Browsing by Subject "Therapy"

Now showing 1 - 4 of 4

Open Access
Contribution of notch signaling on HCC stem cell status and utilizing TLR agonists and notch inhibition to improve HCC theraphy
(2014) Ertuna, Yusuf İsmail
Hepatocellular carcinoma (HCC) is the seventh most common cancer type worldwide, and ranked third place among cancer-related deaths within both sexes. As in many solid tumors, HCC shelters a cancer stem cell subpopulation, and is held responsible for the resistance developed during chemo-and-radio-therapy of HCC. The only option to cure HCC is liver transplantation, which is the bottleneck to provide a remedy to patients due to limited availability. Understanding the stem cell behavior of HCC would critically contribute to develop effective eradication strategies. In this study, a panel of 17 HCC cell lines was evaluated for their CSC status. Of these cell lines, six of them were determined to be positive for CD133 expression, a cardinal CSC marker. Next, HepG2, Huh7 and Hep3B-TR, (a desensitized TGF-beta-1 receptor clone) were selected and Notch activity vs. CSC fraction was investigated by analyzing CD133+/EpCAM+ levels. Our results revealed that DAPT (a notch inhibitor) led to a drop in CD133+/EpCAM+ levels in HepG2 and Huh7 by half, but not in Hep3B-TR cells, implicating a possible TGFβ1R involvement on CSC generation/maintenance. Treatment of cells with a notch ligand, Jagged-1, however, had little or no positive effect on CD133+/EpCAM+ expressions in all tested cells. Additionally, HCC cells' response to different TLR ligands and the resulting transcript expressions of TLRs were investigated by PCR. Of note, TLRs are widely used in immunotherapy of cancers. Here we aimed to combine Notch inhibitor along with selected TLR ligand, thereby improving tumor clearance in athymic mice xenografted with HCC. We found that in three selected cell lines upon TLR2 ligand stimulation, TLR5 and TLR7 were highly upregulated. Afterwards, treating these HCC cell lines with these ligands we observed that TLR3, TLR7/8 and TLR9 levels were activated. In the final part of this study, tumor-bearing mice with Huh7, were subjected to a combination therapy with TLR ligands +/- DAPT. We demonstrated that combination therapy comprising TLR3, 7/8 and 9 ligands and DAPT (only two injections, a week apart) induced significant tumor regression.
Open Access
Exosomes: Natural nanovesicle candidates used in the diagnosis and treatment
(Turkish Society of Immunology, 2013) Kahraman, T.; Gíiçlíiler G.; Gürsel I.
Exosomes are nano-vesicles released by all known cells. Although they were called as residual cells acting as a cleaner of undesired molecules out of cell during the first discovery in 1980s, recent studies have revealed critical physiological tasks of these vesicles over the past 20 years. These vesicles which can be produced by all body fluids play an important role in many biological activities including intracellular communication, signal conduction, genetic material transfer, and regulation of immune response. Due to their several tasks, exosomes play a crucial role in the disease pathogenesis. Considering all these tasks, exosomes can be considered in both diagnosis and treatment. Exosomes originating from distinct cells have immunosuppressive and immunostimulatory features and, thereby, therapeutic attempts which regulate immune function in case of autoimmune and immunosuppression. In addition, thanks to being natural nano-carriers, exosomes may pave the way for the development of new-generation vaccines containing both adjuvant and antigen. Besides therapeutic applications, there are evidences indicating that exosomes can be used in the diagnosis of several cancer forms including prostate cancer, glioblastoma, squamous-cell lung carcinoma and hepatocellular carcinoma, as they play a role in the disease pathogenesis. © 2014 Turkish Journal of Immunology.
Open Access
Synthesis of novel 6-(4-substituted piperazine-1-yl)-9-(β-dribofuranosyl)purine derivatives, which lead to senescence-induced cell death in liver cancer cells
(ACS, 2012) Tunçbilek, M.; Güven, Ebru Bilget; Önder, T.; Çetin-Atalay, Rengül
Novel purine ribonucleoside analogues (9-13) containing a 4-substituted piperazine in the substituent at N-6 were synthesized and evaluated for their cytotoxicity on Huh7, HepG2, FOCUS, Mahlavu liver, MCF7 breast, and HCT116 colon carcinoma cell lines. The purine nucleoside analogues were analyzed initially by an anticancer drug-screening method based on a sulforhodamine B assay. Two nucleoside derivatives with promising cytotoxic activities (11 and 12) were further analyzed on the hepatoma cells. The N-6-(4-Trifluoromethylphenyl)piperazine analogue 11 displayed the best antitumor activity, with IC50 values between 5.2 and 9.2 mu M. Similar to previously described nucleoside analogues, compound 11 also interferes with cellular ATP reserves, possibly through influencing cellular kinase activities. Furthermore, the novel nucleoside analogue 11 was shown to induce senescence-associated cell death, as demonstrated by the SA beta-gal assay. The senescence-dependent cytotoxic effect of 11 was also confirmed through phosphorylation of the Rb protein by p15(INK4b) overexpression in the presence of this compound.
Open Access
Synthesis of oligomers, polymers and cucurbituril- based polyrotaxanes towards polymer light emitting diode and photodynamic therapy application
(2014-06) Idris, Muazzam
In the first part of this study, porphyrin-thiophene monomers, oligomers and polymer are synthesized for photodynamic therapy application. Water solubility and the ability of a photosensitizer to generate singlet oxygen for tumor destruction are important conditions for ideal photosensitizer in photodynamic therapy application. For this purpose, water soluble pendent groups are attached to the porphyrin monomers before coupling with thiophene monomer to form oligomers and polymer. The presence of sulfur atom in thiophene facilitates intersystem crossing due to spin-orbit coupling and thus will increase singlet oxygen generation. Consequently, the ability of singlet oxygen generation of the polymer is found to be higher than oligomers followed by monomers. In the second part of the thesis, the effects of cucurbit[n]uril on photophysical, electrochemical and thermal properties of ionic conjugated polymers in water are described. Conjugated polymers are well known for their interesting optical properties and are used in the area of light emitting diodes. However, their stacking nature reduces their fluorescent quantum yields and thus limits their further applications. If the interactions among the polymers chains are reduced or the polymer backbones are insulated in some means, the emission efficiency of the polymers could be enhanced. For this purpose, two different green emitting fluorene-thiophene based polymers (29 and 33) and their cucurbituril based polyrotaxanes counterparts (30 and 34) are synthesized through Suzuki Coupling. In both polyrotaxane 30 and 34, enhancement in optical properties was observed showing fluorescent quantum yields of 0.46 and 0.55 in water respectively comparing to polymers 29 and 33 which has only 0.10 and 0.35 in water respectively. Their optical and electroluminescent properties were further utilized by fabricating devices as multilayer white polymer light emitting diodes (PLEDs). The synthesized molecules are characterized by 1H-NMR, 13C-NMR, ESI mass spectrometry, UV-VIS, photoluminescence, time resolved fluorescence spectroscopy, FT-IR, elemental analysis gel permeation chromatography, size exclusion chromatography, thermogravimetric analysis and cyclic voltammetry.