate the ability of quercetin, MK siRNA, and the combination of both to inhibit spheroid formation, apoptosis and cell cycle arrest. Image-based cytometer, RT-qPCR, Western blotting and transwell migration assays were performed. Key findings: Quercetin treatment for 24-72 h inhibited PC3 and CD44+/CD133+ stem cell proliferation in a time-and dose-dependent manner. Knockdown of endogenous MK expression significantly suppressed proliferation of CD44(+)/CD133(+) and CD44(+) cells as well as their parent cells. Co-administration of MK siRNA and quercetin reduced the cell survival, induced apoptosis and caused G1 phase cell cycle arrest more effectively than the individual therapy. Knockdown of MK significantly enhanced the inhibitory effect of quercetin on CD44(+)/CD133(+) migration and spheroid formation. In addition, the combined therapy inhibited the phosphorylation of PI3K, AKT and ERK1/2, and reduced the protein expression of p38, ABCG2 and NF-kappa B. Significance: Quercetin alone exhibited significant cytotoxic effects on CD44(+)/CD133(+). MK plays an important role in the proliferation of CD44(+)/CD133(+) and CD44(+) cells in particular, and quercetin and MK-silencing therapy may be an important strategy in targeting CSCs that play a role in relapse, migration and drug resistance.Öğe Midkine silencing enhances the anti-prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-?B(Springer, 2020) Erdogan, Suat; Turkekul, Kader; Dibirdik, Ilker; Doganlar, Zeynep B.; Doganlar, Oguzhan; Bilir, AyhanProstate cancer (PCa) is the most common cancer in men worldwide. Midkine (MK) is overexpressed in PCa, as well as in tumor-initiating cells termed cancer stem cells (CSCs). Apigenin is a dietary flavone with considerable anti-tumor activities. In this study, we explored the possible therapeutic use of MK silencing, apigenin treatment, and a combination of both on human PCa and prostate cancer stem cells (PCSCs). CD44(+)CD133(+) PC3 and CD44(+) LNCaP CSCs were isolated from their parent cell lines. Both MK knockdown and apigenin treatment resulted in loss of cell viability in PCSCs, and these effects were significantly elevated when apigenin was applied with MK silencing. Combined treatment of CD44(+)CD133(+) PC3 cells with apigenin and MK siRNA was also more effective in inducing apoptotic and non-apoptotic cell death when compared with individual applications. Treatment of CD44(+) LNCaP cells with apigenin significantly decreased viability, although the combination treatment did not markedly alter the individual therapy. Molecular events underlying cell cycle arrest and inhibition of the survival, proliferation, and migration of CD44(+)CD133(+) PC3 cells were found to be associated with upregulated p21, p27, Bax, Bid, caspase-3, and caspase-8 expression, as well as downregulated p-p38, p-ERK, NF-kappa B, and PARP. In addition, the combination of apigenin treatment and MK silencing showed better outcomes on the anticancer efficacy of docetaxel in CD44(+)CD133(+) PC3 cells. In conclusion, MK-regulated events are different between PCSCs, and when combined with apigenin plus MK silencing, docetaxel treatment may be a valuable approach for the eradication of PCSCs.Öğe Multifaceted impact of adipose conditioned media: Obesity-driven promotion of prostate cancer and cancer stem cell dynamics(Wiley, 2024) Erdogan, Suat; Serttas, Riza; Dibirdik, Ilker; Turkekul, KaderObesity is an established risk factor for the development and progression of prostate cancer (PC). This study used adipose conditioned media (ACM) from differentiated adipocytes to assess its effect on PC development and aggressiveness. Due to limited research on ACM's impact on isolated PC stem cells (PCSCs), we also examined CD44+ PCSCs. ACM notably boosted interleukin-1 beta (IL-1 beta), IL-6, and IL-8 production in normal prostate epithelial cells and LNCaP cells. It also increased IL-6 and IL-8 production in PC3 and CD44+ LNCaP cells, and IL-1 beta and IL-6 production in CD44+ PC3 cells. This indicates that ACM induces the production of inflammatory cytokines in both cancer and prostate epithelial cells. Furthermore, ACM promoted proliferation in androgen receptor (AR)-negative PC3 cells, CD44+ PC3 PCSCs, and nonmalignant RWPE cells, without affecting AR-positive LNCaP cells. In addition, ACM-enhanced invasion and migration potential in both PC3 and CD44+ PC3 cells. Western blot analysis indicated the involvement of NF-kappa B and AKT pathways in ACM-induced proliferation in PC3 cells and NF-kappa B in PCSCs. In ACM-treated PC3 cells, E-cadherin was downregulated, while N-cadherin, Snail, vimentin, fibronectin, and Twist were upregulated, suggesting ACM-induced invasion via classical epithelial-to-mesenchymal transition (EMT) pathways. In response to ACM, PCSCs exhibited increased expression of E-cadherin, Snail, and vimentin, which are partial EMT markers promoting stemness and resistance to apoptosis. In addition, increased expressions of Nanog, Oct3/4, survivin, and Bcl-2 were observed. Although the molecules we studied have diverse effects on cellular regulation, our data emphasize obesity's multifaceted role in promoting and aggressing PC, notably affecting PCSC populations. The link between cancer and obesity has been well-established. Excess adipocyte tissue can promote inflammation and hormone imbalances, all of which contribute to cancer development. This study investigated the effectiveness of adipose tissue secretions on different types of prostate cancer (PC) cells, the proliferation and migration of normal prostate epithelial cells. The findings revealed that adipose tissue contributed to the proliferation, invasion, and migration of PC and cancer stem cells. In addition, it showed a potential relationship between adipose tissue and the proliferation of normal prostate epithelial cells.Öğe Naringin Combined with NF-?B Inhibition and Endoplasmic Reticulum Stress Induces Apoptotic Cell Death via Oxidative Stress and the PERK/eIF2?/ATF4/CHOP Axis in HT29 Colon Cancer Cells(Springer/Plenum Publishers, 2021) Albayrak, Dogan; Doganlar, Oguzhan; Erdogan, Suat; Merakli, Meryem; Dogan, Ayten; Turker, Pelin; Bostanci, AytenCurrently, combination therapy is considered the most effective solution for a selective chemotherapeutic effect in the treatment of colon cancer. This study investigated the death of both colon cancer HT29 cells and healthy vascular smooth muscle TG-Ha-VSMC cells (VSMCs) induced by naringin combined with endoplasmic reticulum (ER) stress and NF-kappa B inhibition. Naringin combined with tunicamycin and BAY 11-7082 suppressed the proliferation of HT29 cells in a dose-dependent manner and induced particularly apoptotic death without significantly affecting healthy VSMCs according to Annexin V/PI staining and AO/EB staining analyses. Insufficient antioxidant defense and heat shock response as well as excessive ROS generation were observed in HT29 cells following combination therapy. Quantitative real-time PCR and western blot analysis demonstrated that drug combination-induced mitochondrial apoptosis was activated through the ROS-mediated PERK/eIF2 alpha/ATF4/CHOP pathway. Additionally, naringin combination significantly reduced the sXBP expression induced by tunicamycin+BAY 11-7082 in a dose-dependent manner. In conclusion, this study found that naringin combined with tunicamycin+BAY 11-7082 efficiently induced apoptotic cell death in HT29 colon cancer cells via oxidative stress and the PERK/eIF2 alpha/ATF4/CHOP pathway, suggesting that naringin combined with tunicamycin plus BAY 11-7082 could be a new combination therapy strategy for effective colon cancer treatment with minimal side effects on healthy cells.
