bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4432: Discovery of novel Pin1 inhibitors by structure-guided fragment evolution that downregulate cyclin D1 expression in PC-3 prostate cancer cells
Authors: Moore Jonathan D. , Potter Andrew , Ray Stuart , Oldfield Victoria , Nunns Claire L. , Fromont Christophe , Northfield Christopher J. , Gueritz Louisa , Bryant Christopher J. , Scrace Simon F. , Robinson David , Matassova Natalia , Baker Lisa , Surgenor Allan E. , Dukurno Pawel , Davis Ben , Richardson Christine M. , Murray James B. 
Published: February 2011

Abstract
Pin1 is a peptidyl-prolyl isomerase (PPIase) that is specialized for catalysing isomerization around pSer/Thr-Pro bonds. As isomerisation around such bonds can promote major conformational changes within proteins, Pin1 is able to influence signaling dynamics and outcomes within pathways regulated by proline-directed kinases such as: MAP kinases, cyclin-dependent kinases and GSK-3β. Pin1 overexpression is only weakly oncogenic in itself, but enhances transformation by ErbB2 or activated Ras alleles. Remarkably however, cells from Pin1 deficient mice are resistant to transformation by Ras and ErbB2. As Pin1-deficient mice have a mild phenotype, there are considerable grounds for hope that Pin1 inhibitors will have value for the therapy of cancer and also inflammatory disorders.
Here we report the discovery of our second series of cell active Pin1 inhibitors. Screening of a 700 member fragment library at high concentrations in a PPIase assay revealed 37 potential novel hits. Only two of these hits could be verified to bind Pin1 by 2D NMR, and we were able to obtain a crystal structure of just one of the novel hits bound to Pin1, a pyridyl pyrazole acid. After examining a number of 6-5 unfused ring system acids, we selected a phenyl-imidazole acid as a start point. A program of structure-guided medicinal chemistry led to the discovery of a series of ligands that occupied a novel combination of surfaces within the Pin1 active site, distinct from that occupied by our previously published amino acid-derived inhibitors. This effort culminated in VER-158197, a sub-micromolar (∼750 nM) inhibitor of Pin1 that exhibits high permeability in a CaCo-2 permeability assays and inhibits the growth of Pin1-dependent PC-3 prostate cancer cells (GI50 ∼ 13 uM). Mode of action studies indicated that VER-158197 downregulated cyclin D1 expression and prevented the phosphorylation of p70 S6 Kinase on Thr389 that is normally observed in repsonse to insulin stimulation.
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 4432.
Abstract 4434: Combined targeting of Aurora B (AZD1152) and MEK1/2 (AZD6244) kinases leads to enhancement of anti-tumour effects in vivo.
Authors: Odedra Rajesh , Heaton Simon , Logie Armelle , Mundt Kirsten E. , Anderson Elizabeth , Smith Paul D. , Wilkinson Robert W. 
Published: February 2011

Abstract
Future cancer treatment regimes may involve novel drug combinations aimed at targeting different pathways involved in tumour proliferation and survival. Understanding the mechanisms involved in such combinations and identifying the optimum schedule/sequence will be key to guiding clinical development.
The Aurora kinases play a critical role in mitosis and have been suggested as promising targets for therapy due to their frequent over expression in a variety of tumours. AZD1152 is a selective Aurora B kinase inhibitor, with a novel anti-tumour mechanism of action, inducing endoreduplication, apoptosis and inhibition of cytokinesis. The MAPK signaling pathway is implicated in uncontrolled cell proliferation and cell survival in many cancers. AZD6244 (ARRY-142886), a selective, ATP non-competitive inhibitor of MEK1/2, has demonstrated G1 arrest and anti-tumour activity in a range of preclinical models.
In the present study, we dosed AZD1152 and AZD6244 in combination to nude mice bearing human NSCLC tumour (Calu-6) xenografts. Pharmacodynamic analysis of Calu-6 xenografts treated with either AZD1152 or AZD6244 as monotherapies (MonTx) indicated downstream biomarker effects in accordance with their targets (for e.g. suppression of phosphorylation of histone H3 and ERK, respectively). When the same doses of AZD1152 (150mg/Kg/day s.c. for 2 days via osmotic minipumps) or AZD6244 (25mg/kg/BID p.o.) were dosed in a chronic disease setting, both drugs significantly suppressed Calu-6 tumour growth (versus respective vehicle groups, p&lt;0.005). In combination, the two drugs were dosed in sequence, either AZD1152 → AZD6244 or AZD6244 → AZD1152. Whilst both sequences proved superior to the vehicle arms, only AZD1152
→ AZD6244 proved superior to both MonTx arms in terms of apoptosis induction and tumour growth inhibition. These data indicate a promising therapeutic strategy for combining AZD1152 and AZD6244, and suggest that the sequence of drug administration may be critical when combining these inhibitors. Both AZD1152 and AZD6244 are currently in clinical trials.
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 4434.
Abstract 4439: Anti-cancer actions of omega-3 polyunsaturated fatty acids in human cervical cancer
Authors: Jing Kaipeng , Shin Soyeon , Song Kyoung-Sub , Kim Nayeong , Jeong Soyeon , Kim Jong-Seok , Park Hae-Duck , Han Chang , Wu Tong , Kang Jing X. , Park Jong-Il , Park Seung-Kiel , Kweon Gi-Ryang , Yoon Wan-Hee , Hwang Byung-Doo , Lim Kyu 
Published: February 2011

Abstract
Over 90% of human cervical carcinoma is associated with high risk human papillomavirus (HPV), and a number of biological effects that could contribute to cancer suppression by ω3-polyunsaturated fatty acids (ω3-PUFAs) have been reported. However, the anti-cancer effect of ω3-PUFAs on cervical cancer has been not known yet. In this study, we report inhibitory mechanisms of ω3-PUFAs on cell growth and invasion in cervical cancer. DHA inhibited the cell growth in a dose- and time-dependent manner. In flow cytometry analysis, cell cycle of DHA-treated HeLa cells was arrested in G2/M phase and SubG1 cells also increased. Moreover, apoptotic cell death was confirmed by TUNEL assay, the induction of PARP cleavage and down-regulation of Bcl-2. The invasiveness of cells was significantly inhibited by DHA treatment in vitro transwell assay as well. The MMP-9 and MMP-2 promoter activities were decreased after DHA treatment. Cox-2 and VEGF promoter activities were also inhibited by DHA. Furthermore, DHA decreased the levels of reporter activity of NF-κB, which is transcription factor that regulates MMPs, Cox-2 and VEGF expression. In in vivo experiments, when human papillomavirus type 16 (HPV16)-transformed mouse TC-1 cells were injected into the tail vein of Fat1 mice (Fat1 transgenic mice express a Caenorhabditis elegans ω3-desaturase converting ω6- to ω3-PUFAs endogenously.) and WT (wild type) mice, lung metastasis of TC-1 cells was dramatically inhibited in Fat1 transgenic mice compared to WT mice. Taken together, these findings provide evidence that ω3-PUFAs may inhibit metastasis as well as cell growth and invasion through suppression of MMPs/COX-2/VEGF expression by inhibition of NF-κB expression in cervical cancer cells, indicating that the utilization of ω3-PUFAs may represent a potential effective therapy for the chemoprevention and treatment of human cervical cancer.[This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government(MEST) (#E00026) and by the Infection Signaling Network Research Center (R13-2007-020-01000-0) at Chungnam National University].
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 4439.
Abstract 4440: Using nanocurcumin to treat medulloblastoma and glioblastoma
Authors: Lim Kah Jing , Maitra Anirban , Bisht Savita , Eberhart Charles , Bar Eli 
Published: February 2011

Abstract
We attempted to treat medulloblastoma and glioblastoma, malignant tumors of the central nervous system, with curcumin, a polyphenolic compound derived from the Indian spice turmeric. Curcumin was delivered in a nanoparticle-encapsulated formulation (nanocurcumin) to increase its solubility and bioavailability. Nanocurcumin caused a dose-dependent decrease in cell growth as measured by MTT in multiple brain cancer cell lines, including the embryonal tumor derived cultures DAOY, D283, and PFSK, and the glioblastoma neurosphere line HSR-GBM1. Notably, doses used in these studies did not cause a comparable inhibition in the growth of NIH 3T3 cells or non-neoplastic human fetal cortical neurospheres. The reductions in viable cell mass observed were associated with a combination of G2/M arrest and apoptotic induction. The proportion of G2/M cells increased between 25% and 106% in the various lines, while the percentage of apoptotic cells increased at least two-fold. Nanocurcumin was also found to reduce the CD133+ stem-like cancer cell population in medulloblastoma and glioblastoma cells. In the primary glioblastoma culture JHH-GBM14, the CD133+ population decreased from 7.7% to 0.6%. In addition, 10uM nanocurcumin suppressed clonogenicity of our brain tumor cell lines by more than 97%. Curcumin has been shown to target multiple pathways in different tumor types. We found that Stat3 activity was reduced by nanocurcumin in the DAOY medulloblastoma cell line, via reductions in phospho-Tyr705 and phospho-Ser727. Nanocurcumin also reduced the expression of Hes 5, one of the target genes in the Notch pathway. However, we did not find significant changes in protein expression of Bcl2, MEK, ERK and Akt following nanocurcumin treatment. In conclusion, our results suggest that nanocurcumin can inhibit malignant brain tumor growth, at least in part due to reduction in Stat activity.
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 4440.
Abstract 4441: Stichoposides induce apoptosis through the generation of ceramide in human leukemia cells
Authors: Park Joo-In , Yun Seong-Hoon , Shin Sung-Won , Park Eun-Seon , Lee Seon-A , Han Jin-Yeong , Jeong Jin-Sook , Stonik Valentin A , Kwak Jong-Young 
Published: February 2011

Abstract
Marine triterpene glycosides are physiologically active natural compounds, isolated from sea cucumbers (holothurians) and demonstrate a wide spectrum of biological effects. Stichoposides are extracted from Thelenota anax (family Stichopodidae). Previous studies demonstrated that stichoposides had antifungal, cytotoxic, and antitumor activities. However, the specific molecular mechanisms underlying this effect remain to be elucidated. Stichoposide-induced apoptosis was examined in human leukemia cells in relation to mitochondrial injury and perturbations in signaling pathways. Stichoposide C (STC) induces apoptosis in these cells in a dose-dependent manner and leads to the activation of FAS, recruitment of FADD, activation of caspase-8, cleavage of Bid, mitochondrial damage and activation of caspase-3. In contrast, stichoposide D (STD) induces apoptosis in these cells in a dose-dependent manner and causes to activation of extrinsic pathway, not to activation of intrinsic pathway. In addition, STC- and STD-induced apoptosis are mediated by ER stress pathway, showing that Salubrinal, ER pathway inhibitor, inhibits apoptosis by STC and STD. STD activated acid sphingomyelinase (SMase) and neutral SMase, resulting in the generation of ceramide, but STC slightly activated them. By using specific inhibitor for acid SMase or neutral SMase and siRNA knockdown experiments, stichoposides-induced apoptosis was blocked. Thus, these results indicate that ceramide generation by stichoposides may contribute to stichoposides-induced apoptosis. Thus, these data suggest that stichoposides may have therapeutic relevance in the treatment of human leukemia.
This study was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) through the Medical Research Center for Cancer Molecular Therapy at Dong-A University (R13-2002-044-05002-0).
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 4441.
Abstract 4445: Pegylated arginine deiminase induces mitochondrial apoptosis and synergizes with cisplatin in ASS1-negative malignant pleural mesothelioma
Authors: Delage Barbara , Chelala Claude , Chacko Alex , Jithesh Puthen V. , Fennell Dean A. , Lemoine Nicholas R. , Szlosarek Peter W. 
Published: February 2011

Abstract
We have explored the role of pegylated arginine deiminase (ADI-PEG20), an arginine catabolizing enzyme, in argininosuccinate synthetase 1 (ASS1)-negative malignant pleural mesothelioma (MPM). MPM is a chemorefractory disease, increasing worldwide, with a median survival of less than 1 year. Novel treatments are urgently required. MPM tumors, lacking ASS1, are auxotrophic for arginine and therefore sensitive to arginine depletion driven by ADI-PEG20.
First we assessed the impact of ADI-PEG20 on global gene expression to identify novel interacting pathways in the ASS1-negative MPM cell line, JU77, using the human genome U133 Plus 2.0 Array from Affymetrix combined with bioinformatic analysis. Next, three ASS1-negative MPM cell lines (MSTO-211H, 2591 and JU77) were treated in triplicate with different fixed ratios of ADI-PEG20 and cisplatin. Cellular viability was determined 6 days post-treatment by MTS colorimetric assay. Apoptosis protein induction by ADI-PEG20 and platinum, alone and in combination, was measured by western blot after mitochondrial and cytosolic fractionation. Drug interactions were analyzed using the isobologram method of Chou and Talalay.
ADI-PEG20 modulated several thousand genes involved in cell cycle, DNA damage, immune, and inflammatory pathways in the ASS1-negative JU77 MPM cell line by 24hrs of drug treatment. In contrast, stable transfection of ASS1 cDNA in ASS1-negative MPM cell lines resulted in resistance to ADI-PEG20 with minimal evidence of gene modulation by 24hr of drug treatment as assessed in the JU77 MPM cell line. ADI-PEG20 triggered mitochondria-dependent apoptosis as evidenced by Smac release from mitochondria into the cytosol of ASS1-negative MPM cell lines. We confirmed that arginine depletion by ADI-PEG20 altered the mTOR/p70S6K signaling pathway and led to dephosphorylation of the translation regulation proteins S6K and E4-BP1. The expression of cell cycle regulating proteins p21 and cyclin D1 was decreased by arginine depletion, alone and in combination with cisplatin. The enhancement of cisplatin cytotoxicity by ADI-PEG20 with loss of ASS1-negative MPM cell viability as early as 24hr post treatment, supports the demonstrated strong synergy between the two drugs.
In summary, the antitumor effect of platinum was potentiated markedly using ADI-PEG20, suggesting that combining arginine depletion with the current standard of care, platinum and antifolates, may offer an improvement over doublet chemotherapy alone.
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 4445.
Abstract 4448: Disruption of nedd4 and connexin 46 interaction by gap junction activator in breast cancer cells
Authors: Nguyen Thu Annelise , Ding Ying , Bigelow Kristina 
Published: February 2011

Abstract
Breast cancer is the second most common cancer among women; it is also the second leading cause of cancer death among women in the United States. Progress in understanding the etiology of this disease and developing therapies has been slow due to multiple deregulations of various genes. Cancer cells exhibit many defects in cell communication that contribute to the loss of tissue homeostasis (excess cell proliferation, invasion, and metastasis). Most normal cells have functional gap junctional intercellular communication (GJIC), while most, if not all, tumors cells have dysfunctional GJIC. GJIC consists of connexin proteins, which mediate the direct passage of small molecules from one cell to the next. They are involved in the regulation of the cell cycle, cell differentiation, cell signaling and previous studies have been suggested their participation in tumor formation and progression. It is believed that restoring GJIC is linked to drug sensitivity and reduction of tumorigenicity. Thus, increasing gap junction activity or enhancing GJIC in tumor cells provides the targets to enhance anti-neoplastic therapies. Several GJIC enhancers have been reported; however, an effective clinical drug targeting gap junction is not available at this time. Recently, we synthesized a new class of substituted quinolines (code name: PQ) and found that they possess potent inhibitory activities against T47D breast cancer cells (IC50 value of PQ1 is 119 nM) through the enhancement of GJIC. Since the mechanism of action of GJIC enhancement caused by PQ is unknown, the current study is to determine the target proteins that PQ interacts with, which may lead to the mechanism of enhancement of GJIC and inhibition of cancer cell growth. Using surface plasmon resonance (SPR) spectroscopy, we have found that PQ1 has a strong binding with Nedd4, E3 ubiquitin ligase which previously been shown to involve in the degradation of gap junction. T47D breast cancer cells were treated with various concentrations of PQ1 for 24 hours. Whole cell extract was isolated and subjected to immunoprecipitation assay, followed by western blot analysis. The results show that 100 nM PQ1 can cause a 2-fold decrease in the interaction of Nedd4 and connexin 46 compared to control without treatment or solvent. Since gap junction turnover has been shown to be facilitated by lysosomal and proteasomal degradation, disruption of Nedd4 and connexin 46 suggests that PQ1 may inhibit the lysosomal and proteasomal degradation of connexin 46 in breast cancer cells. Future study will focus on whether PQ causes an increase in gap junction activity via inhibition of Nedd4-ubiquination of connexin.
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 4448.
Abstract 4449: Effects of endocrine therapy on mRNA- and microRNA expression profiles in prostate cancer
Authors: Lehmusvaara Saara , Erkkilä Timo , Lähdesmäki Harri , Kujala Paula , Tammela Teuvo L.J. , Visakorpi Tapio 
Published: February 2011

Abstract
Introduction & Objectives: The gold standard treatment for advanced prostate cancer is endocrine therapy either by castration (surgical or chemical) or with antiandrogens. Although endocrine therapy has been used for decades, the molecular consequences of androgen deprivation are poorly understood. The aim of this study was to investigate how endocrine therapy affects genome-wide gene expression and to ascertain whether chemical castration or antiandrogen use leads to unique gene expression profiles.
Methods: 30 patients were randomized equally into three groups: no treatment, bicalutamide (antiandrogen) 150 mg daily, and goserelin (GnRH agonist) 3.6 mg every 4 weeks. Following the neoadjuvant treatment for 12 weeks, patients underwent radical prostatectomy. Freshly frozen specimens were collected for expression profiling of both protein (mRNA) and microRNA (miRNAs) coding genes using Illumina (probes for ∼25 000 mRNAs) and Agilent (723 miRNAs) microarrays, respectively. The amount of cancer, benign epithelium, and stroma in the specimens was assessed using H&E stained slides. Statistical analyses were first done without taken into account the tissue composition of specimens. Subsequently, tailor-made in silico Bayesian modeling tool was used to predict the mRNA and miRNA expression patterns in the different cellular compartments. mRNA expression from microarray data and in silico predictions were validated with qPCR from microdissected tissue samples.
Results: In unsupervised hierarchical clustering of mRNA profiles, specimens from bicalutamide and goserelin arms were clustered separately from control samples, but not separately from each other. Out of 600 significantly differently expressed mRNAs between control and treatment arms (p&lt;0.05), only 56 were unique for bicalutamide treatment and 13 for goserelin treatment. Interestingly, tissue compartment analysis showed that bicalutamide affects more specifically cancer cells while goserelin has more effect to stroma and normal epithelium. In the miRNA profiles, there were only minor changes in the bicalutamide and goserelin treatment arms compared with control arm. Only 6 miRNAs were significantly differently expressed (p&lt;0.05). Also, there was more variety in miRNA expression between different tissue compartments than treatment arms.
Conclusions: In conclusion, androgen deprivation had more effect on mRNA than miRNA expression. Most of the differentially expressed genes behaved similarly after GnRH agonist and antiandrogen treatments.
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 4449.