bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1611: Identification of target molecules and anti-leukemic effects of novel phospha sugar derivative, TMPP
Authors: Nakamura Satoki , Takemura Tomonari , Yokota Daisuke , HIrano Isao , Ono Takaaki , Shigeno Kazuyuki , Ohnishi Kazunori 
Published: February 2011

Abstract
[Background and Aims] We synthesized two phospha sugar derivatives, 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TMPP) by reacting 3-methyl-1-phenyl-2-phospholene 1-oxide with bromine, and we has reported their potential as an antileukemic agent in cell lines. In this study, we have investigated that TMPP have antileukemic effects as shown in various leukemia cell lines as well as primary AML patient specimens. Moreover, we have identified the target molecules of TMPP by using docking simulation. [Methods] In human leukemia cell lines (HL60, NB4, U937, NOMO-1, CEM, MOLT4, SUP-B15, and YRK2 cells), the anti-leukemic effects were elevated by cell proliferation assay, Cell cycle analysis, Western blotting. In AML cells derived from AML patients and normal hematopoietic progenitor cells derived from healthy volunteers, the changes of viability by treatment with TMPP were evaluated. By using docking simulation, the target molecules were identified in leukemia cells treated with TMPP. [Results] TMPP showed inhibitory effects on leukemia cell proliferation, with mean IC50 values of 10.2 nmol/L for TMPP, indicating that inhibition appeared to be dependent on the number of bromine atoms in the structure. Further, TMPP at 8.4 nmol/L induced G2/M cell cycle block in leukemia cells, and TMPP at 17.3 nmol/L induced apoptosis in these cells. TMPP treatment reduced cell cycle progression signals (FoxM1, KIS, Cdc25B, Cyclin D1, Cyclin A, and Aurora-B) and tumor cell survival (Bcl-2, p27Kip1 and p21Cip1). Further, treatment with TMPP significantly reduced the viability of AML specimens derived from AML patients, but only slightly reduced the viability of normal ALDHhi progenitor cells. We also found that TMPP showed the strong activity against Aurora kinase B and Bcl-2 by using docking simulation. [Conclusion] We demonstrate that TMPP inhibits Aurora kinase B and Bcl-2 and shows a dominant Aurora B kinase inhibition-related cell cycle arrest and the induction of mitochondrial potential catastrophe-related apoptosis in acute leukemia cells. Moreover, we identified Aurora kinase B and Bcl-2 as the target molecules of TMPP. We conclude that TMPP has great therapeutic potential in anticancer therapy in a wide range of cancers.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1611.
Abstract 1620: Deregulation of cohesion establishment factor DCC1 promotes colorectal cancer cell growth
Authors: Yamaguchi Kiyoshi , Nakamura Yusuke , Furukawa Yoichi 
Published: February 2011

Abstract
Defective in sister chromatid cohesion 1 homolog (dcc1) was identified as a member of alternative replication factor C complex in yeast. Dcc1 has been known to play a crucial role in chromatid cohesion together with other subunits (ctf18 and ctf8), and that it is essential for DNA replication in yeast. We previously carried out genome-wide expression profile analysis of human colorectal tumors using cDNA microarray, and identified a set of genes whose expression was deregulated in tumor cells. In this study, we focused on human DCC1, because its expression was frequently up-regulated in the majority of colorectal cancer tissues. Quantitative PCR analysis corroborated its elevated expression in 12 of additional 20 colorectal tumors compared to their matched non-cancerous colonic mucosa. To examine whether DCC1 is involved in proliferation of cancer cells, we generated small interfering RNAs (siRNAs) targeting human DCC1. Notably, treatment of colorectal cancer cells with DCC1-specific siRNAs significantly suppressed their proliferation, suggesting that its elevated expression is essential for the growth of colorectal cancer cells. To clarify the mechanism of its overexpression, we carried out a reporter assay using 1-kb of its 5’-flanking region and 5’-UTR. As a result, we found that a region between −10 and +70 of transcription starting site was responsible for the activity, and identified three putative E2F1-binding sequences within this region. Further analysis revealed that the three motifs regulate the promoter activity. These data suggests that deregulated E2F1-signaling may play a role in the proliferation of cancer cells in part through the increased DCC1 expression, and that DCC1 may serve a target molecule for the development of new anti-cancer drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1620.
Abstract 1621: PRAF2 knockdown inhibits cell proliferation and migration of neuroblastoma cells
Authors: Yco Lisette P. , Bachmann Andre S. 
Published: February 2011

Abstract
Prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is a novel 19-kDa protein with four transmembrane-spanning domains that belongs the PRAF protein family that plays a role in vesicle trafficking and cargo transport. PRAF2 is strongly expressed in several cultured neuroblastoma (NB) cells (for example, SK-N-SH, SH-SY5Y, LAN-1). NB is a tumor that derived from the precursor cells of sympathetic nervous system and the most common extracranial solid tumor of childhood. Recently, our lab identified PRAF2 as a candidate prognostic marker of NB. In the present study, we examined the function of PRAF2 in cell cycle progression of human NB cells. In order to analyze the role of PRAF2, we generated a stable RNA interference (RNAi) short hairpin (sh) PRAF2 knockdown NB cell line (SK-N-SH shPRAF2). We observed that PRAF2 downregulation suppressed the cell viability of SK-N-SH cells. Moreover, PRAF2 knockdown also inhibited migration of SK-N-SH cells. Notably, PRAF2 downregulation also elevated the protein levels of cyclin-dependent kinase (Cdk) inhibitor p27Kip1 in these cells, therefore suggesting a role for PRAF2 in the regulation of NB cell cycle regulation and cell proliferation. In summary, our results suggest that reduction of PRAF2 protein level inhibits cell proliferation and migration in SK-N-SH cells that renders PRAF2 a promising target for therapeutic intervention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1621.
Abstract 163: DTMETH: A novel method for increased length quantitative CpG methylation analysis
Authors: Liloglou Triantafillos , Filia Anastasia , Daskalos Alexandros , Nikolaidis Georgios , Bottomley Helen , Ma Peter N. , Finkelnburg Britta , Field John K. 
Published: February 2011

Abstract
DNA methylation analysis has been blooming in the last decade as there is increasing evidence for epigenetic control of new pathways involved in normal cell function as well as the pathogenesis of human disease. A large number of methods have been devised to address the needs of DNA methylation detection in clinical samples. A DNA methylation detection method of preference should be able to interrogate multiple CpGs over long stretches of DNA, quantify DNA methylation, include multiple bisulphite conversion controls, provide increased sensitivity and low background. Here we present DTMETH, a novel method for DNA methylation analysis that bears the above characteristics. In principle, the desired locus is amplified from bisulphite treated-DNA using primers at CpG-free areas. Primers bear short 5’ tails which contain two cytosines (forward) or guanines (reverse) that will serve as normalisation tools. After a spin-column cleanup process, the PCR product is subjected to DTMETH. This is a thermostable reaction utilising FS Taq and labelled ddC (Applied Biosystems). The latter will be only incorporated at methylated cytosines, as post-bisulphite unmethylated cytosines are converted to uracils. The DTMETH products are cleaned by ethanol precipitation and subjected to analysis on a capillary sequencer. ddC peak areas corresponding to methylated Cs are normalised by the peak areas of the control Cs on the primer tail. As proof of principle we present DNA methylation analysis for the p16 gene. We amplified a 269 bp region of the gene's 5’UTR containing 28 CpGs. The assays provide excellent linearity and reproducibility. We used it to screen 90 non-small cell lung carcinomas for p16 methylation in comparison to an established pyrosequencing assay. p16 hypermethylation was detected in 23 samples with both methods, 3 samples with DTMETH only, while 64 samples were negative. DTMETH combines the read lengths of dideoxy terminator sequencing, and enables quantitation without the need of cloning. It is highly versatile, offering easy assay design and due to its thermostable nature can easily overcome secondary structure issues arising from the low complexity bisulphite DNA sequence composition.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 163.
Abstract 1630: Critical role of Shp2 protein tyrosine phosphatase in tumorigenesis of carcinoma
Authors: Ren Yuan , Chen Zhengming , Chen Liwei , WinPiazza Hla , Enkemann Steven , Haura Eric , Wu Jie 
Published: February 2011

Abstract
Increasing evidence suggests that tumorigenic function requires coordinated action of both protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Certain PTPs, similar to PTKs, may play positive roles in the initiation and maintenance of human cancer. Shp2 is a non-receptor PTP encoded by the human PTPN11 gene. Gain-of-function Shp2 mutants have been linked to hematologic malignancies. While the role of Shp2 in carcinoma is less clear, Shp2 is a positive regulator of signaling by receptor tyrosine kinases such as EGFR, MET, and ALK that are involved in pathogenesis of carcinomas. To determine if Shp2 is required for tumor growth of carcinoma, we suppressed Shp2 expression and PTP activity using shRNAs and a PTP-inactive mutant in breast, prostate, and lung carcinoma cells. Shp2 knockdown and inactivation prevented tumor xenograft growth of these carcinoma cells. Biochemical analyses indicated that Shp2 inhibition suppressed Src, Erk1/2, and c-Myc activities, whereas it elevated p27 (CDKN1B) both in cell cultures and in tumors. These results suggest that Shp2 is a non-oncogene addiction gene critically involved in malignant growth of carcinoma and a potential target for development of a novel PTP-targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1630.
Abstract 1634: Reduced NIMA-related kinase 2 (Nek2) expression levels enhance paclitaxel sensitivity in breast cancer cells
Authors: Lee Jaehyung 
Published: February 2011

Abstract
While many clinical trials have shown that the taxane, paclitaxel (Taxol™), is a very powerful anticancer drug, paclitaxel is still controversial in its applicability for cancer treatment because of the resistance of tumor cells to its effects. Therefore, the purpose of this study is to determine whether the sensitivity of paclitaxel is improved with the addition of antisense oligonucleotides (ASO) against NIMA related kinase 2 (Nek2) in the breast cancer cells. Nek2, a serine/threonine kinase is a gene emerging as important to cancer development because of its regulatory role in mammalian cell mitosis. Moreover, abnormally increased Nek2 expression and activity levels are the main trait of various cancer cells. For these reasons, regulation of the Nek2 expression levels may prove important as a target for cancer treatment. Studies suggest that depletion of Nek2 results in mitotic arrest and ultimately leads to apoptosis in cancer cells. Because many cancer cells have demonstrated resistance to anticancer drugs, more effective therapeutic treatments for cancer patients are necessary. To overcome this treatment resistance, gene silencing through ASO has emerged as an attractive alternative. ASO are able to inhibit cancer progression because they bind to and depress, the expression of genes targeted for their involvement in tumor development. There are currently clinical trials using ASO for cancer patients suffering from a variety of cancers such as breast, colon, and prostate.
In this study, we investigated drug sensitivity by using plus ASOs targeted against Nek2 to treat breast cancer cells. MDA-MB-468 breast cancer cells transfected with Nek2 ASO were treated with paclitaxel to evaluate cell proliferation, cell cycle distribution, and apoptosis. We detected that MDA-MB-468 cells treated together with Nek2 ASO and paclitaxel showed more synergistic results compared with either agent alone. Nek2 ASO worked with paclitaxel in the arrest of the cell cycle at the G2-M phase and lead to apoptosis as well. This study suggests that Nek2 ASO and paclitaxel combination treatment of cancer cells may strongly improve the sensitivity of cancer cells. Thus, these results possibly provide a new strategy for the treatment of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1634.
Abstract 1638: Preclinical evaluation of the PI3K inhibitor BEZ235 in nasopharyngeal carcinoma cell lines
Authors: Ma Brigette B. , Lui Vivian WY , Ho Kakiu , Lau Cecilia PY , Ng Margaret HL , Cheng Suk-Hang , Tsang Chi-Man , Tsao Sai-Wah , Shi Michael , Hui Edwin P. , Chan Anthony TC 
Published: February 2011

Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is endemic to parts of Asia and ubiquitously associated with Epstein-Barr virus (EBV) infection. AKT is frequently activated in NPC and PIK3CA amplification can be found in 40% of NPC tissues. BEZ235 is a dual inhibitor of PI3K and mTOR, which results in inhibition of downstream effectors AKT, S6 ribosomal protein and 4EBP1. The preclinical activity of BEZ235 was evaluated in 6 NPC cell lines (Table 1). Western Blot analysis showed all 6 NPC cell lines showed basal activation of AKT and mTOR. The effect of BEZ235 on cell growth was evaluated by exposing NPC cell lines to increasing concentrations of BEZ235 (0.1nM, 0.5nM, 1nM, 10nM, 100nM, 1µM& 10µM) for up to 72 hrs followed by MTT assay. Over 80% of growth inhibition was achieved in all NPC cell lines except C666-1 (∼70% inhibition), with the respective IC50 concentrations in the nanomolar range (Table 1). Two representative cell lines (HONE1-LMP-1 and CNE-2 cells) were selected for assessing the effect of BEZ235 on AKT-mTOR signaling, apoptosis, cell cycle and synergism with chemotherapy. Treatment of HONE1-LMP-1 and CNE-2 cells with BEZ235 at 5nM and 50nM for 24-48 hours, resulted in cell cycle arrest at G1 phase, apoptosis (indicated by the induction of PARP cleavage), and moderate reduction of cyclin D1 expression. After BEZ235 treatment, the expression level of phosphorylated (p-)AKT, pS6K, p4EBP-1 and p-mTOR were reduced, but the level of p-p44/42 MAPK was increased in both HONE1-LMP-1 and CNE-2 cells. No synergistic effect on growth inhibition was observed when HONE1-LMP-1 and CNE-2 cells were treated with concomitant BEZ235 and chemotherapy (cisplatin, or paclitaxel). Our preliminary result suggests that BEZ235 has promising activity in most NPC cells, while the increase in p-p44/42 MAPK observed in some cell lines suggest the presence of compensatory MAPK activation that have been previously described with mTORC1 inhibitors in other cancer types. Further investigations are warranted.Table 1: IC50 (growth)% growth inhibition by BEZ235% cells at G1 arrest after BEZ235 (5nM) treatment for 24hrsEBV-associated NPC cell linesHK1-LMP14.1nM∼85%-HONE-1-LMP14.9nM∼75%62%C666-19.5nM∼70%-Poorly-differentiated NPC cell linesHONE-16.4nM∼85%-CNE-25.7nM∼90%58%Well-differentiated NPC cell lineHK14.7nM∼90%-
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1638.
Abstract 1639: The novel c-MET inhibitor, ARQ 197, shows additive growrh-inhibitory effect with erlotinib through enhanced degradation of c-MET protein via ubiquitin/proteasome pathway
Authors: Kanome Tomoko , Kadofuku Tsuyoki , Yamaoka Toshimitsu , Hirose Takashi , Akinaga Shiro , Adachi Mitsuru , Saijo Nagahiro , Ohmori Tohru 
Published: February 2011

Abstract
Background
c-MET, a receptor of hepatocyte growth factor (HGF), is known to be overexpressed in a variety of human cancers. Recently several c-MET inhibitors are being developed as cancer chemotherapy against this compelling molecular target. ARQ 197 is a new small molecule c-MET inhibitor. Since ARQ 197 shows efficient anti-cancer activity without many severe adverse events in Phase I clinical trials, it is expected to be a useful anticancer agent for clinical treatment. This drug is known to bind to c-MET at neighbor area of its ATP binding site and it does not work as an ATP mimic. In this study, we investigated the molecular mechanism of inhibitory effect on c-MET by ARQ 197 in a non-small cell lung cancer cell (NSCLC) line.
Materials and Method
We established a c-MET-overexpressed NSCLC line, PC-9/MET, by long term exposure of PC-9 cells to EGFR-tyrosine kinase inhibitor. The cytotoxicity of ARQ 197 was measured by MTT assay. The expression of c-MET protein and mRNA were detected by Western blotting analysis and real time RT-PCR method, respectively. In a c-MET degradation analysis, bortezomib was used for inhibition of proteasome.
Results
ARQ 197 is equally cytotoxic to parental PC-9 and EGFRTKI-resistant PC-9/MET cell line with GI50 values around 200 nM (?). ARQ 197 showed an additive growth- inhibitory effect with erlotinib in PC-9/MET cells as assessed by an Isobologram analysis. In ARQ 197-treated PC-9/MET cells, a clear decrease of phospho c-MET protein as well as phospho AKT and ERK proteins was observed, however, ARQ 197 also induced a down-regulation of c-MET protein in the cells without any effect on c-MET mRNA level. This ARQ 197 induced degradation was reversed by a concomitant treatment with a proteasome inhibitor, bortezomib in the cells. However, bortezomib did not affect cytotoxicity of ARQ 197 in the same cells.
Conclusion
These data suggest that ARQ 197 may inhibit c-MET through downregulation of this protein in addition to inhibition of its kinase activity. Furthermore, it may enhance c-MET degradation by the ubiquitin/proteasome pathway. These c-MET inhibitory activities by ARQ 197 should be important for the additive combined effect with erlotinib in PC-9/MET cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1639.
Abstract 1665: Selection of potential responders to FOLFOX therapy in advanced stage colorectal cancer
Authors: Midorikawa Yutaka , Tsuji Shingo , Takahashi Takao , Yagi Koichi , Mamiya Takao , Takayama Tadatoshi , Yoshida Kazuhiro , Sugiyama Yasuyuki , Aburatani Hiroyuki 
Published: February 2011

Abstract
Combinations of oxaliplatin combined with various schedules of antimetabolite 5- fluorouracil and leucovorin (FOLFOX) have been the first-line treatment for unresectable colorectal cancer (CRC) and survival benefits for the patients undergoing FOLFOX therapy were demonstrated. That is, the median duration of survival for the group treated with FOLFOX has been reported to be about 20 months, compared with 8 months for the best supportive care group. However, the rate of effect is not so high and has been reported to be approximately 50%. Molecular characterization gene expression profiling will undoubtedly improve the prediction of treatment responses and ultimately the clinical outcome of cancer patients, which has never been accomplished by conventional clinicopathological classification. To identify responders for FOLFOX therapy, we performed random forest analysis based on gene expression data about 49 unresectable colorectal cancer (CRC) patients. Random forest is a prediction model with the classification accuracy for each sample, outlier measure without additional test set analysis, and contribution for class division of each gene can be created. Through this analysis, predictor genes are selected by decision tree analysis using out-of-bag error estimation, which is repeated from 10,000 to 1,000,000 times, and rate of effect of therapy can be determined individually. Computed tomography was performed for all the patients after 4 course of FOLFOX therapy, and 11 patients were diagnosed as progressive disease (PD), 10 stable disease (SD), and 28 partial response (PR), respectively, i.e., the rate of effect of therapy was 57.1%. Using random forest, we could identify 8 predictor genes of response to FOLFOX therapy, SLC25A30, RPS3A, FZD7, MERTK, HABP4, PFKFB2, KIAA0329, and ZBTB41. Consensus clustering based on these predictor genes could classify tumor samples according to drug sensitivity. Furthermore, in cross validation with out-of-bags method, such predictor genes were available to predict PD, SD, and PR patients with an overall accuracy of 77.7% on average (30.7 to 99.8 %). Thus, we could obtain the individual information about efficacy of chemotherapy by about 20% improvement before therapy. Taken together, random forest analysis on gene expression data for unresectable CRC patients could predict responders for FOLFOX therapy with high accuracy rate, and this prediction can be one of factors of decision making of treatment for the patients with colorectal cancer, which will lead us to personalized therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1665.