bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5468: JNK-1 inhibition leads to antitumor activity in ovarian cancer
Authors: Rodriguez-Aguayo Cristian , Vivas-Mejia Pablo , Benito Juliana Maria , Fernandez Ariel , Francois-Xavier Claret , Chavez-Reyes Arturo , Sood Anil K. , Lopez-Berestein Gabriel 
Published: February 2011

Abstract
Recent findings suggest that JNK mediates oncogenic functions in several cancer types including head and neck, gastric, and breast cancers, and melanoma, thus it may be an attractive therapeutic target. Specifically, JNK1 but not JNK2 has been shown to be important in promoting cell survival by controlling cell cycle arrest and apoptosis. Little is known about the role of JNK1 in ovarian cancer growth. Therefore, we examined the potential of JNK1 as a therapeutic target in the current study. We utilized a novel small molecule inhibitor, WBZ_4, which was designed, synthesized, and characterized by our team to curb the potential for side effects of the original compound, imatinib. WBZ_4 was designed to target both c-Kit and JNK1 while avoiding the Abl-kinase. The redesign process was based on comparing the residence time of water molecules that solvate the interfacial aligned residues across known targets of imatinib. Non-conserved sites with low residence time that had a higher propensity to dehydrate (de-wetting hot spots) were used to build blueprints for each target. By adding a methyl group to the original imatinib, we were able to attack a de-wetting hot spot present in C-Kit and JNK1 but absent from BCR-Abl, thereby increasing the specificity of the drug towards the desired targets. Here, we report on the biological effects of JNK-1 inhibition, both in vitro and in vivo using experimental models of ovarian cancer. We found a significant association of pJNK with progression free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose dependent fashion in four ovarian cancer cell lines. In vivo, while imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The anti-tumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights as compared to non-silencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition. These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the re-designed WBZ_4 compound should be considered for further clinical development.
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 5468.
Abstract 547: Changes in proteomic and epigenetic expression patterns in tumour associated fibroblasts (TAF) by interaction with urinary bladder carcinoma cells
Authors: Enkelmann Astrid , Heinzelmann Joana , Escher Niko , Walter Martina , Weidig Michaela , Wunderlich Heiko , Junker Kerstin 
Published: February 2011

Abstract
Background: Tumour development and progression is strongly affected by interaction of tumour cells and tumour stroma. For different tumour models (e.g. breast cancer) a supportive effect of TAF on the tumour genesis was demonstrated. Purpose of the present work is the isolation and characterisation of TAF from primary urinary bladder tumour specimen. A further part of this study will deal with the influence of urinary bladder carcinoma cell lines on protein expression of TAF.
Material and Methods: TAF were isolated from cultured urinary bladder tumour specimen. Therefore, primary tumour material was treated with EDTA followed by differential trypsinisation. Non-tumour fibroblasts were isolated from foreskin and normal urinary bladder tissue. Analyses of protein patterns were carried out on cultivated fibroblasts by SELDI-TOF-MS. TAF and foreskin fibroblasts were co-cultivated with urinary bladder cancer cell lines in separated cell culture compartments followed by SELDI-TOF-MS analyses. Furthermore total RNA was isolated from TAF and non-tumour fibroblasts to analyse the miRNA expression profile by miRNA Microarray.
Results: By optimizing cell culture routines it was possible to isolate and subsequently cultivate TAF from primary tumour material of the urinary bladder. SELDI-TOF-MS measurements reveal differences in the proteomic patterns of TAF and non-tumour fibroblasts. Microarray analyses indicate different expression levels of several miRNAs in TAF and non-tumour fibroblasts. Co-cultivation of urinary bladder carcinoma cells and TAF or non-tumour fibroblasts induces modified protein patterns in the different cell types.
Conclusion: TAF can be isolated and cultivated separately from primary tumour material. TAF are characterised by the expression of a specific protein pattern and miRNA profile in comparison to non-tumour fibroblasts. Co-cultivation with tumour cells revealed the induction of a modified expression profile in fibroblasts and vice versa. The present results will provide a more detailed understanding of the function of TAF in the tumour development of urinary bladder carcinoma.
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 547.
Abstract 5470: Safe and targeted anticancer therapeutic efficacy of a novel antioxidant-conjugated difluoro-diarylidenyl-piperidone (HO-3867) against ovarian cancer
Authors: Kuppusamy Periannan , Selvendiran K. , Tong L. , Bratasz A. , Kuppusamy ML. , Trigg NJ. , Rivera BK. , Kálai T. , Hideg K. 
Published: February 2011

Abstract
The anticancer efficacy of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) against ovarian cancer is reported. Studies were performed using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1 and OVCAR3, as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 demonstrated a preferential toxicity towards ovarian cancer cells, while sparing healthy cells. HO-3867 induced G2/M cell-cycle arrest in A2780 cells by modulating cell-cycle regulatory molecules p53, p21, p27, cdk2 and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in STAT3 (Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor (VEGF), suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian tumors in a dosage-dependent manner without any apparent toxicity. We further analyzed of xenografted tumor tissues showed that HO-3867 inhibits pSTAT3 (Tyr705 and Ser727) and Jak1 and increased apoptotic markers of cleaved caspase-3 and PARP. The results clearly showed that HO-3867 exhibited significant cytotoxicity towards ovarian cancer cells by inhibiting the JAK/STAT3-signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer 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 5470.
Abstract 5472: Class III beta-tubulin in castration resistant human prostate cancer
Authors: Terry Stephane , Ploussard Guillaume , Maillé Pascale , Allory Yves , Nicolaiew Nathalie , Soyeux Pascale , Kheuang Laurence , Culine Stephane , Buttyan Ralph , de la Taille Alexandre , Vacherot Francis 
Published: February 2011

Abstract
BACKGROUND: Class III β-tubulin (βIII-tubulin) is expressed in tissues of neuronal lineage but it is also expressed in several human malignancies including non small cell lung carcinoma, breast and ovarian cancer. Overexpression of βIII-tubulin in these tumors is associated with an unfavorable outcome and resistance to taxane-based therapies. βIII-tubulin deregulation however is still poorly documented in prostate cancer. Previously, we reported that βIII-tubulin expression is increased in prostate cancer (PCa) cells by androgen ablation. Here we sought to better characterize the contribution of βIII-tubulin to castration resistant PCa, the stage of the tumor most responsible for mortality from PCa. METHODS: βIII-tubulin expression was assayed by immunohistochemistry in prostate tumors obtained from patients with castration resistant PCa. Protein expression was scored as null (0), weak (1), moderate (2) and strong (3) and considered significant when the score was 2 or more in more than 10% of cancer cells. Consecutive sections were also immunostained for neuroendocrine biomarkers, neuron specific enolase (NSE) and chromogranin A (CgA). An androgen independent (AI) variant of LNCaP cells (AI-LNCaP) was assessed for the effects of docetaxel treatment on βIII-tubulin expression. Finally, DU145 cells stably overexpressing βIII-tubulin were tested for their sensitivity to docetaxel relative to control vector-transfected cells. RESULTS: 24/40 specimens of castration resistant tumors were found to express significant levels of βIII-tubulin. In 6 out of 22 cases analyzed, regions of the tumor positively co-stained for both βIII tubulin and NSE, however none of 8 evaluated cases showed co-staining for βIII-tubulin and CgA. AI-LNCaP cells treated with 5 to 10 nM docetaxel showed a time dependent increase in βIII-tubulin expression. DU145 cells stably overexpressing βIII-tubulin were found to be more resistant to docetaxel than the parental counterpart with a 2-fold increase in the IC50. CONCLUSION: Our data indicate that βIII-tubulin is expressed in the majority of castration resistant prostate tumors. Although βIII-tubulin immunostaining of prostate tumor cells sometimes coincides with staining for neuroendocrine markers, most βIII-tubulin positive tumor cells examined did not show coincidental staining so increased βIII-tubulin expression may occur independently of NE differentiation. Regardless, our in vitro studies support a role for βIII-tubulin in the emergence of doxetaxel resistance by androgen independent human PCa 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 5472.
Abstract 5475: Dynamin inhibition: A new therapeutic approach for the treatment of cancer
Authors: Joshi Sanket , Gaddipatti Swetha , Gilbert Jayne , Smith Charlotte M. , Gordon Christopher P. , Sakoff Jennette , McCluskey Adam , Robinson Phillip J. , Braithwaite Antony W. , Chircop Megan 
Published: February 2011

Abstract
Cytokinesis is the final stage of cell division and involves ingression of the plasma membrane between segregating chromosomes followed by membrane abscission, resulting in the production of two daughter cells. Abscission involves the formation of a central γ-tubulin midbody ring within the intracellular bridge prior to final separation. The endocytic protein dynamin II (dynII) is required for this abscission step. We propose that dynII inhibition represents a new pharmacological intervention for the treatment of cancer via the induction of cytokinesis failure. Our pilot data in Hela cells shows that inhibition of dynII with myristyl trimethylammonium bromide (MiTMAB)(IC50 = 3.1 ± 0.2uM) and octadecyl trimethylammonium bromide (OcTMAB)(IC50 = 1.9 ± 0.2uM) induces cytokinesis failure. Using immunoflourescence, cell cycle analysis and live cell imaging we have shown that cells exposed to these compounds progress through mitosis with normal timing and complete furrow ingression successfully. However, abscission fails causing the membrane to regress generating binucleated cells. These cells initially accumulate in the G2+M phase of the cell cycle but ultimately undergo apoptotic cell death. In further support of our findings we have shown Chlorpromazine, a registered anti-psychotic known to induce cytokinesis failure, to also inhibit dynII (IC50 = 1.3 ± 0.4uM). Using the MTT growth inhibition assay in a panel of 9 cancer cell lines we have shown MiTMAB, OcTMAB and Chlorpromazine to be potent inhibitors of cell growth (IC50 = 0.6 - 3.9uM, 0.5 - 3.5 uM, and 13 - 32uM, respectively). Multinucleation and cytokinesis failure was also induced in Hela cells depleted of dynII using small interfering RNA (siRNA). These findings highlight dynamin II inhibition as a novel therapy for the treatment of 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 5475.
Abstract 5476: gp130 knockdown by short hairpin RNA synergistic effect of bortezomib induced apoptosis in multiple myeloma cells
Authors: Park Juwon , Lee Chansu , Oh Jeong In , Kim Byung-Su , Kwon Jung Hye , Kim Byoung Kook , Ahn Kwang-Sung , Yoon Sung-Soo 
Published: February 2011

Abstract
Although bortezomib, one of targeted anti-cancer drugs, effectively suppresses the growth of multiple myeloma (MM) cells via inactivation of NF-κB, activation of IL-6 mediated cell signaling could be suppressed bortezomib mediated apoptosis. Previously we found that the expression levels of IL-6 and sIL-6R in MM patient's bone marrow serum was higher than control. A set of reports suggested that those levels affect the progression of MM. In addition, bortezomib mediated apoptosis directly associated with the activities of NF-κB in MM cells. However, at present, their precise roles, especially IL-6 mediated cell signaling associating with NF-κB activation, in the progression of MM and therapeutic response to anti-cancer treatment still remain largely unknown. In this study, U266 cells treated with combination of IL-6 and sIL-6R showed the prolongation of the phosphorylation of ERK and STAT3 when compared with IL-6 alone. Transient transfection of gp130 shRNA in MM cells (MM/gp130 shRNA) showed inhibition of IL-6/sIL-6R induced ERK and STAT3 phosphorylation. Next, the effect of IL-6 and sIL-6R in an anti-myeloma agent, bortezomib, was investigated. In cell proliferation assay, U266 and RPMI8226 cells exposed to IL-6 and sIL-6R were decreased induction of apoptosis by bortezomib. In addition, MM/gp130 shRNA cells treated with bortezomib showed significantly inhibited c-Myc and cyclinD1 and increased apoptosis by borteozomib compared with parental cells. In this study indicated that the synergic activation of ERK and STAT3 phosphorylation as the result of IL-6 with sIL-6R could diminished by knockdown of gp130 and its effect could be potentiated the apoptotic efficacy of bortezomib in MM 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 5476.
Abstract 548: Interaction between mammary adenocarcinoma cells and macrophages in a three-dimensional model of tumor spheroids
Authors: Roldan Julieta S. , Najenson Ana C. , Roca Fernanda , Marino Lina , Jasnis Maria A. , Fiszman Gabriel L. 
Published: February 2011

Abstract
Solid tumors contain heterogeneous cellular subpopulation due to a limit supply of oxygen, nutrients and wastes. This microenvironment affects local cell growth, survival and overall therapeutic efficacy. Three-dimensional (3D) cell model reflect this situation and is a good model to study of the interaction with the immune system.
Spheroids of the murine LM3 and human MCF-7 mammary adenocarcinoma cell lines were cultured with RAW 264.7 macrophages and human monocytes isolated from peripheral blood from normal volunteers respectively Spheroids were maintained in culture dishes pre-treated with 1.5% agar. In both tumor models, macrophages/monocytes were added after 10-13 days spheroids growth. Control cultures were maintained as monolayers in normoxic and hypoxic conditions (hypoxic chamber 1% O2 saturated during 4-6h). A growth curve of the spheroids were performed, reaching a peak of &gt;300um (+/-) at day 15. In MCF-7 model, cell viability, monocyte distribution inside spheroids and protein expression were determined by hematoxiline-eosine staining and immunohitochemistry with specific antibodies. Results showed that 3D growth followed a concentric organization of proliferant (Ki67+), quiescent (Ki67-/Bcl-2+) and dead cells (CAS+) from periphery towards the hypoxic core (HIF-1+). In LM3 spheroids an enhanced arginase activity (140,64±2,05 vs. 18,17±1,22, p&lt;0,05) and nitric oxide (NO) levels (10,21±1,15 vs 0,55±0,50, p&lt;0,05) were also detected compared to LM3 cells growing as monolayer. It was also detected a decrease NO levels during spheroids growth (4 days: 38,7±8,3 vs. 13 days: 10,21±1,15). On the other hand, arginase activity and NO levels of spheroids cocultured with macrophages were lower than the spheroids alone (96,41±3,63 vs.317,7048±8,82 and 4,1±1,56 vs. 10,22±1,15; p&lt;0,05 respectively). These results show that arginine metabolic pathways, either by NOS or arginase, are both more activated in spheroids than in tumor cell monolayer and coculture spheroids. In MCF7 and LM3 models, HIF-1alpha and iNOS expression was detected by western blot using hypoxic monolayers as a control.
Culture system in 3D appears to be an ideal model to analyze the role of hypoxia and the mechanisms that modulate interactions between tumor and immune 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 548.
Abstract 549: Interleukin-11 induces survivin expression in brain endothelial cells
Authors: Liu Zhi , Yuan Robin , Armstrong Don , Louie Stan , Schönthal Axel H. , Chen Thomas C. , Hofman Florence 
Published: February 2011

Abstract
The tumor vasculature, which provides nutrients and oxygen to cancer cells, is particularly relevant in the highly vascular primary brain tumor, glioblastoma multiforme (glioma). The tumor-associated blood vessels within gliomas have been shown to be abnormal in their structure and function as compared to the normal vasculature. Previous studies from this laboratory have shown that these tumor-associated brain endothelial cells are resistant to chemotherapy; and this resistance is a result, in part, of the overexpression of survivin in these cells. Survivin, a member of the inhibitor of apoptosis gene family, is responsible for drug resistance in cancer cells, yet little is known about its role and regulation in the endothelial cells of the tumor vasculature. The mechanism of this survivin overexpression in the brain vasculature is the focus of this report. Here we present data showing that Interleukin (IL)-11, a cytokine known to stimulate survivin, is produced by human gliomas and is responsible for the increase in survivin in the brain endothelial cells. To demonstrate this, we examined glioma cell lines for IL-11 production. Our studies showed that the glioma cell lines, U87 and U251, secrete high levels of IL-11, as compared to normal cells. Furthermore, when brain endothelial cells are treated with exogenous IL-11, they exhibit increased levels of survivin, similar to the elevated basal level of tumor-associated endothelial cells. These studies suggest that tumor-derived IL-11 may play an important role in the overexpression of survivin in endothelial cells. Since survivin is important in chemoresistance, IL-11 or its receptor may be a relevant target for regulating survivin in the glioma vasculature, and thereby mediating an effective chemosensitizing mechanism and anti-vascular therapy for brain 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 549.
Abstract 5490: In vitro and in vivo evaluation of LipoFufol, a new triple stealth liposomal formulation of modulated 5-FU: impact on efficacy and toxicity
Authors: Ciccolini Joseph , Fanciullino Raphaelle , Giacometti Sarah , Vacus Joël , Mignard Caroline , Koob Zina , Iliadis Athanassios 
Published: February 2011

Abstract
5-FU is a mainstay for treating various solid tumors in adults, including digestive cancers. At bedside, treatment efficacy is often hampered by drug resistance and severe toxicities, mostly due to impaired liver detoxification related to dihydropyrimidine dehydrogenase (DPD) deficiency. We have developed a stealth liposomal formulation of 5-FU combined with two modulators (2′-deoxy-inosine and folinic acid) designed to exhibit higher antiproliferative properties while being less affected by liver uptake and subsequent DPD-related dysregulations. Lipofufol is a 100 nm diameter, pegylated liposome that proved to be stable at room temperature for at least 4 weeks. When used in vitro in the highly 5-FU-resistant human colorectal cell line SW620, mean IC50 values for standard 5-FU, 5-FU + folinic acid and LipoFufol were 29 µM, 14µM and 2µM respectively, indicative of a greater antiproliferative effect. Pharmacokinetics study was performed in rodents after I.V. administration and showed that liposomal 5-FU clearance was strongly reduced by 62% (e.g. 0.087 l/h VS. 0.231 l/h), as compared with standard 5-FU. Toxicity study was undertaken to check whether Lipofufol could be less toxic in DPD-deficient individuals, and confirmed that milder (e.g., neutrophils count: −75% VS. −96%) and shorter (e.g., 6 VS. 11 days) neutropenia was observed in DPD-deficient rats treated with liposomal 5-FU, as compared with deficient animals exposed to standard 5-FU. Tolerance studies and search for MTD were further performed in tumor-bearing mice and showed that LipoFufol could be administered safely up to 20 mg/kg I.V. on a 3QW basis for 3 consecutive weeks. In mice bearing LS174t human colorectal orthotopic xenografts, longer survival was achieved in animals treated with 20 mg/kg Lipofufol, as compared with animals treated with 80 mg/kg of standard 5-FU (e.g., 80% VS. 40% survival at 3 weeks). Overall, our data show that Lipofufol exhibits a greater anticancer efficacy both in vitro and in vivo, including in highly resistant models, with an optimized and safer pharmacokinetics profile skipping, at least in part, the DPD deficiency issue.
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 5490.