bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3631: AN019, a potent anticancer agent, suppresses tumors, ErbB-2, and angiogenesis in pancreatic cancer cells
Authors: Gondi Christopher S. , Gorantla Bharathi , Rao A.K.S. Bhujanga , Amala K. , Naidu M.U.R. , Jogi K.V. , Ramana G.V. , Chowdary M. Praveen , Rao Jasti S. 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR), a member of the HER family of receptor tyrosine kinases, has been identified as a therapeutic target for pancreatic cancer. Excessive ErbB-2 signaling is associated with the development of a wide variety of solid malignancies. In this study, we used the pancreatic cancer cell lines MIA PaCa-2 and PANC-1 to demonstrate the suppressive, anti-angiogenic, and anti-proliferative effects of a novel compound known as AN019. Here, we show that AN019 inhibits the invasiveness of pancreatic cancer cells in a dose-dependent manner and is superior to treatment with Gemcitabine alone. Angiogenic assays demonstrated that AN019 treatment retarded the invasive potential of pancreatic cancer cells and provided greater angiogenic inhibition than Gemcitabine. In addition, western blot analysis demonstrated that AN019 inhibits expression of ErbB-2 in a dose-dependent manner in MIA PaCa-2 and PANC-1 cells. In contrast, Gemcitabine lacked a similar dose response. Finally, the proliferation assay showed that while AN019 retarded proliferation in a dose-dependent manner, Gemcitabine did not. Our in vivo studies showed that expression of ErbB-2 and VEGF decreased in a dose-dependent manner in AN019-treated animals with subcutaneously implanted MIA PaCa-2 tumors. A treatment combination of AN019 and Gemcitabine had an effect similar to that of treatment with AN019 alone, thereby indicating no specific contribution from Gemcitabine. Our results demonstrate AN019 is superior to Gemcitabine, and AN019 is a specific suppressor of ErBB-2 in vitro and in vivo. In addition, AN019 has anti-proliferative and anti-angiogenic properties. Taken together, these results clearly indicate the potential therapeutic use of AN019 as an anti-cancer agent.
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 3631.
Abstract 3633: eEF2 in acquired lapatinib resistance in HER2 positive breast cancer cells
Authors: McDermott Martina , Browne Brigid , Crown John , O'Brien Neil , Slamon Dennis , Henry Michael , Meleady Paula , Clynes Martin , Dowling Paul , O'Donovan Norma 
Published: February 2011

Abstract
Approximately 25% of breast cancers overexpress HER2. Although HER2 targeted therapies, trastuzumab and more recently lapatinib, have improved prognosis for HER2 breast cancer patients not all HER2 positive tumors respond to HER2 targeted therapies. Using phosphoproteomic profiling, we examined mechanisms of resistance in an in vitro model of acquired lapatinib resistance.
SKBR3 cells were conditioned in lapatinib containing media (200 nM) for six months, after which time the resulting SKBR3-L cells exhibited significantly reduced growth inhibition (27.7 ± 0.1 %) when treated with lapatinib (1 µM) treatment compared to parental SKBR3 (90.7 ± 0.2 %) (p&lt;0.01). Using phosphoproteomic profiling, eukaryotic elongation factor 2 (eEF2) was identified as a phosphoprotein which was significantly altered in the SKBR3-L cells compared to the parental SKBR3 cells. One form of phospho-eEF2 was up-regulated and 6 forms were down-regulated in SKBR3-L compared to SKBR3. eEF2 is a phosphoprotein with an essential role in protein synthesis. Phosphorylation of eEF2 at Thr56 and Thr58 by eEF2 kinase inhibits eEF2 activity. eEF2 kinase activity is regulated by the mTOR pathway, via phosphorylation by p70S6 kinase.
To examine the role of eEF2 in lapatinib resistance, levels of phospho-eEF2, eEF2, phospho-p70S6K and p70S6K, were examined in a panel of HER2 positive breast cancer cell lines following 24 hour treatment with lapatinib (1 µM). Treatment with lapatinib resulted in a decrease in phospho-p70S6K and an increase in phospho-eEF2, with no change in the levels of total protein, in lapatinib sensitive cell lines.
In order to further examine the role the mTOR pathway and eEF2, plays in acquired resistance to lapatinib, the effect of rapamycin, alone and in combination with lapatinib, was investigated in SKBR3 par and SKBR3-L cells. Combined treatment with lapatinib (200 nM) and rapamycin (2 nM) results in similar inhibition of growth (64.5 ± 3.3 %) in SKBR3-L cells as lapatinib alone in SKBR3 parental cells (62.5 ± 0.6 %).
In conclusion, response to lapatinib is associated with decreased eEF2 activity in HER2 positive cell lines. Furthermore, inhibition of mTOR signaling, which causes inhibition of eEF2 activity, appears to restore sensitivity to lapatinib in our model of acquired lapatinib resistance.
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 3633.
Abstract 363A: PAX2 is an oncogene in type I ovarian cancer
Authors: Song Huijuan , Tung Celestine S. , Tsang Yvonne TM , Mok Samuel C. , Gershenson David M. , Wong Kwong-Kwok 
Published: February 2011

Abstract
Ovarian cancer is the second most common gynecologic malignancy, but the most lethal gynecologic cancer. Ovarian cancer is divided into Type I and Type II subgroups. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas and are characterized by high frequency of KRAS, BRAF, PTEN, or beta-catenin mutations. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas and are characterized by high genetic instability and high frequency of TP53 mutation. Using gene expression profiling, we found that Pax2, a transcription factor of the Pax gene family, is highly expressed in type I ovarian tumors but is less expressed in Type II tumors. Pax2 is one of the nine Pax genes which have a conserved DNA sequence motif called the paired box, a 128 amino acid domain in the amino-terminal portion of the protein. Pax2 regulates tissue development and cellular differentiation in embryos and Pax2 expression is attenuated after development. Unattenuated Pax2 expression has been found in several cancer types, but the function of Pax2 in ovarian cancer is not clearly understood.
In this study, we further validated the expression of Pax2 in Type I ovarian cancer by immunohistochemistry, western blot analysis and quantitative real-time PCR. Furthermore, the expression of Pax2 in two Type I ovarian cancer cell lines (RMUGL and TOV21G) was knockdown by Pax2 specific shRNA. By comparing to the control non-target shRNA cancer cell lines and the parental cell lines, Pax2 knockdown cell lines have significant reduction in growth rate as measured by WST cell proliferation assay. From the gene expression profiles of three independent Pax2 knockdown cell lines, we identified 196 genes that were significantly affected by the down-regulation of Pax2. Many of these genes are involved in cell cycle control, cellular growth and proliferation, and the TP53 pathway such as BBC3, CHEK1, GADD45A and GADD45B and JUN genes. This suggests that Pax2 may play an oncogenic role in the pathogenesis of ovarian cancer through a TP53-dependent pathway. Since immunotherapy targeting Pax2 is currently being developed, Pax2 could be a therapeutic target for Type I ovarian 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 363A.
Abstract 3642: AS1411 causes a specific increase in levels of cell surface nucleolin in responsive cell lines
Authors: Teng Yun , Jones David , McLaughlin Fiona , Bates Paula J. 
Published: February 2011

Abstract
AS1411 is a 26-mer guanine-rich oligodeoxynucleotide that has antiproliferative activity against many types of cancer cells, but not against normal cells. It is currently being tested as an anticancer agent in Phase II clinical trials. Previously, we reported that this agent has a novel mechanism of action that involves formation of a stable G-quadruplex structure that can bind as an aptamer to nucleolin, a multifunctional protein expressed at high levels by cancer cells. Nucleolin is a predominantly nuclear protein, but can also be present in the cytoplasm and on the surface of cells, where it has been reported to mediate the endocytosis of several ligands. Cell surface nucleolin is believed to play an important role in AS1411 activity, although the precise details have yet to be elucidated. In the present study, we have evaluated the levels of cell surface nucleolin in human cell lines that are responsive or resistant to AS1411, before and after treatment with AS1411. Levels were examined by flow cytometry, with gating to exclude non-viable permeable (PI-positive) cells, and by western blotting of cell surface proteins, isolated using a cell-impermeable biotinylating agent. The amount of cell surface nucleolin appeared to be similar in untreated cells that were either sensitive to AS1411 (DU145 prostate cancer cells and MV-4-11 leukemia cells) or resistant to AS1411 (Hs27 non-malignant skin fibroblasts). However, in the sensitive cell lines, we observed a dramatic and time-dependent increase in levels of cell surface nucleolin in response to AS1411 treatment, whereas there was no significant change in the resistant Hs27 cells. We determined that this AS1411-induced increase in cell surface nucleolin in the cancer cells was not simply a reflection of apoptosis because it was not observed when apoptosis was induced by UV irradiation. We did not observe any changes in the levels of nucleolin in nuclear, cytoplasmic, or membrane extracts, or in total cell lysates, following treatment with AS1411, suggesting a specific re-localization of nucleolin rather than an increase in overall levels. These new results do not support our previous hypothesis that baseline levels of cell surface nucleolin determine responsiveness to AS1411. However, they do clearly demonstrate that “externalization” of nucleolin is a specific response to AS1411 and thereby confirm the important role of cell surface nucleolin in the mechanism of action of AS1411.
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 3642.
Abstract 3654: Clofarabine: factors influencing cytotoxicity and resistance in hematologic and solid malignancies
Authors: Wang Xin , Mirzaee Saeedeh , Lotfi Kourosh , Eriksson Staffan , Albertioni Freidoun 
Published: February 2011

Abstract
Clofarabine is a new-generation nucleoside analog that was synthesized to combine the most favorable pharmacological properties of its congener fludarabine and cladribine. It acts as a strong inhibitor of DNA polymerase, DNA synthesis and ribonucletide reductase (R1/R2). Like other nucleoside analogues, clofarabine must be activated within cells to the 5′-triphodphate form initially by deoxycytidine kinase (dCK). In this study, the anticancer effect of clofarabine was investigated in three solid tumor cell lines, HCT116 (a colon carcinoma cell line), U1810 (a human non-small cell lung carcinoma cell line), and MCF7 (a mammary carcinoma cell line) and compared to four leukemic cell lines, CCRF-CEM, HL60, K562 and MOLT4. Clofarabine was investigated to enter into HCT116, U1810, and MCF7 in a clearly detectable manner by LigandTracer® White. At 10 µM a high signal is achieved and approaches equilibrium after 1∼2 hrs. Pre-incubation with 10 µM clofarabine resulted in rapid inhibition of thymidine incorporation and DNA synthesis. Induction of apoptosis by clofarabine was cell line dependent, but the average apoptotic level was higher in leukemic cell lines than solid tumor cell lines; however it seemed the sensitivity for apoptosis of cell line is correlated with the activity of dCK and thymidine kinase 1 (TK1) in the solid tumor cell lines. Upon treatment with 10 μM clofarabine for 24 hrs, apoptosis induction increased compared to untreated cells 3.1-, 2.9- and 2.1-fold; the activity of dCK 7.3-, 3.7- and 3.1-fold and the activity of TK1 4.2-, 1.4- and 1.2-fold in U1810, HCT116 and MCF7 cells, respectively. In general, the expression of R1, dCK and TK1 in leukemic cells was higher than in solid tumor cells, but the expression of R2, p53R2 and p53 varied among the cell lines. However, there was an inverse correlation between induction of apoptosis at 100nM clofarabine (upon 24 hours incubation) and the expression of p53R2 (spearman rank test −0.67, p=0.1). In addition, clofarabine treatment causes retardation in S-phase, which seems to be related to the activity of TK1 and the protein expression of R2 in U1810, HCT116 and MCF7 cells. This study is a first step to extend the application of clofarabine toward the solid tumors.
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 3654.
Abstract 3655: Metronomic chemotherapy with cyclophosphamide (Cy) and celecoxib (Cel) in murine mammary adenocarcinoma tumor models: Mechanism of action
Authors: Mainetti Leandro E. , Rozados Viviana R. , Rossa Ana , Roggero Eduardo , Rico María J. , Gervasoni Silvia I. , Giordano Ricardo , Scharovsky O. Graciela 
Published: February 2011

Abstract
Metronomic chemotherapy (MCT) refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. CY, administered in low dose, is able to modulate the immune response. It can also reduce tumor angiogenesis, like the COX-2 inhibitor CEL does. We have already demonstrated that the administration, as an intervention strategy, of metronomic CY + CEL in M-406 and M-234p mammary adenocarcinomas-bearing mice inhibited tumor growth, increasing the survival rate. Our present aim was to study the mechanism by which that therapeutic effect was achieved. CBi and Balb/c inbred mice were s.c. challenged on day 0 with M-406 or M-234p mammary tumors, respectively, and treated from day 8 (M-406) and 5 (M-234p) on with: I) no further treatment (controls); II) CY in the drinking water (25-30 mg/kg body weight/day); III) CEL (30 mg/kg p.o.), five times/week; IV) Treated as II + III. Blood samples were taken on days 0, 20 (M-406) and 30 (M-324p) to evaluate VEGF serum level determined by ELISA and the % of circulating regulatory T cells (Tregs) by flow cytometry. The same tumor challenges and therapeutic schedules were performed in nude mice. Tumors were excised on days 20 and 30 for M-406 and M-234p, respectively, fixed and paraffin embedded for detection by immunohistochemistry of CD34 and Ki67 molecules. The VEGF serum level of M-406-bearing control animals (group I) was, on day 20, significantly higher than that measured on day 0 (p&lt;0,001), while groups II, III y IV showed, on day 20, lower values than group I (p&lt;0.01) in the same day, and similar than those on day 0. The % of CD4+ CD25+ Foxp3+ Treg cells in serum showed no differences between days 0 and 20 in all the experimental groups. The antitumoral effect of MCT was the same in euthymic and athymic mice. Immunohistochemistry for CD34 showed slight differences between control and treated animals that were not significant. Also, the staining for the proliferation marker Ki67 did not evinced differences among the experimental groups. The results obtained with M-234p tumor model were similar to those of M-406. In conclusion, the antitumor effect of MCT with CY plus CEL in mammary tumor models would be achieved, at least in part, by the inhibition of tumor angiogenesis, without modulation of the antitumor immune response.
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 3655.
Abstract 3657: 6-(Het)aryl-7-Deazapurine Ribonucleosides as Potent Novel Cytostatic Agents that Interfere with RNA Synthesis
Authors: Dzubak Petr , Nauŝ Petr , Pohl Radek , Votruba Ivan , Ameral Ria , Birkus Gabriel , Wang Ting , Mackman Richard , Ray Adrian , Cihlar Tomas , Hocek Michal , Hajdúch Marián 
Published: February 2011

Abstract
A series of 33 7-deazapurine ribonucleosides bearing an alkyl, aryl or hetaryl group in position 6 and H, F or Cl atom in position 7 was successfully synthesized. Significant cytostatic effects against both hematological and solid tumor cell lines were found for most of these compounds under in vitro conditions. The most potent were 7-H and 7-F derivatives of 6-furyl-/ 6-thienyl-7-deazapurine ribosides displaying nanomolar GIC50 values (comparable to gemcitabine or clofarabine) in several cancer cell lines. Intracellular phosphorylation to mono- and tri-phosphates and consequent inhibition of RNA synthesis, but not DNA synthesis, were demonstrated in preliminary studies of metabolism and mechanism of action. One of the most active compounds (6-thienyl-7-F-7-deazapurine riboside) was tested for in vivo toxicology in mice, and dose limiting toxicities were weight lost and leucopenia. However, the compound demonstrated highly significant antitumor activity at doses equivalent to MTD and ½ MTD, and afforded the extension of survival in treated mice bearing P388D1 leukemia (p&lt;0.001 compared to untreated animals). Antitumor effect was comparable to doxorubicin in P388D1 model. Interestingly, the intraperitoneal administration of the compound resulted in good local control of intraperitoneally transplanted tumors. Supported by grants awarded by the Czech Ministry of Education (MSM 6198959216 and LC07017).
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 3657.
Abstract 3662: Melatonin inhibits cell proliferation and induces apoptosis in human acute leukemia T and lymphoma B cells via a receptor independent mechanism
Authors: Sanchez-Hidalgo Marina , Lee Melanie , de la Lastra Catalina Alarcón , Guerrero Juan M. , Packham Graham 
Published: February 2011

Abstract
Loss of melatonin (MLT) production due to age contributes to immunosenescence onset and age-related diseases such as cancer. MLT reduces proliferation in many different cancer cell lines. However, MLT effects on subjects with immune cell cancer are controversial, and little is known about its action mechanisms in human malignant lymphoid cells. In the current study, we examined the effect of different doses of MLT (0.5, 1 and 2 mM) administration on human acute leukemia T cells (Jurkat), Burkitt (Ramos), diffuse large B cell lymphoma (Sudhl4) and follicular B no-Hodgkin lymphoma (Dohh2) cells analyzing cell cycle arrest, apoptosis, caspase cascade activation pathway and the role of melatonin transmembrane receptors. The data showed that high concentrations (millimolar) of melatonin significantly inhibited progression from G1 to S phase of the cell cycle and increased apoptotic cell death via caspase cascade activation and poly-ADP-ribose polymerase (PARP) and caspase-3 and −9 cleavages in all cell lines studied. There was also evidence of caspase-8 activation in Ramos and Sudhl4 cells. Reduced levels of procaspase-8 were detected in Dohh2 cells after melatonin treatment, thus evidence of activation even though the cleaved fragment was not detected. Interestingly, downregulation of Bcl-2 and Bcl-XL expression was also observed in melatonin treatment in Dohh2 cells whereas Mcl-1 antiapoptotic protein expression remained unchanged in each malignant cell line studied. A significant decrease in mitochondrial membrane potential (ΔΨm) was also detected in Ramos cells. Finally, using luzindole (LZD), as a MT1 and MT2 melatonin membrane receptor antagonist, we observed that MLT inhibited cell proliferation and apoptotic cell death by means of a melatonin membrane receptor independent pathway. This novel finding shows that a nontoxic natural indoleamine may be a potential therapy for some types of human lymphoid malignancies.
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 3662.
Abstract 3670: Reduced expression of p27 and the occurrence of CpG island methylator phenotype in insulinomas
Authors: Chen Yuan-Jia , Zhou Qiao , Chen Yuan-Fang , Wu Hai-Yan , Xiao Yu 
Published: February 2011

Abstract
Aim Little is known about the molecular pathogenesis of sporadic insulinoma which is a type of rare endocrine tumors, and there is a lack of reliable biomarkers to differentiate benign from malignant tumors. Thus we analysed the CpG island methylator phenotype (CIMP) of multiple genes in sporadic insulinamas, as well as the expression of p27 and the relationship between p27 and CIMP.
Materials and Methods Using methylation specific PCR, we examined the methylation status of p16, MLH1, RAR-β, O6-MGMT, THBS1 in 33 sporadic insulinomas and 20 paired pancreatic tissues. The expression of p27 was detected by immunohistochemistry staining. The experimental data were correlated with clinical-pathological characteristics, and were analysed by t-test, chi-square test or Fisher's exact test.
Results The incidence of CIMP-High was found in 33% of insulinomas, higher than its rate in the paired pancreatic tissues, but the difference was not significant (P=0.209). The methylation status of O6-MGMT and p16 were inversely correlated (P=0.003). Compared with the paired pancreaticl tissues, the expression of p27 was reduced in tumors (85% vs. 39%, P=0.008). Moreover, the reduced expression of p27 was significantly related to the methylation of O6-MGMT (P=0.016). The reduced expression of p27 might be related with higher rate of CIMP, but the difference did not reach significance due to the limited number of tumors. The experimental data were not significantly associated with clinical-pathological characteristics in this study.
Conclusion CIMP-High and reduced expression of p27 were observed in a subtype of insulinomas, and these molecular alterations might play a role in tumorigenesis of insulinoma.
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 3670.