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Renal cell carcinoma (RCC) is the predominant type of kidney cancer. Mammalian target of rapamycin (mTOR) inhibitor everolimus is currently used as a second-line therapy for sorafenib or sunitinib-refractory metastatic RCC patients. The clinical limitation confronted during everolimus therapy is the onset of drug resistance that decreases the efficacy of the drug. Elevated level of anti-apoptotic Bcl-2 protein is proposed to be an emerging feedback loop for the acquired drug-resistance in various cancer types. In this study, the Bcl-2 inhibitor ABT-737 was used in combination with everolimus to enhance its anti-tumor effectiveness in everolimus-resistant RCC cell lines. Everolimus and ABT-737 combination synergistically led to a decrease in the proliferation of primary site A-498 and metastatic site Caki-1 RCC cell lines, which was accompanied by a reduction in protein levels of cell cycle and mTOR pathway proteins. In both RCC cell lines, everolimus-ABT-737 combination not only induced apoptosis, caspase and PARP-1 cleavage but also a decrease in Bcl-2 protein levels in parallel with a concomitant increase in Bim and Noxa levels. In order to confirm our in vitro findings, we have generated everolimus-resistant RenCa cell line (RenCares) to establish a RCC mouse xenograft model. Animals co-treated with everolimus and ABT-737 exhibited a complete suppression of tumor growth without any notable toxicity. This study thus proposes the everolimus-ABT-737 combination as a novel therapeutic strategy for the treatment of RCC to overcome the current clinical problem of everolimus resistance. © Ivyspring International Publisher. Türkiye Bilimsel ve Teknolojik AraÅ?tirma Kurumu: 114S332 This work was partly supported by The Scientific and Technological Research Council of Turkey (Grant number 114S332) and Yeditepe University Hospital. A. H. Nayman is a recipient of doctoral fellowships from the Yeditepe University. H. Siginc is a recipient of doctoral fellowship from The Scientific and Technological Research Council of Turkey. We thank Emrah Nikerel (Yeditepe University, Turkey) for advices concerning the statistical analysis. We would also like to acknowledge Burcin Asutay and Engin Sumer (Yeditepe University, Turkey) for their technical support.

© 2016 Elsevier Masson SASProstate cancer is a multistep and complicated cancer type that is regulated by androgens at the cellular level and remains the second commonest cause of death among men. Discovery and development of novel chemotherapeutic agents enabling rapid tumor cell death with minimal toxic effects to healthy tissues might greatly improve the safety of chemotherapy. The present study evaluates the anti-cancer activity of a novel heterodinuclear copper(II)Mn(II) complex (Schiff base) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (Pluronic) P85. We used assays for cell proliferation, apoptosis, cell migration and invasion, DNA binding and cleavage to elucidate the molecular mechanisms of action, in addition to the anti-inflammatory potency of the new combination. The combined treatment of Schiff base and P85 lead to a remarkable anti-cancer effect on prostate cancer cell lines. Cell proliferation was inhibited in Schiff base-P85 treatment. The activity of this formulation is on DNA binding and cleavage and prevents inflammation in in vitro conditions. This is the first study presenting the anti-cancer activity of the present Schiff base derivative and its combination with P85 to treat prostate cancer in vitro.

In fibrotic conditions increases in TG2 activity has been linked to an increase in the deposition of extracellular matrix proteins. Using TG2 transfected Swiss 3T3 fibroblasts expressing TG2 under the control of the tetracycline-regulated inducible promoter, we demonstrate that induction of TG2 not only stimulates an increase in collagen and fibronectin deposition but also an increase in the expression of these proteins. Increased TG2 expression in these fibroblasts led to NF-kappa B activation, resulting in the increased expression of transforming growth factor (TGF) beta(1). In addition, cells overexpressing TG2 demonstrated an increase in biologically active TGF beta(1) in the extracellular environment. A specific site-directed inhibitor of TG abolished the NF-kappa B and TGF beta 1 activation and the subsequent elevation in the synthesis and deposition of extracellular matrix proteins, confirming that this process depends on the induction of transglutaminase activity. Treatment of TG2-induced fibroblasts with nontoxic doses of nitric oxide donor S-nitroso-N-acetylpenicillamine resulted in decreased TG2 activity and apprehension of the inactive enzyme on the cell surface. This was paralleled by a reduction in activation of NF-kappa B and TGF beta(1) production with a subsequent decrease in collagen expression and deposition. These findings support a role for NO in the regulation of TG2 function in the extracellular environment. Aston University; European UnionEuropean Union (EU) [MRTN-CT-2006-036032]; Scientific & Technological Research Council of Turkey Health Sciences DivisionTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [104S606] This work was supported in part by Aston University, Grant MRTN-CT-2006-036032 from the European Union, and Grant 104S606 from the Scientific & Technological Research Council of Turkey Health Sciences Division.

© 2022New thiosemicarbazides (3, 5-6), 1,2,4-triazoles (14-15) and thioethers (22-68) from derived (S)-Naproxen were synthesized in this study. The structure of these compounds were elucidated by spectral (FT-IR, 1H NMR, 13C NMR) methods, besides elemental analysis and TLC. The molecular binding of the compounds on MetAP-2 was performed. Anticancer effects of the synthesized compounds were studied by using MTT assay method on MCF-7 (includes oestrogene and progesterone receptors) and MDA-MB-231 (lacks estrogen and progesterone receptors) adenocarcinoma cell lines at 0, 10, 25, 50, 75 and 100 μM concentrations for 24 h. The IC50 values of novel (S)-Naproxen derivatives were determined between from 5 to 100 μM on MCF-7 breast cancer cell line and MDA-MB-231 cell lines. The apoptotic activity of selected compounds 22 and 42 were first analyzed by Annexin V staining using Tali Image-Based Cytometer. Mitochondrial membrane potential changes determined in fluorescence plate reader following JC-1 stain for compounds 22 and 42 in MCF-7 and MDA-MB-231 cells. The effect of these compounds on the cell viability 4T1 mouse mammary tumor cell line was tested at 1 to 5 times of calculated IC50 value (IC50x1, IC50x2, IC50x3, IC50x4, and IC50x5). Next in order to determine the toxicity of the combination of compound 51 and Docetaxel, WST-1 cell viability and proliferation assay was performed with 4T1.

Synthesis and characterization of well-defined amphiphilic block copolymers containing poly(2-ethyl-2-oxazoline) as hydrophilic block and poly(?-caprolactone) or poly(L-lactide) as hydrophobic block is achieved by copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry. The clickable precursors, ?-alkyne-functionalized poly(?-caprolactone) and poly(L-lactide) and ?-azido-functionalized poly(2-ethyl-2-oxazoline) are simply prepared and joined using copper sulfate/ ascorbic acid catalyst system at room temperature. The structures of precursors and amphiphilic block copolymers are characterized by spectroscopic, chromatographic and thermal analyses. The cytotoxic activities of resulting amphiphilic block copolymers and their precursors are investigated in the prostate epithelial and cancer cells under in-vitro conditions. The treatment of the healthy prostate epithelial cell line PNT1A reveals that no significant cytotoxicity, whereas some significant toxic effects on the prostate cancer cell lines are observed. © BME-PT. TUBITAK-213M725 The authors would like to thank Turkish Scientific and Technological Council (TUBITAK-213M725) for financial supports.

Tissue transglutaminase (TG2) is the ubiquitously expressed member of transglutaminase family and shown to play a critical role in the development and progression of drug resistance malignancies. We have previously showed the association of TG2 upregulation with progression and metastasis of renal cell carcinoma (RCC) and low disease-free survival. In the present study we further investigate the role of TG2 in cell adhesion, migration and invasion of RCC by silencing TG2 expression in Caki-2 and A-498 primary site and Caki-1 and ACHN metastatic site RCC cell lines. Downregulation of TG2 expression led up to a 60% decrease in actin stress fiber formation and adhesion to ß 1 integrin (ITGB1) substrates fibronectin, collagen type I and laminin in both primary and metastatic site RCC cell lines. In addition, treatment with siRNAs against TG2 impaired the migration capacity and cellular invasiveness of ITGB1 substrates in all 4 RCC cell lines. Lastly, the knockdown of TG2 in metastatic Caki-1 cells diminished the expression of CD44, CD73-and CD105 cancer stem cell-like markers. We conclude, for the first time, that TG2 expression is critical for cancer cell adhesion, migration, invasiveness and cancer cell-stemness during RCC progression and dissemination. Therefore, combined targeting of TG2 with drugs widely used in the treatment of RCC may be a promising therapeutic strategy for RCC. © 2017 Informa UK Limited, trading as Taylor & Francis Group. 289964 109S431 This work was supported in part by EU Marie Curie ITN “TRANSPATH” under Grant number 289964, and by TUB€ İTAK under Grant number 109S431.

Prostate cancer is a multistep and complicated cancer type that is regulated by androgens at the cellular level and remains the second commonest cause of death among men. Discovery and development of novel chemotherapeutic agents enabling rapid tumor cell death with minimal toxic effects to healthy tissues might greatly improve the safety of chemotherapy. The present study evaluates the anti-cancer activity of a novel heterodinuclear copper(II)Mn(II) complex (Schiff base) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (Pluronic) P85. We used assays for cell proliferation, apoptosis, cell migration and invasion, DNA binding and cleavage to elucidate the molecular mechanisms of action, in addition to the anti-inflammatory potency of the new combination. The combined treatment of Schiff base and P85 lead to a remarkable anti-cancer effect on prostate cancer cell lines. Cell proliferation was inhibited in Schiff base-P85 treatment. The activity of this formulation is on DNA binding and cleavage and prevents inflammation in in vitro conditions. This is the first study presenting the anti-cancer activity of the present Schiff base derivative and its combination with P85 to treat prostate cancer in vitro. © 2016 Elsevier Masson SAS

Background: Effects of whole cell type immunization on mice Ehrlich tumours were evaluated. Materials and Methods: After preliminary study, mice were divided two major groups; 1x1000 and 100x1000 live Ehrlich cell transferred major groups, each divided into four subgroups (n: 10). Study groups were immunized with Ehrlich cell lysates in 0, 3, 7, 14 th days and after 30 days of last immunization, live Ehrlich cells were transferred. Mice were observed for six months and evaluated for total and cancer free days. Results: Out of 100x1000 cell transferred solid type study group, all study group mean and tumour free periods were statistically longer than control groups. All 1x1000 Ehrlich cell transferred study groups survived significantly longer than 100x1000 Ehrlich cell transferred groups. Conclusions: Ehrlich mice tumours were prevented and survival prolonged with whole cell type immunization. Effects are related to the number of transferred tumor cells.

Objective: Tissue transglutaminase (TGM2) up-regulation is involved in the progression and dissemination of carcinomas through ß1 integrin (ITGB1) association. Given that TGM2 interaction with syndecan-4 (SDC4) on the cell surface is important in the activation of ITGB1 and integrin-mediated survival signaling, we investigated the roles of TGM2, ITGB1, and SDC4 in the development and metastasis of renal cell carcinoma (RCC). Material and methods: Expression levels of TGM2, ITGB1, and SDC4 mRNA were analyzed in primary tumor samples (n = 95) and their healthy counterparts in addition to control and RCC epithelial cell lines. TGM2 catalytic activity in 60 randomly selected patient samples was measured by enzyme-linked sorbent plate assay. Results: TGM2 expression ratio showed a significant 2.9-fold decrease in 67 (70.5%) of the primary RCC tumors (P

Oxalate is the most common component of kidney stones and elevated urinary levels induce renal tubular cell toxicity and death which is essential for crystal attachment. Endothelial cells, in some studies have been shown to regulate certain functions of renal proximal tubule cells. The aim of this study was to evaluate the effect of endothelial cells on tubular cell apoptosis in a coculture system mimicking the in vivo renal physiological settings. The human umbilical vein endothelial cells (HUVEC) and human renal proximal tubule epithelial cells (RPTEC) were exposed to increasing concentrations (0-1.0 mM) of oxalate with or without 10 µM PDTC pretreatment for 24 h. In HUVEC, RPTEC and HUVEC-RPTEC co-cultures, the cell viability was measured using the WST-1 assay and cell death with the TUNEL analysis using the flow cytometry. The treatment of RPTECs with oxalate lead to 8.9-26.2% cell death which was reduced to 0-1.6% with the PDTC pretreatment. The death rate of RPTECs was significantly increased by 15-19% at different oxalate concentrations when co-cultured with HUVECs. In contrast, cell viability was not substantially altered in PDTC pretreated RPTECs that were co-cultured with HUVECs. Apoptosis was the way of cell death as similar rate of apoptosis was observed in cell culture systems. Although cell viability of RPTECs was further reduced when co-cultured with HUVECs, it was restored with the pretreatment of PDTC. This is the first study focusing on the role of endothelial cells on RPTEC apoptosis following hyperoxaluria. © Springer-Verlag 2012.

An experimental study in rats was performed to evaluate the presence and the degree of both tubular apoptotic changes and crystallization at cortical, medullar and papillary regions of the kidney during hyperoxaluric phase and assess the possible protective effects of vitamin E and verapamil on these pathologic changes (particularly in papillary part of the affected kidneys). A total of 32 rats have been included into the study program. Hyperoxaluria was induced by continuous administration of ethylene glycol (0.75%). In addition to hyperoxaluria induction, animals in Groups 2 and 3 did receive a calcium channelblocking agent (verapamil) and vitamin E, respectively. Histologic alterations of the kidneys including crystal formation together with apoptotic changes were evaluated on days 1, 14 and 28, respectively. Both apoptotic changes and the presence and degree of crystallization were assessed separately in renal cortical region, medulla and particularly papillary parts of the removed kidneys. Although verapamil did well limit the degree of crystal formation and apoptosis and brought it to the same levels observed in control group animals in all parts of the kidneys during intermediate phase, addition of vitamin E was failed to show the same protective effect during both intermediate and late phase evaluations. As demonstrated in our study, the limitation of both crystal deposition and apoptotic changes might be instituted by calcium channel-blocking agents. Clinical application of such agents in the prophylaxis of stone disease might limit the formation of urinary calculi, especially in recurrent stone formers. © Springer-Verlag 2011.

63rd International Congress and Annual Meeting of the Society-for-Medicinal-Plant-and-Natural-Product-Research (GA) -- August 23-27, 2015 -- Budapest, Hungary WOS: 000367558100415 Cistus laurifolius L. (Cistaceae) is known as 'laden' in Anatolia and the leaves of the plant are used against rheumatismal diseases traditionally [1]. The ethanol extract of the leaves were submitted to solvent-solvent extractions and n-hexane, chloroform, ethyl acetate, n-butanol, remaining water subextracts were obtained. The extract and subextracts were investigated for their inhibitory effects on Nuclear Factor kappa B (NF-κB) transcrption factor on lipopolysaccharide induced Raw 264.7 macrophages. Only remaining water subextract exerted 20% inhibition. The subextract was fractionated by chromatographic methods but the fractions were found to be not effective. Thus, remaining water subextract was directed for further in vitro anti-inflammatory investigations. The effects on nitric oxide (NO), prostaglandine E2 (PGE2), tumor necrosis factor (TNFα) and interleukins (IL-1α, IL-1β, IL-2, IL-6) were studied by Griess and ELISA. The effects on iNOS and COX-2 protein levels and the phosphorylation levels of mitogen activated protein kinases (ERK1/2, JNK, p38) and I kappa B alpha (IκBα) were examined by Western Blot method. The subextract was applied to Raw 264.7 macrophage cells at 25, 50 and 100 µg/mL concentrations and it provided up to 57% decrease of NO production and up to 55% decrease of PGE2 production of cells. The iNOS and COX-2 protein levels were decreased accordingly. The subextract exerted inhibitory effect on TNFα (37%). This subextract inhibited the phosphorylation of IκBα at 50 and 100 µg/mL concentrations while JNK phosphorylation was concentration-dependently inhibited.

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