• Nuclear Medicine and Molecular Imaging
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• v.40 no.5
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• pp.263-270
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• 2006

Purpose: Several radioisotope-labeled thymidine derivatives such as $[^{11}C]$thymidine was developed to demonstrate cell proliferation in tumor. But it is difficult to track metabolism with $[^{11}C]$thymidine due to rapid in vivo degradation and its short physical half-life. 3'-$[^{18}F]$fluoro-3'-deoxythymidine ($[^{18}F]$FLT) was reported to have the longer half life of fluorine-18 and the lack of metabolic degradation in vivo. Here, we described the synthesis of the 3'-$[^{18}F]$fluoro-3'-deoxythymidine ($[^{18}F]$FLT) and compared with $([^{18}F]FET)\;and\;([^{18}F]FDG)$ in cultured 9L cell and obtained the biodistribution and PET image in 9L tumor hearing rats. Material and Methods: For the synthesis of $[^{18}F]$FLT, 3-N-tert-butoxycarbonyl-(5'-O-(4,4'-dimet hoxytriphenylmethyl)-2'-deoxy-3'-O-(4-nitrobenzenesulfonyl)-${\beta}$-D-threopentofuranosyl)thymine was used as a FLT precursor, on which the tert-butyloxycarbonyl group was introduced to protect N3-position and nitrobenzenesulfonyl group. Radiolabeling of nosyl substitued precursor with $^{18}F$ was performed in acetonitrile at $120^{\circ}C$ and deproteced with 0.5 N HCI. The cell uptake was measured in cultured 9L glioma cell. The biodistribution was evaluated in 9L tumor bearing rats after intravenous injection at 10 min, 30 min, 60 min and 120 min and obtained PET image 60 minutes after injection. Results: The radiochemical yield was about 20-30% and radiochemical purity was more than 95% after HPLC purification. Cellular uptake of $[^{18}F]$FLT was increased as time elapsed. At 120 min post-injection, the ratios of tumor/blood, tumor/muscle and tumor/brain were $1.61{\pm}0.34,\;1.70{\pm}0.30\;and\;9.33{\pm}2.22$, respectively. The 9L tumor was well visualized at 60 min post injection in PET image. Conclusion: The uptake of $[^{18}F]$FLT in tumor was higher than in normal brain and PET image of $[^{18}F]$FLT was acceptable. These results suggest the possibility of $[^{18}F]$FLT at an imaging agent for brain tumor.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4499-4505
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• 2014

Glioblastoma, the most aggressive and malignant form of glioma, appears to be resistant to various chemotherapeutic agents. Hence, approaches have been intensively investigated to targeti specific molecular pathways involved in glioblastoma development and progression. Aloe emodin is believed to modulate the expression of several genes in cancer cells. We aimed to understand the molecular mechanisms underlying the therapeutic effect of Aloe emodin on gene expression profiles in the human U87 glioblastoma cell line utilizing microarray technology. The gene expression analysis revealed that a total of 8,226 gene alterations out of 28,869 genes were detected after treatment with $58.6{\mu}g/ml$ for 24 hours. Out of this total, 34 genes demonstrated statistically significant change (p<0.05) ranging from 1.07 to 1.87 fold. The results revealed that 22 genes were up-regulated and 12 genes were down-regulated in response to Aloe emodin treatment. These genes were then grouped into several clusters based on their biological functions, revealing induction of expression of genes involved in apoptosis (programmed cell death) and tissue remodelling in U87 cells (p<0.01). Several genes with significant changes of the expression level e.g. SHARPIN, BCAP31, FIS1, RAC1 and TGM2 from the apoptotic cluster were confirmed by quantitative real-time PCR (qRT-PCR). These results could serve as guidance for further studies in order to discover molecular targets for the cancer therapy based on Aloe emodin treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2693-2696
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• 2015

The diagnostic value of membrane glycolipid biochemistry index, the lipid-bound sialic acid (LSA) and total sialic acid (TSA) in cerebrospinal fluid (CSF) was evaluated in 30 intracranial and 65 gastrointestinal tumors. The plasma LSA, TSA and red cell membrane sialic acid (R-SA) in were determined according to the method of Sevenmerhulm. Our results showed that the levels of LSA and TSA in CSF of intracranial tumor patients was higher than that of normal group(p<0.01). The concentration of TSA and LSA in patients with malignant glioma was higher than that of benign meningioma patients(P<0.01). No significance was found between intracranial halmatoma patients and normal control group for levels of membrane glycolipids (p>0.05). Results also found that the plasma LSA, TSA and R-SA of gastric carcinoma were significantly higher than those of control group (p<0.05); while no significant difference was found in the plasma LSA, TSA and R-SA levels between chronic gastritis, gastrohelcoma and normal control group (p>0.05). Plasma LSA, TSA and R-SA levels of gastric carcinoma patient were significantly higher than those of chronic gastritis patients and gastrohelcoma patients(p<0.05). It was also found that plasma LSA, TSA and R-SA contents were significantly higher in large intestine carcinoma patients than in benign in stestine tumor patients (p<0.05) while no significant difference was found between intestine benign tumor and normal control group (p>0.05). The levels of LSA, TSA and R-SA were obviously higher in the patients with metastasis than in the ones without (p<0.05.) The membrane glycolipid biochemistry index LSA and TSA in CSF are sensive markers for diagnosing intracranial tumors. For gastrointestinal malignant tumors the plasma LSA TSA and red blood cell membrane SA may be considered as auxiliary indicators for diagnosis. They can be used for distinguishing benign from malignant tumors.

• BMB Reports
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• v.47 no.10
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• pp.575-580
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• 2014

In this study, we investigate whether arsenite-induced DNA damage leads to p53-dependent premature senescence using human glioblastoma cells with p53-wild type (U87MG-neo) and p53 deficient (U87MG-E6). A dose dependent relationship between arsenite and reduced cell growth is demonstrated, as well as induced ${\gamma}H2AX$ foci formation in both U87MG-neo and U87MG-E6 cells at low concentrations of arsenite. Senescence was induced by arsenite with senescence-associated ${\beta}$-galactosidase staining. Dimethyl- and trimethyl-lysine 9 of histone H3 (H3DMK9 and H3TMK9) foci formation was accompanied by p21 accumulation only in U87MG-neo but not in U87MG-E6 cells. This suggests that arsenite induces premature senescence as a result of DNA damage with heterochromatin forming through a p53/p21 dependent pathway. p21 and p53 siRNA consistently decreased H3TMK9 foci formation in U87M G-neo but not in U87MG-E6 cells after arsenite treatment. Taken together, arsenite reduces cell growth independently of p53 and induces premature senescence via p53/p21-dependent pathway following DNA damage.

• Journal of Life Science
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• v.17 no.8 s.88
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• pp.1039-1045
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• 2007

Glioblastoma multiforme (GBM) is the most frequently occurring brain cancer. Although the existence of cancer stem cells (CSCs) in GBM has been established, there is little evidence to explain the link between CSCs and chemoresistance. In this study, we investigated that only a few cells of A172 and established GBM2 survived after 1,3-bis(2chloroethyl)-1-nitrosourea (BiCNU) exposures and these sur-vived cells resist the subsequent BiCNU treatment. In addition, these BiCNU-resistant small pop-ulations derived from GBM cells increased the phosphorylations of Erk and Akt and highly expressed CD133 stem cell surface marker. Furthermore, we observed that the BiCNU-resistant cancer cells de-rived from GBM have grown tumors when transplanted into severe combined immuno-deficient (SCID) mouse brain. These results demonstrate that BiCNU-resistant subpopulation cells derived from GBM have cancer stem-like cell properties. Therefore, it may provide provide further evidence that CSCs in GBM have chemotherapeutic drug resistance.

• Journal of Life Science
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• v.22 no.5
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• pp.697-701
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• 2012

Activated protein C (APC) has an anticoagulant effect and a non-hemostatic effect such as regulation of cell metastasis and modulation of inflammation. In this study, we investigated whether APC could modulate apoptosis in cancer cells. Tumor necrosis factor (TNF)-${\alpha}$, cyclohexamide, and FAS markedly induced apoptosis in human renal carcinoma Caki cells. When Caki cells were pretreated with APC, the percentage of death receptor-induced apoptosis did not change. Furthermore, we checked the effect of APC on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human glioma T98G and human breast carcinoma MDA231 cells. APC also had no effect on TRAIL-induced apoptosis in both cell lines. However, pretreatment with APC inhibited combination treatment (kahweol plus TRAIL and kahweol plus melatonin)-induced apoptosis and PARP cleavage in Caki cells. Taken together, our results suggest that APC can modulate anti-cancer therapeutic efficiency.

• Molecules and Cells
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• v.40 no.10
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• pp.761-772
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• 2017

Glioblastoma is the most frequent and most aggressive brain tumor in adults. Solute carrier family 8 member 2 (SLC8A2) is only expressed in normal brain, but not present in other human normal tissues or in gliomas. Therefore, we hypothesized that SLC8A2 might be a glioma tumor suppressor gene and detected the role of SLC8A2 in glioblastoma and explored the underlying molecular mechanism. The glioblastoma U87MG cells stably transfected with the lentivirus plasmid containg SLC8A2 (U87MG-SLC8A2) and negative control (U87MG-NC) were constructed. In the present study, we found that the tumorigenicity of U87MG in nude mice was totally inhibited by SLC8A2. Overexpression of SLC8A2 had no effect on cell proliferation or cell cycle, but impaired the invasion and migration of U87MG cells, most likely through inactivating the extracellular signal-related kinases (ERK)1/2 signaling pathway, inhibiting the nuclear translocation and DNA binding activity of nuclear factor kappa B ($NF-{\kappa}B$), reducing the level of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA)-its receptor (uPAR) system (ERK1/2-$NF-{\kappa}B$-MMPs/uPA-uPAR), and altering the protein levels of epithelial to mesenchymal transitions (EMT)-associated proteins E-cardherin, vimentin and Snail. In addition, SLC8A2 inhibited the angiogenesis of U87MG cells, probably through combined inhibition of endothelium-dependent and endothelium-nondependent angiogenesis (vascular mimicry pattern). Totally, SLC8A2 serves as a tumor suppressor gene and inhibits invasion, angiogenesis and growth of glioblastoma.

• Korean Journal of Pharmacognosy
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• v.48 no.4
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• pp.261-267
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• 2017

As part of the search for bioactive constituents of Korean medicinal plants, twelve steroids (1-12) were isolated from the rhizomes of Dioscorea nipponica. The isolated compounds were identified as diosgenin ($3{\beta}$, 25R)-spirost-5-en-3-ol (1), 25(R)-dracaenoside E (2), dioscin (3), gracillin (4), prosapogenin B (5), 25(R)-dracaenoside G (6), diosgenin 3-O-${\beta}$-D-glucopyranosyl($1{\rightarrow}3$)-${\beta}$-D-glucopyranoside (7), ophipogonin C′ (8), 7-oxodioscin (9), protodioscin (10), hypoglaucin F (11), and protoneogracillin (12). Their structures were characterized by spectroscopic data and identified by comparing these data with those in the literatures. All the isolates (1-12) were evaluated for their neuroprotective effects through induction of nerve growth factor in C6 glioma cells and effects on nitric oxide (NO) production in murine microglia cell line BV-2. Compounds 7 and 12 were found to induce upregulation of NGF secretion without causing significant cell toxicity and compound 4 exhibited potent anti-neuroinflammatory activity.

• Biomolecules & Therapeutics
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• v.20 no.1
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• pp.68-74
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• 2012

Anthocyanins have received growing attention as dietary antioxidants for the prevention of oxidative damage. Astrocytes, which are specialized glial cells, exert numerous essential, complex functions in both healthy and diseased central nervous system (CNS) through a process known as reactive astrogilosis. Therefore, the maintenance of glial cell viability may be important because of its role as a key modulator of neuropathological events. The aim of this study was to investigate the effect of anthocyanin on the survival of glial cells exposed to oxidative stress. Our results demonstrated that anthocyanin extracts from black soybean increased survival of U87 glioma cells in a dose dependent manner upon oxygen-glucose deprivation (OGD), accompanied by decrease levels of reactive oxygen species (ROS). While treatment cells with anthocyanin extracts or OGD stress individually activated autophagy induction, the effect was signifi cantly augmented by pretreatment cells with anthocyanin extracts prior to OGD. The contribution of autophagy induction to the protective effects of anthocyanin was verifi ed by the observation that silencing the Atg5 expression, an essential regulator of autophagy induction, reversed the cytoprotective effect of anthocyanin extracts against OGD stress. Treatment of U87 cells with rapamycin, an autophagy inducer, increased cell survival upon OGD stress comparable to anthocyanin, indicating that autophagy functions as a survival mechanism against oxidative stress-induced cytotoxicity in glial cells. Our results, therefore, provide a rationale for the use of anthocyanin as a preventive agent for brain dysfunction caused by oxidative damage, such as a stroke.

• Archives of Pharmacal Research
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• v.23 no.5
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• pp.518-524
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• 2000

We examined the modulation of protein kinase C (PKC) subtypes during apoptosis induced by ginsenoside Rh2 (G-Rh2) in human neuroblastoma SK-N-Bl(2) and rat glioma C6Bu-1 cells. Apoptosis induced by C-Rh2 in both cell lines was confirmed, as indicated by DNA fragmentation and in situ strand breaks, and characteristic morphological changes. During apoptosis induced by G-Rh2 in SK-N-BE(2) cells, PKC subtypes $\alpha$, $\beta$ and $\gamma$ were progressively increased with prolonged treatment, whereas PKC $\delta$ increased transiently at 3 and 6 h and PKC $\varepsilon$ was gradually down-regulated after 6 h following the treatment. On the other hand, PKC subtype $\beta$ markedly increased at 24 h when maximal apoptosis was achieved. In C6Bu-l cells, no significant changes in PKC subtypes $\alpha$, $\gamma$, $\delta$, $\varepsilon$ and $\beta$ were observed during apoptosis induced by G-Rh2. These results suggest the evidence for a possible role of PKC subtype in apoptosis induced by G-Rh2 in SK-N-BE(2) cells but not in C6Bu-1 cells, and raise the possibility that G-Rh2 may induce apoptosis via different pathways interacting with or without PKC in different cell types.