• Bulletin of the Korean Chemical Society
• /
• v.30 no.9
• /
• pp.2083-2086
• /
• 2009

Human vascular endothelial growth factor receptor 2 (hVEGFR2) is an important signaling protein involved in angiogenesis and attractive drug target in cancer therapy. It has been reported that flavonols, a class of flavonoids, have anti-angiogenic activity in various cancer cell lines. We performed receptor-oriented pharmacophore based in silico screening for identification of hVEGFR2 inhibitors from flavonol database. By comparing with three X-ray complex structures of hVEGFR2 and its inhibitors, we evaluated the specific interactions between inhibitors and receptors and determined a single pharmacophore map. This map consisted of four features, a hydrogen bonding acceptor (HBA) on Cys917, two hydrogen bonding donors on Glu917 (HBD1) and Glu883 (HBD2), and one hydrophobic interaction (Lipo) with Val846, Ala864, Val897, Val914 and Phe1045 of hVEGFR2. Using this map, we searched a flavonol database including 9 typical flavonols and proposed that five flavonols, kaempferol, quercetin, fisetin, morin, and rhamnetin can be potent inhibitors of hVEGFR2. 3-OH of C-ring and 4’-OH of B-ring of flavonols are the essential features for hVEGFR2 inhibition. This study will be helpful for understanding the mechanism of inhibition of hVEGFR2 by natural products.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.21
• /
• pp.9137-9142
• /
• 2014

Background: To explore the expression of DcR3 protein and its clinicopathological significance in bladder urothelial carcinomas (BUC). Materials and Methods: Immunohistochemistry was performed to detect the expression of DcR3, caspase-3, Bcl-2, VEGF, Ki-67, PCNA and P53 in 166 BUC and 56 normal bladder tissues. Western blotting was used to detect the expression of DcR3 in the supernatants of cultured BUC cells. Results: Overexpression of DcR3 was found in BUC tissues and cell lines, with significant elevation as compared to normal bladder tissues (p<0.0001). Higher DcR3 expression was related to the status of invasion, lymph node metastasis and recurrence. Furthermore, DcR3 expression was negatively correlated with caspase-3 and positively associated with Bcl-2, VEGF, Ki-67 labeling index (LI), PCNA LI and P53 (all p<0.0001), respectively. Conclusions: DcR3 may play a crucial role as an oncogene in tumorigenesis, deterioration and progress of BUC via influencing related pathways of apoptosis, proliferation and angiogenesis. The detection of DcR3 protein in the formalinfixed and paraffin-embedded samples could assist to predict in prognosis of BUC patients.

• BMB Reports
• /
• v.47 no.4
• /
• pp.221-226
• /
• 2014

Drug-resistance and imbalance of apoptotic regulation limit chemotherapy clinical application for the human hepatocellular carcinoma (HCC) treatment. The reactivation of p53 is an attractive therapeutic strategy in cancer with disrupted-p53 function. Nutlin-3, a MDM2 antagonist, has antitumor activity in various cancers. The post-translational modifications of p53 are a hot topic, but there are some controversy ideas about the function of phospho-$Ser^{392}$-p53 protein in cancer cell lines in response to Nutlin-3. Therefore, we investigated the relationship between Nutlin-3 and phospho-$Ser^{392}$-p53 protein expression levels in SMMC-7721 (wild-type TP53) and HuH-7 cells (mutant TP53). We demonstrated that Nutlin-3 induced apoptosis through down-regulation phospho-$Ser^{392}$-p53 in two HCC cells. The result suggests that inhibition of p53 phosphorylation on $Ser^{392}$ presents an alternative for HCC chemotherapy.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 2003.11a
• /
• pp.81-81
• /
• 2003

The present study was taken to examine the inhibitory effect of extracts of Scytosiphon lomentaria, a marine alga growing in Jeju Island, on the growth of cancer cells and to develop an anti-cancer agent using components of S. lomemtaria. The effect was observed by the measurement of metabolic activity using colorimetric 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. In results, crude extract of this alga markedly inhibited the growth of leukemia cell lines such as HL-60 and KG-1, but could scarcely inhibit the growth of normal cells (HEL299) and adenocarcinoma cells (SNU-16 and HCT-I5). When HL-60 cells were treated with the extract, DNA fragmentation and the increase of proportion of sub-G1 hypodiploid cells were observed. Therefore, the inhibitory effect of S. lomemtaria on the growth of HL-60 cells seems to arise from the induction of apoptosis. In order to understand the mechanism of apoptosis inducton by S. lomemtaria, we examined the changes of Bcl-2 and Bax expression. The extract reduced Bcl-2, an anti-apoptotic protein, but increased Bax, a pro-apoptotic protein in a dose-dependent manner. When we examined the activation of caspase-3, an effector of apoptosis, the expression of active form(19 kDa) of caspase-3 was increased and the increase of their activities was demonstrated by the cleavage of poly(ADP-ribose)polymerase, a substrate of caspase-3, to 85 kDa. The results indicate that extract of S. lomentaria induces the apoptosis of HL-60 cells via the down-regulation of Bc1-2 and the activation of caspases.

• Molecular & Cellular Toxicology
• /
• v.5 no.4
• /
• pp.328-334
• /
• 2009

TBX3 has demonstrated oncogenic activity as a downstream target of the Wnt/$\beta$-catenin signaling pathway. In this study, the aim was to determine whether overexpression of the TBX3 protein is involved in the development and/or progression of gastric cancers. We analyzed the expression pattern of the TBX3 and $\beta$-catenin proteins in a series of 186 sporadic gastric cancers. Altered expression of the TBX3 and $\beta$-catenin proteins was observed in 54 (29.0%) and 48 (25.8%) of the 186 gastric cancers. Statistically, overexpression of the TBX3 and $\beta$-catenin proteins was not associated with the clinical and pathological parameters studied including: histological type, tumor location, tumor size, and the 5-year survival (P>0.05). However, TBX3 overexpression was closely associated with lymph node metastasis and aberrant $\beta$-catenin expression (P<0.05). In addition, overexpression of the TBX3 protein was confirmed by Western blot analysis of primary gastric cancer tissues and cell lines. These data suggest that TBX3 overexpression may play a role in the development and progression of sporadic gastric cancers.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.4
• /
• pp.1771-1774
• /
• 2014

The rhabdomyosarcoma (RMS) is the most common type of soft tissue tumor in children and adolescents; yet only a few screens for oncogenic mutations have been conducted for RMS. To identify novel mutations and potential therapeutic targets, we conducted a high-throughput Sequenom mass spectrometry-based analysis of 238 known mutations in 19 oncogenes in 17 primary formalin-fixed paraffin-embedded RMS tissue samples and two RMS cell lines. Mutations were detected in 31.6% (6 of 19) of the RMS specimens. Specifically, mutations in the NRAS gene were found in 27.3% (3 of 11) of embryonal RMS cases, while mutations in NRAS, HRAS, and PIK3CA genes were identified in 37.5% (3 of 8) of alveolar RMS (ARMS) cases; moreover, PIK3CA mutations were found in 25% (2 of 8) of ARMS specimens. The results demonstrate that tumor profiling in archival tissue samples is a useful tool for identifying diagnostic markers and potential therapeutic targets and suggests that these HRAS/ PIK3CA mutations play a critical role in the genesis of RMS.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.14
• /
• pp.5779-5785
• /
• 2015

The present study was designed to investigate cholangiocarcinoma (CCA) antibodies in hamster serum. Hamster CCA cell lines were processed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A candidate biomarker was confirmed by immunoprecipitation and western blot, and was further analyzed using ELISA and sera from normal control hamsters, hamsters with opisthorchiasis and hamsters with various stages of CCA, as well as from CCA patients and healthy individuals. One candidate marker was identified as $HSP90{\alpha}$, as indicated by a high level of anti-$HSP90{\alpha}$ in hamster CCA sera. It was found that the levels of anti-$HSP90{\alpha}$ were specifically elevated in the sera of hamsters with CCA compared with other groups and progressively increased with the clinical stage. At the cut-off point of 0.4850 on the receiver operating characteristic curve, anti-$HSP90{\alpha}$ could discriminate CCA from healthy control groups with a sensitivity of 76.2%, specificity of 71.4% and total accuracy 75.5%. In the present study, we have shown that anti-$HSP90{\alpha}$ may be a potential useful serum biomarker to discriminate CCA cases from healthy persons.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.24
• /
• pp.10647-10652
• /
• 2015

Background: The aim of our study was to establish COLD-PCR combined with an unlabeled-probe HRM approach for detecting KRAS codon 12 and 13 mutations in plasma-circulating DNA of pancreatic adenocarcinoma (PA) cases as a novel and effective diagnostic technique. Materials and Methods: We tested the sensitivity and specificity of this approach with dilutions of known mutated cell lines. We screened 36 plasma-circulating DNA samples, 24 from the disease control group and 25 of a healthy group, to be subsequently sequenced to confirm mutations. Simultaneously, we tested the specimens using conventional PCR followed by HRM and then used target-DNA cloning and sequencing for verification. The ROC and respective AUC were calculated for KRAS mutations and/or serum CA 19-9. Results: It was found that the sensitivity of Sanger reached 0.5% with COLD-PCR, whereas that obtained after conventional PCR did 20%; that of COLD-PCR based on unlabeled-probe HRM, 0.1%. KRAS mutations were identified in 26 of 36 PA cases (72.2%), while none were detected in the disease control and/or healthy group. KRAS mutations were identified both in 26 PA tissues and plasma samples. The AUC of COLD-PCR based unlabeled probe HRM turned out to be 0.861, which when combined with CA 19-9 increased to 0.934. Conclusions: It was concluded that COLD-PCR with unlabeled-probe HRM can be a sensitive and accurate screening technique to detect KRAS codon 12 and 13 mutations in plasma-circulating DNA for diagnosing and treating PA.

• Journal of Life Science
• /
• v.14 no.4
• /
• pp.567-572
• /
• 2004

This study was carried out to investigate the affects on antimicrobial and cytotoxicity of red cabbage (Brassica oleracea L.,BO). In the paper disc test, antimicrobial activity of BO fractions was increased in proportion to its concentration. Among the various solvent fractions of methanol extract (BOM) of BO, the ethylacetate partition layer (BOMEA) showed the strongest antimicrobial activity We also determined the cytotoxicity and Quinone Reductase induced effect of BO extract and fractions on human cancer cells. The cytotoxicity of BO fractions on HepG2, HeLa and MCF-7 cells was evaluated by MTT assay. The BOMEE and BOMEA showed strong cytotoxic effects on all cancer cell lines we used. The quinone reductase induced effect of BO fractions on HepG2 cells, the hexane partition layer (BOMH) at a dose of 200 $\mu{g}$/ml was 2.88 times more effective compared to the control values of 1.0.

• CELLMED
• /
• v.5 no.3
• /
• pp.15.1-15.12
• /
• 2015

Comparative studies have established that the North-Eastern (NE) region of India which is a part of the Eastern Himalayan region is affluent in both traditional knowledge based phytomedicine and biodiversity. About 1953 ethno-medicinal plants are detailed from the NE region of India out of which 1400 species are employed both as food and ethnopharmacological resources. Nearly 70% of species diversity has been reported from the two Indian biodiversity hotspots-The Western Ghats and the Eastern Himalayas and these hotspots are protected by tribal communities and their ancient traditional knowledge system. Paris polyphylla Smith belongs to the family Melanthiaceae and is a traditional medicinal herb which is known to cure some major ailments such as different types of Cancer, Alzheimer's disease, abnormal uterine bleeding, leishmaniasis etc. The major phytoconstituents are dioscin, polyphyllin D, and balanitin 7. Phylogeny of Paris was inferred from nuclear ITS and plastid psbA-trnH and trnL-trnF DNA sequence data. Results indicated that Paris is monophyletic in all analyses. Rhizoma Paridis, which is the dried rhizome of Paris polyphylla is mainly used in Traditional Chinese Medicine and its mode of action is known for only a few cancer cell lines. The current review determines to sketch an extensive picture of the potency, diversity, distribution and efficacy of Paris polyphylla from the Eastern Himalayan region and the future validation of its phytotherapeutical and molecular attributes by recognizing the Intellectual Property Rights of the Traditional Knowledge holders.