Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells

Kaya, Tijen Temiz,Altun, Ahmet,Turgut, Nergiz Hacer,Ataseven, Hilmi,Koyluoglu, Gokhan Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.3

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

Synthesis and Antinociceptive Activity of (5-Chloro-2(3H)-Benzoxazolon-3-yl) Propanamide Derivatives

Onkol, Tijen,Sahin, M.Fethi,Yidirim, Engin,Erol, Kevser,Ito, Shigero The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.11

In this study, (5-chloro-2(3H)-benzoxazolon-3-yl)propanamide derivatives were synthesized. The chemical structures of the compounds were elucidated by their IR and $^1H-NMR$ spectral data and microanalysis. The compounds were tested for anti nociceptive activity by using the tail clip, tail flick, hot plate, and writhing methods. The varying levels of anti nociceptive activity of the compounds were compared with those of dipyrone and aspirin. Among these compounds, compound 5e, 5g, and 5h have been found to be significantly more active than the others and the standards in all the tests.

Anticancer Effect of COX-2 Inhibitor DuP-697 Alone and in Combination with Tyrosine Kinase Inhibitor (E7080) on Colon Cancer Cell Lines

Altun, Ahmet,Turgut, Nergiz Hacer,Kaya, Tijen Temiz Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.7

Colorectal cancer remains one of the most common types of cancer and a leading cause of cancer death worldwide. In this study, we aimed to investigate effects of DuP-697, an irreversible selective inhibitor of COX-2 on colorectal cancer cells alone and in combination with a promising new multi-targeted kinase inhibitor E7080. The HT29 colorectal cancer cell line was used. Real time cell analysis (xCELLigence system) was conducted to determine effects on colorectal cell proliferation, angiogenesis was assessed with a chorioallantoic membrane model and apoptosis was determined with annexin V staining. We found that DuP-697 alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. For the antiproliferative effect the half maximum inhibition concentration ($IC_{50}$) was $4.28{\times}10^{-8}mol/L$. Antiangiogenic scores were 1.2, 0.8 and 0.5 for 100, 10 and 1 nmol/L DuP-697 concentrations, respectively. We detected apoptosis in 52% of HT29 colorectal cancer cells after administration of 100 nmol/L DuP-697. Also in combination with the thyrosine kinase inhibitor E7080 strong antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells were observed. This study indicates that DuP-697 may be a promising agent in the treatment of colorectal cancer. Additionally the increased effects observed in the combination with thyrosine kinase inhibitor give the possibility to use lower doses of DuP-697 and E7080 which can avoid and/or minimize side effects.

Effect of Web-supported Health Education on Knowledge of Health and Healthy-living Behaviour of Female Staff in a Turkish University

Nurgul, Keser,Nursan, Cinar,Dilek, Kose,Over, Ozcelik Tijen,Sevin, Altinkaynak Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.2

Background: Once limited with face-to face courses, health education has now moved into the web environment after new developments in information technology This study was carried out in order to give training to the university academic and administrative female staff who have difficulty in attending health education planned for specific times and places. The web-supported training focuses on healthy diet, the importance of physical activity, damage of smoking and stress management. Materials and Methods: The study was carried out in Sakarya University between the years 2012-2013 as a descriptive and quasi experimental study. The sample consisted of 30 participants who agreed to take part in the survey, filled in the forms and completed the whole training. The data were collected via a "Personel Information Form", "Health Promotion Life-Style Profile (HPLSP)", and "Multiple Choice Questionnaire (MCQ). Results: There was a statistically significant difference between the total points from "Health Promotion Life-Style Profile" and the total points from the sub-scale after and before the training (t=3.63, p=0.001). When the points from the multiple choice questionnaire after and before training were compared, it was seen that the average points were higher after the training (t=8.57, p<0.001). Conclusions: It was found that web-supported health training has a positive effect on the healthy living behaviour of female staff working at a Turkish university and on their knowledge of health promotion.

OPEN ACCESS : Age Impaired endothelium-dependent vasodilation is improved by resveratrol in rat mesenteric arteries

( Semil S Gocmez ),( Philip J Scarpace ),( Melissa A Whidden ),( Benedek Erdos ),( Nataliya Kirichenko ),( Yasemin Sakarya ),( Tijen Utkan ),( Nihal Tumer ) 한국운동영양학회 2016 Physical Activity and Nutrition (Phys Act Nutr) Vol.20 No.1

[Purpose] To determine whether resveratrol improves the adverse effects age on vascular function in mesenteric arteries (MAs), and diminishes the hyperactivity in adrenal gland with age. [Methods] Male F344 x Brown Norway rats were assigned to 6-month control (YC), 6-month resveratrol (YR), 24-month control (OC) and 24-month resveratrol (OR). Resveratrol (15 mg/kg) was provided to resveratrol groups in drinking water for 14 days. [Results] Concentration response curves to phenylephrine (PE, 10(-9)-10(-5)M), acetylcholine (Ach, 10(-9)-10(-5)M) and resveratrol (10(-8)-10(-4)M) were evaluated in pressurized isolated MAs. The Ach concentration-response curve was right shifted with maximal response diminished in OC compared with YC rats. These effects were reversed by resveratrol treatment. The resveratrol-mediated relaxant responses were unchanged with age or resveratrol suggesting an endothelium-independent mechanism. Resveratrol tended to increase endothelial nitric oxide synthase; caused no effect on copper-zinc superoxide dismutase; and normalized the age-related elevatation in DβH and NPY levels in adrenal medulla, two indicators of sympathetic activity [Conclusion] These data indicate that resveratrol reverses age-related dysfunction in endothelium-dependent vasodilation in MAs and partially reverses hyperactivity of adrenomedullary function with age. This treatment may have a therapeuticpotential in the treatment of cardiovascular diseases or hypertension in the elderly.

NLRP1-Mediated Antidepressant Effect of Ketamine in Chronic Unpredictable Mild Stress Model in Rats

Feyza Aricioğ,lu,Canan Yalcinkaya,Ceren Sahin Ozkartal,Erdem Tuzun,Serap Sirvanci,Cem Ismail Kucukali,Tijen Utkan 대한신경정신의학회 2020 PSYCHIATRY INVESTIGATION Vol.17 No.4

Objective NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictable mild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated with suppression of NLRP1. Methods Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronic ketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test were performed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissected and prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemical analysis. Results CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment ameliorated them. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB, endothelial nitric oxide synthase, IL-1β, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba- 1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment. Conclusion In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shown to be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.

Antidepressant-like Effects Induced by Chronic Blockade of the Purinergic 2X7 Receptor through Inhibition of Non-like Receptor Protein 1 Inflammasome in Chronic Unpredictable Mild Stress Model of Depression in Rats

Feyza Aricioglu,Ceren Sahin Ozkartal,Tugce Bastaskin,Erdem Tüzün,Cansu Kandemir,Serap Sirvanci,Cem Ismail Kucukali,Tijen Utkan 대한정신약물학회 2019 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.17 No.2

Objective: Purinergic 2X7 receptor (P2X7R) activation is known to be involved in pathogenesis of depression. Our aims were to investigate P2X7R-activated inflammasome pathways in parallel with induction of depression and to test the antidepressant-like effects of the selective P2X7R antagonist Brilliant Blue G (BBG) in a rat model of chronic unpredictable mild stress (CUMS). Methods: Male Wistar albino rats were divided into control, CUMS, CUMS+BBG25 (25 mg/kg/day) and CUMS+BBG50 (50 mg/kg/day) groups (n=10 for each group). Various stressors were applied to rats for 6 weeks to establish the CUMS model and daily BBG treatment was started at the end of 3rd week. Sucrose preference test and forced swim test (FST) were performed to assess antidepressant-like effects. Brain samples were obtained for real-time polymerase chain reaction and immunohistochemistry analysis. Results: In FST, duration of immobility was reduced in the CUMS+BBG50 group. Also, BBG treatment significantly enhanced sucrose preference. While NLRP3 gene expression levels were unchanged in rats exposed to the CUMS protocol, expression levels of other inflammasome pathway factors NLRP1, caspase-1, ASC, NF-B, IL-1, IL-6 and P2X7R were increased. BBG treatment reduced expression levels of these factors. Likewise, Iba-1 and GFAP immunoreactivities were enhanced by the CUMS protocol and this action was reversed by BBG treatment. Conclusion: Chronic administration of BBG in CUMS model results in antidepressant-like activity in a dose dependent manner. Molecular and histological results show that these effects might be at least partially related to the suppression of inflammasome-related neuroinflammatory responses and suggest involvement of NLRP1 in depression.