bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A34: Analysis of gossypol-induced cytotoxicity in malignant peripheral nerve sheath tumor cells.
Authors: Kaza Niroop , Roth Kevin A. 
Published: June 2012

Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas. MPNSTs are the leading cause of mortality in patients with neurofibromatosis type 1 (NF1), an autosomal dominant genetic disease. Current treatment modalities have been ineffective resulting in high recurrence (40–68%) and poor five year survival rate between 16–52% in these tumors. This necessitates the need for novel therapeutic options. The anti-apoptotic members of the Bcl-2 family have been reported to be over expressed in a variety of cancers and have been implicated in rendering cancer cells resistant to apoptosis. Gossypol, a naturally occurring phenolic compound, functions as a BH3 mimetic by occupying the BH3-binding groove of anti-apoptotic proteins of the Bcl-2 family. Gossypol has been shown to induce cell death in prostate cancer, breast cancer, glioma and some hematological cancer cell lines. In this study, we assessed the effect of AT101 (gossypol) on MPNST cells. We observed that AT101 caused a dose and time dependent decrease in viability in MPNST cells which was not accompanied by an increase in caspase activation. AT101 also caused accumulation of autophagic vacuoles. Blocking the initiation of autophagy attenuated the cell death caused by AT101, while blocking apoptosis did not provide any protection. In summary, AT101 induces autophagic vacuole accumulation leading to cell death independent of caspase activation in MPNST cells. Further studies are needed to elucidate the mechanisms through which AT101 causes cell death in MPNSTs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A34.
Abstract A35: DNA microarray analysis of the effect of fusarochromanone on human malignant bladder cancer cells.
Authors: King Trey , Key Mickeal , Clifford John , Gill Jennifer Roberts , Kim Yoonjee , Mahdavian Elahe , Cvek Urska , Salvatore Brian , Furmanski Brian , Rhoads Robert , Williams-Hart Tara 
Published: June 2012

Abstract
Fusarochromanone (FC-101a) has been identified as a potential, novel anti-cancer compound. Several studies revealed that FC-101a is an inhibitor of many human cancer cell lines, increases apoptosis of melanoma cell lines and significantly reduces tumor growth in mice. The long-term goal of this project is to elucidate how FC-101a inhibits cancer cell growth by identifying its molecular target(s). In this study, we used DNA microarray analysis and realtime PCR to identify genes that are differentially-expressed in response to FC-101a treatment in yeast and human bladder cancer cells. We hypothesize that changes in gene expression in response to FC-101a treatment will elucidate cellular mechanisms by which FC-101a inhibits cancer cell growth. Our study includes human cancer cell lines as a model system and budding yeast as a model organism to identify cellular pathways that are responsive to FC-101a treatment in multiple eukaryotic cell types. In this study, we have determined that among human skin, breast, prostate and bladder cancer cell lines, bladder cancer cells are the most sensitive to FC-101a treatment. Thus, we performed DNA microarray analysis using human bladder carcinoma cells treated with FC-101a for 24, 48 and 72 hours and yeast cells treated with FC-101a for 20 minutes. We identified hundreds of genes that are highly expressed and greater than two-fold up-regulated or down-regulated in FC-101a-treated cells compared with untreated cells. Of these FC-101a-responsive genes common to yeast and human bladder cancer cells, a majority of these genes regulate apoptosis, metabolic pathways, cell cycle progression, DNA replication, cell signaling and DNA recombination and repair.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A35.
Abstract A48: Osteopontin increases heme oxygenase-1 expression and subsequently induces cell migration in glioma cells.
Authors: Lu Dah-Yuu , Yeh Wei-Lan , Chou Shao-Jiun 
Published: June 2012

Abstract
Malignant gliomas are the most common primary brain tumors in adults and the second most common tumor in children. Gliomas are associated high morbidity and mortality because these tumors are highly invasive into surrounding brain tissue, making complete surgical resection impossible. Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor in a variety of neuronal cell populations. However, the molecular mechanisms and pathologic roles underlying GDNF-induced glioma migration remain unclear. In this study, we found that application of recombinant human GDNF enhances the migration of U87 and U251 cells but not C6 cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) mRNA, protein and secretion increase in response to GDNF stimulation. The GDNF-induced increase in cell migration was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. We then examined the involvement of mitogen-activated protein kinases (MAPKs) in glioma cell migration induced by GDNF. GDNF-induced MMP-13 expression and glioma migration were attenuated by MEK/ extracellular signal-regulating kinase (ERK) and c-Jun N-terminal protein kinase (JNK) inhibitors, as well as ERK and JNK dominant-negative mutants. Treatment with GDNF induced MEK/ERK and JNK/c-Jun activation and increased AP-1 DNA binding activity in a time-dependent manner. Treatment with AP-1 inhibitors (tanshinone IIA and curcumin) also reduced GDNF-induced glioma cell migration. In migration-prone sublines, cells with greater migration ability had higher GDNF expression. These results indicate that GDNF enhances migration of glioma cells through the increase of MMP-13 production and is mainly regulated by the MEK/ERK and JNK, c-Jun and AP-1 pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A48.
Abstract A54: Mithramycin inhibits cigarette smoke-mediated induction of ABCG2 in lung and esophageal cancer cells: Implications for targeting cancer stem cells in thoracic malignancies.
Authors: Zhang Mary , Mathur Aarti , Rao Mahadev , Xi Sichuan , Zhang Yuwei , Datrice Nicole , Hong Julie A. , Kemp Clinton D. , Ripley R. Taylor , Atay Scott , Weigand Gordon , Avital Itzak , Li Xinmin , Schrump David S. 
Published: June 2012

Abstract
Limited information is available regarding epigenetic mechanisms by which cigarette smoke mediates initiation and progression of thoracic malignancies. In order to examine this issue, lung and esophageal cancer cells (A549, Calu-6, NCI-SB-ESC1 and NCI-SB-ESC2), were cultured in normal media (NM) with or without cigarette smoke condensate (CSC) under clinically relevant exposure conditions. Microarray analysis revealed that five day CSC exposure significantly up-regulated ABCG2, encoding a xenobiotic pump highly expressed in cancer stem cells. Quantitative reverse transcription-PCR (qRT-PCR), western blot, and immunohistochemistry experiments confirmed up-regulation of ABCG2 in cultured cancer lines, but not normal small airway epithelial cells (SAEC) or immortalized esophageal squamous cells (HET1A) exposed to CSC. Flow cytometry experiments demonstrated that CSC increased the side population (SP) of cultured cancer cells. Transient transfection experiments using ABCG2 promoter reporter constructs revealed that deletion of xenobiotic response elements as well as SP-1 sites markedly attenuated ABCG2 induction by CSC. Chromatin immunoprecipitation (ChIP) experiments revealed that CSC-mediated induction of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor (AHR), SP-1, and Nrf2, as well as increased levels of RNA pol II and H3K9Ac within the ABCG2 promoter. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AHR, SP-1, and Nrf2 levels within the ABCG2 promoter, down-regulated ABCG2 expression, decreased S P, inhibited in-vitro proliferation of lung and esophageal cancer cells, and markedly diminished growth of established tumor xenografts. Microarray analysis revealed significant down-regulation of numerous stem-cell related pathways in lung cancer cells following mithramycin exposure. Collectively, these findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical evaluation of mithramycin for targeting cancer stem cells in thoracic malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A54.
Abstract A62: Monensin-induced oxidative stress reduces prostate cancer cell motility and cancer stem cell markers.
Authors: Ketola Kirsi , Vuoristo Anu , Oresic Matej , Kallioniemi Olli , Iljin Kristiina 
Published: June 2012

Abstract
Therapeutic options for prostate cancer are limited and treatment responses to currently existing therapies are often unsatisfactory. Thus, there is an urgent need for novel agents to target advanced and metastatic prostate cancer cells. We have recently carried out a chemical-biological high-throughput screening of 4,910 known drugs and drug-like molecules in four prostate cancer cell models and two non-tumorigenic prostate epithelial cell lines to identify prostate cancer cell growth selective inhibitors. Only four compounds, antibiotic ionophore monensin, aldehyde dehydrogenase (ALDH) inhibitor disulfiram, histone deacetylase inhibitor trichostatin A and fungicide thiram inhibited selectively cancer cell growth at nanomolar concentrations. The mechanistic studies indicated that monensin inhibited prostate cancer cell growth by inducing oxidative stress and apoptosis. In addition, monensin reduced androgen receptor signaling, showed a synergistic anti-proliferative effect with anti-androgens as well as reduced the levels of MYC and ERG oncogenes and reduced the activity of ALDH in prostate cancer cells. Moreover, antioxidant vitamin C rescued the monensin induced growth inhibition, indicating that oxidative stress plays a key role in the antineoplastic effect of monensin in cultured prostate cancer cells.
Our previous Connectivity Map results indicated that monensin has agonistic effects to NF-κB inactivator and oxidative stress inducer niclosamide. Here, we show that monensin indeed reduced the activity of NF-κB pathway. NF-κB maintains cellular antioxidant defence capacity and its inhibition induces oxidative stress as well as reduces tumorigenesis, metastasis and cancer stem cell potential. Cancer stem cells have a controlled redox balance system including high ALDH and CD44 expression which protect cancer stem cells from oxidative stress. Our results confirmed that monensin reduced the cancer stem cell markers in prostate cancer cells. Moreover, monensin induced epithelial cell differentiation shown as well as reduced motility in cultured prostate cancer cells, suggesting that monensin inhibits prostate tumorigenesis by multiple ways. Furthermore, the steroid profiling indicated that monensin increases the levels of oxidative stress inducing steroids and reduces androgen precursors in cultured prostate cancer cells. In conclusion, our results suggest that impairing the redox control, which has a crucial role in cancer cells enabling survival under high intracellular ROS, is a potent way to target prostate cancer cells and potentially also prostate cancer stem cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A62.
Abstract A76: MDV3100, a novel androgen receptor signaling inhibitor, promotes cell apoptosis and tumor regression in both in vitro and in vivo models of castration-resistant prostate cancer.
Authors: Bernales Sebastian , Guerrero Javier , Gomez Francisco , Alfaro Ivan E. , Iguchi Kanako , Kusayama Toshiyuki , Protter Andrew A. 
Published: June 2012

Abstract
Prostate tumors initially respond to androgen deprivation therapy but eventually progress despite low serum levels of testosterone. In this stage, known as castration-resistant prostate cancer (CRPC), abnormal androgen receptor (AR) signaling persists and classic anti-androgens such as bicalutamide are ineffective at controlling tumor growth. The novel AR signaling inhibitor MDV3100 has been demonstrated to inhibit AR signaling in preclinical models of CRPC. Here, we investigate further the cellular effects of MDV3100 treatment on AR signaling in in vitro models and in vivo xenograft models of CRPC.
Our experiments reveal that MDV3100 (&gt; 100 nM) inhibits dihydrotestosterone (DHT) induced AR-target gene expression in LNCaP cells and LNCaP/AR cells, a CRPC cell culture model in which AR is over-expressed. Inhibition of Prostate-Specific Antigen mRNA expression by MDV3100 was effective at concentrations 10-fold lower than with bicalutamide. As evidenced in other studies and in contrast to bicalutamide, MDV3100 did not display agonistic effects on AR signaling at 10 μM. In contrast to bicalutamide, MDV3100 (&gt; 1 μM) inhibited androgen dependent nuclear translocation of AR, as measured with a quantitative optical based enzyme fragment complementation assay and AR-YFP localization in HEK-293 cells. Furthermore, in the presence of DHT, MDV3100 effectively reduced cell viability of LNCaP cells at concentrations as low as 0.1 μM, 10-fold lower than bicalutamide. MDV3100 also decreased cell viability of LNCaP/AR and W741C-LNcaP cells. We found that the apoptosis marker cleaved-caspase 3 was induced in LNCaP/AR cells treated with 1 M MDV3100 for 48 hours. Under these conditions, MDV3100 was more potent than bicalutamide in decreasing cell viability. Finally, we show that MDV3100 inhibited tumor growth and induced regression of tumor volume in a xenograft model of CRPC generated with LNCaP/AR cells.
These results demonstrate that MDV3100, unlike anti-androgens, is effective in both in vitro and in vivo models of CRPC and that its mechanistic advantages over other anti-androgens could be explained by its ability to inhibit AR nuclear translocation and induce cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A76.
Abstract A77: Efficacy of PARP inhibitor AG014699 in orthotopic GBM xenografts is limited by ineffective drug penetration into the central nervous system.
Authors: Cen Ling , Carlson Brett L. , Schroeder Mark A. , Murray James , Sludden Julieann , Boddy Alan V. , Curtin Nicola J. , Sarkaria Jann 
Published: June 2012

Abstract
Poly (ADP-ribose) polymerase (PARP) inhibition can enhance the efficacy of temozolomide (TMZ) and has been shown to significantly prolong survival in orthotopic GBM xenografts. Here the effects of PARP inhibitor AG014699 (AG699) on the efficacy of TMZ was evaluated and corresponding pharmacokinetic and pharmacodynamic studies were performed in the MGMT methylated GBM12 primary GBM xenograft line. AG699 effectively sensitized GBM12 cells to TMZ in vitro in a neurosphere formation assay: IC50 of 1.56 M for TMZ when combined with 1 μM AG699 compared to 8.16 M TMZ when used alone). Using these same cells, orthotopic xenografts were established and mice were randomized to 3–28 day cycles of placebo or TMZ (50 mg/kg days 1–5) with or without AG699 (1 mg/kg IP days 1–5). Although this model is responsive to other TMZ/PARP inhibitor combinations, the addition of AG699 was ineffective (median survival: placebo 16 days, TMZ 68 days and TMZ/AG699 81 days, p=0.883). In contrast, AG699 significantly potentiated TMZ-induced tumor regrowth delay in a flank tumor model with GBM12 (median time for tumors to reach endpoint: placebo 32 days, TMZ 86 days and TMZ/AG699 121 days, p&lt;0.01). To more clearly understand the discrepancy between intracranial and flank studies, drug accumulation and target inhibition were assessed. Plasma and tissue distribution studies in mice bearing GBM12 orthotopic xenografts showed that 0.5 h after AG699 treatment its level in brain and tumor xenograft was much lower compared with that in liver (see table). In an assessment of catalytic activity, PARP activity in liver was inhibited more than 95% of control at least 2 h after AG699 treatment, while it was inhibited less than 50% and 30% in orthotopic xenograft tissue and normal brain, respectively (Table). Collectively, these data support the hypothesis that the efficacy of AG699 combined with TMZ is limited in the orthotopic model due to limited drug accumulation within the brain, and the mechanisms of which are under investigation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A77.
Abstract A86: A phase 1 study of LY2523355, an Eg5 inhibitor, administered on Days 1, 2, and 3 with or without pegfilgrastim in patients with advanced malignancy (NCT01214629).
Authors: Verschraegen Claire , Cohen Roger B. , Olszanski Anthony J. , Shaheen Montaser , Nishida Yuko , Bauman Julie , Li Lily , Brandt John T. , Nasir Aejaz , Hynes Scott M. , Leohr Jennifer K. , McGlothlin Anna , Westin Eric H. 
Published: June 2012

Abstract
Background: LY2523355 is a potent allosteric inhibitor of the motor protein Eg5 which selectively inhibits bipolar mitotic spindle formation. The objective of this Phase 1 study was to determine a Phase 2 dose and schedule of LY2523355 that may be safely administered to patients with advanced malignancy.
Methods: Study I1Y-MC-JFBA is an open-label, multicenter, dose-escalation study in patients with advanced malignancy. A modified 3+3 dose-escalation scheme was used, followed by a dose confirmation phase with pre- and post-treatment tumor biopsies. Patients received LY2523355 as a 1hr infusion on days 1, 2 and 3 of a 21-day cycle with determination of the MTD with and without pegfilgrastim administration on day 4. Patients were assessed every other cycle by RECIST. Treatment related PD changes in phosphohistone H3 (pHH3) and Eg5 expression were assessed in skin and tumor biopsies by immunohistochemistry.
Results: 46 patients were enrolled in the study as of October 2010. The most frequent related AEs reported (&gt;10%) include leukopenia, neutropenia, fatigue, nausea, stomatitis, vomiting, alopecia, anemia, diarrhea, lymphopenia, pruritis/itching and rash. Dose-limiting toxicities include increased INR, leukopenia, diarrhea, rash (palmar plantar erythrodysesthesia), febrile neutropenia, and mucositis. The single and multiple dose pharmacokinetics of LY2523355 and metabolite were characterized. Dose dependent increase in LY2523355 plasma exposure and a minor degree of intra- and inter-cycle accumulation were observed. An exposure-dependent increase in pHH3 and Eg5 expression and increase in apoptotic cells in tumor and skin biopsies has been demonstrated. One patient with ovarian cancer had a confirmed partial response. Nine other patients had stable disease for at least 2 cycles.
Conclusions: The MTD of LY2523355 for this schedule has been established with and without pegfilgrastim at 6mg/m2/d and 4 mg/m2/d, respectively. These doses have shown a quantifiable PD response in skin and tumor biopsies confirming the importance of maximizing exposure intensity for maximum PD response. Dose confirmation is on-going.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A86.
Abstract B10: Diversity Outbred: A new, highly diverse mouse stock for toxicology and cancer.
Authors: Schile Andrew , Svenson Karen L. , Fancher Karen S. , Valdar William , Chesler Elissa J. , Churchill Gary A. 
Published: June 2012

Abstract
The Diversity Outbred (J:DO) stock is a new heterogeneous, highly diverse mouse resource designed for complex trait analysis and toxicology studies as well as to facilitate rapid mapping with single gene resolution. This stock was derived from crossing partially-inbred Collaborative Cross strains, which are a mixture of eight genetically well-defined JAX® Mice inbred strains, including three wild-derived. Subsequent maintenance follows a randomized outcross non-sibling mating scheme to retain maximum genetic diversity. Each Diversity Outbred mouse is genetically unique, representing a novel combination of alleles present in the founder strains. To determine the extent to which this genetic variation leads to phenotypic variation, over 50 metabolic measurements including plasma glucose, insulin, triglycerides, cholesterol, and body composition were collected, under both standard chow and high fat diet conditions. The Diversity Outbred animals displayed a wide spectrum of metabolic phenotypes, home cage nesting behavior and aggressiveness. Mouse-to-mouse variation is demonstrated by fold-differences in plasma triglycerides and creatine kinase levels, both as high as 11–12. Plasma glucose, free fatty acids, thyroxine, and percentage of fat all showed differences of 3-fold or greater. These fold-changes are comparable to the variation among unique inbred mouse strains, and mimic the diversity within human populations. The J:DO stock represents a new powerful tool for rapid gene mapping, toxicology/pharmacogenomic screens and compound evaluation for a wide variety of human diseases, including cancer and metabolic diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B10.