bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5507: Mechanistic study of a new 4-(3, 5-dimethoxyphenyl)-N-(7-fluoro-3-methoxyquinoxalin-2-yl)piperazine-1-carboxamide compound (RX-5902).
Authors: Lee Young Bok , Kim Deog Joong , Kost Gina Chun , Frank Julie , Ahn Chang-Ho , Liu Zhi-Ren 
Published: August 2014

Abstract
In our previous study, we showed that a novel compound 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl] piperazine induces apoptosis of cancer cells by downregulation of Bcl-2 protein levels and causing G2/M cell cycle arrest. We observed also a synergistic effect in growth inhibition when combined with known anticancer agents in cancer cells and potent anti-growth activity in drug-resistant cancer cells as well as anti-proliferation of cancer cells at IC50 values of low nanomolar concentrations. Oral administration of the compound led to inhibition of tumor growth and enhanced survival in several tumor xenograft models. Our recent studies indicated that the compound interacts with p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. p68 has been demonstrated to play a vital role in cell proliferation and tumor/cancer progression. Our studies showed that the compound did not exert its anti-cancer effects by inhibition of RNA unwinding by p68. Instead, the compound completely abrogated the β-catenin stimulated ATPase activity of p68 with an IC50 of 61 nM. More extensive studies are ongoing to validate and further characterize our interesting discovery.
Citation Format: Young Bok Lee, Deog Joong Kim, Gina Chun Kost, Julie Frank, Chang-Ho Ahn, Zhi-Ren Liu. Mechanistic study of a new 4-(3, 5-dimethoxyphenyl)-N-(7-fluoro-3-methoxyquinoxalin-2-yl)piperazine-1-carboxamide compound (RX-5902). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5507. doi:10.1158/1538-7445.AM2013-5507
Abstract 5528: Identification of compounds modifying radiation-therapy using a 3D-microtissue technology.
Authors: Anastasov Natasa , Höfig Ines , Lichtenberg Jan , Stroebel Simon , Salomon Michael , Thirion Christian , Kelm Jens , Atkinson Michael J. 
Published: August 2014

Abstract
The two key issues in chemo- and radiation therapy is the development of tumor resistance as well as toxic effects on normal tissue. In this sense new strategies are required to increase efficacy of radiation to improve the therapeutic impact and reduce toxicological side effects. The performance of 3D cell culture systems over classical 2D culture systems has been shown to provide a closer representation of tissue-level biology. This has led to the rapid adoption of 3D systems for both drug discovery and toxicology. InSphero has developed a highly reproducible hanging drop technology able to generate monotypic cell spheroids (microtissues) in a 96-well format. The innovative 3D-microtissue plate technology has been adapted for analysis of the cellular response of radioresistant T47D breast cancer cells to combined radio-chemotherapy (RCTx). We have validated the model by comparing the treatment of microtissues with 10 different chemotherapeutic compounds, each tested alone and in combination with an acute 2Gy radiation exposure. The T47D cells were stably transduced with GFP-lentiviral vector enabling faster high throughput quantification of 3D microtissue growth assessment using an Operetta working Software and detection system ‘Harmony 3.0’ (PerkinElmer, USA). We studied the ability of RCTx to modify 3D-microtissue growth 3, 6 and 10 days after treatment. Results for five compounds (Actinomycin D, Staurosporine, Docetaxel, Doxorubicin and Vinblastine) showed that the IC50 values were improved by the addition of the single 2Gy radiation dose, indicating that they are capable of inducing a radiosensitation effect on radioresistant breast cancer cells. Panels of commercial secondary functional assays were adapted to the 3D-microtissue high throughput assay. Cellular viability and cytotoxicity were measured directly in microtissues using the CellTiter-Glo Reagent (Promega, USA). Apoptosis was measured using an ELISA based M30-Apoptosense assay (TECOmedical AG, Switzerland). These results all confirm that the assay operated with the 3D-microtissue model system is able to detect compounds that modulate tumors cell survival after irradiation.
Citation Format: Natasa Anastasov, Ines Höfig, Jan Lichtenberg, Simon Stroebel, Michael Salomon, Christian Thirion, Jens Kelm, Michael J. Atkinson. Identification of compounds modifying radiation-therapy using a 3D-microtissue technology. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5528. doi:10.1158/1538-7445.AM2013-5528
Abstract 5529: In vitro platforms representing tumor complexity for target validation and drug discovery.
Authors: Hickman John A. 
Published: August 2014

Abstract
PREDECT is one of the major Innovative Medicines Initiatives (IMI) of the European Union with 21 laboratories collaborating in a Public-Private partnership, aiming to create more appropriate in vitro platforms for target validation and drug discovery. Genomic and proteomic data on cancers from patient material provides hypotheses regarding potential novel drug targets. Laboratory platforms to validate whether target modulation would provide a clinical benefit are usually highly reductionist, often using long-established cell lines growing in 2 dimensions in vitro. These models do not reflect the complexity of a tumour in situ, where biochemical pathways are wired with connections to the complex tumour environment provided by stromal, immune and endothelial cells. PREDECT has the goal of comparing the pathological and molecular profiles of novel in vitro platforms with those of human tumours. In a stepwise manner, material from in situ tumours will be "deconstructed," for example through tissue slices, 3-D heterogenously complex models (with stroma etc), simple 3D models, complex 2D models to simple 2D models and the profiles of each platform compared with an in situ tumour, both in the resting state and when perturbed by drugs or RNA interference. "Reconstruction" of tumor complexity will also be attempted and profiled. Proteomics of models of breast, prostate and lung cancer will be compared in a Work Package based on a centralised TMA platform, immunohistochemistry and a Web-based microscopy. A systems approach will interrogate the fidelity of in vitro platforms to represent the complexity and heterogeneity of human tumors. Because clinical material presents both logistic and quality problems for ongoing and intense studies of target validation, PREDECT aims to use material from genetically engineered mouse models, and some "advanced" xenografts, whose pathology and molecular profiles closely match cohorts of human tumours. PREDECT hopes to provide more appropriate platforms both for target validation and subsequent preclinical studies which will replace a current cascade of tests which are poorly predictive of clinical activity.
Citation Format: John A. Hickman. In vitro platforms representing tumor complexity for target validation and drug discovery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5529. doi:10.1158/1538-7445.AM2013-5529
Abstract 5590: Screening of pediatric and adult sarcoma cell lines reveals novel patterns of sensitivity toward approved oncology drugs and investigational agents.
Authors: August E. Michael , Delosh Rene , Laudeman Julie , Ogle Chad , Reinhart Russell , Selby Michael , Silvers Thomas , Morris Joel , Teicher Beverly A. 
Published: August 2014

Abstract
Sarcomas represent a heterogeneous group of neglected cancers with significant unmet medical need. To date, large-scale screening of compounds for activity against sarcomas has not been carried out in any systematic fashion to enable drug discovery. Our laboratory has compiled a panel of &gt; 85 human pediatric and adult sarcoma cell lines, a tumor type not represented in the NCI60, and has carried out a high throughput screen of approximately 60 of these lines against the Approved Oncology Drugs (AOD) and Investigational Agents libraries, using inhibition of proliferation as an endpoint. The AOD library is comprised of 93 FDA-approved anticancer agents, and is available from The NCI/DTP Open Chemical Repository. The Investigational Agents library includes about 350 small molecules of interest. The compounds were screened for inhibition of cell proliferation in 9-point concentration response, starting at 10 uM and diluting by half-logs. The cells were cultured in 384-well plates for 24 hrs, at which time compounds were added with a final DMSO concentration of 0.25%. Viability was determined after 96 hrs of exposure using Alamar Blue. The % viability was determined relative to a vehicle-treated control, and this value was plotted relative to compound concentration to determine the EC50. The Ewing sarcoma lines (19) were unexpectedly more sensitive to pemetrexed, cabazitaxel, and floxuridine, and were, as expected, sensitive to topoisomerase 1 inhibitors relative to other sarcomas and to historical NCI60 data. Synovial sarcoma lines were sensitive to vinorelbine, vandetinib, and gemcitabine relative to other sarcomas. Further analyses and findings from the data will be presented. Funded by NCI Contract no. HHSN261200800001E.
Citation Format: E. Michael August, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, Thomas Silvers, Joel Morris, Beverly A. Teicher. Screening of pediatric and adult sarcoma cell lines reveals novel patterns of sensitivity toward approved oncology drugs and investigational agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5590. doi:10.1158/1538-7445.AM2013-5590
Abstract 5599: A novel treatment strategy targeting shugoshin 1 in hematological malignancies.
Authors: Ikezoe Takayuki , Yang Jing , Nishioka Chie , Yokoyama Akihito 
Published: August 2014

Abstract
The shugoshin 1(SGOL1), a member of centromeric proteins, plays an important role in mitosis. The present study explored the levels of SGOL1 in hematological malignancies and found that SGOL1 was aberrantly expressed in various types of human leukemia cell lines (n=10, e.g., HL60, U937, MOLM-13, K562, EOL-1, etc.) and freshly isolated leukemia cells from individuals with acute myelogenous leukemia (AML, n=43, p&lt;0.001) compared with bone marrow mononuclear cells isolated from healthy volunteers (n=9), as measured by real-time RT-PCR. Forced-expression of SGOL1 in hematopoietic stem/progenitor cells (HSPCs) significantly increased colony numbers for CFU-M and CFU-GM compared with control vector transduced infected HSPCs, suggesting that SGOL1 might act as an oncogene in hematopoietic cells. In addition, we found that repression of SGOL1 by a small interfering RNA (siRNA) slowed the proliferation of NB4, EOL-1 and U937 cells compared to the control siRNA transfected cells, in parallel with appearance of precocious dissociation of centromeric cohesion and separation of sister chromatids in these cells. Furthermore, we found that repression of SGOL1 by an siRNA accumulated EOL-1 and U937 cells in the G2/M phase of the cell cycle, in conjunction with up-regulation of spindle checkpoint protein BubR1, followed by apoptosis via caspase pathways. Taken together, SGOL1 may be a promising molecular target for individuals with AML.
Citation Format: Takayuki Ikezoe, Jing Yang, Chie Nishioka, Akihito Yokoyama. A novel treatment strategy targeting shugoshin 1 in hematological malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5599. doi:10.1158/1538-7445.AM2013-5599
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5602: Cyclin D2- mediated cardiomyocyte cell cycle activity reverses doxorubicin-induced cardiotoxicity.
Authors: Zhu Wuqiang , Soonpaa Mark H. , Zhang Wenjun , Shou Weinian , Payne Mark , Field Loren J. 
Published: August 2014

Abstract
Introduction: Doxorubicin (DOX) is an effective anticancer agent which also induces acute and chronic cardiotoxicities. We have generated a juvenile mouse model to study DOX-induced cardiotoxicity in children. Cardiomyocyte apoptosis with an ensuing loss of myocardial function is observed in this model. Here, we hypothesize that activation of cardiomyocyte cell cycle protects against DOX-induced cardiotoxicity. Methods: Two week old MHC-cylin D2 (D2) mice and their non-transgenic (NON-TXG) littermates were given weekly DOX injections for 5 weeks (25 mg/kg total dose). Animals were studied 1 week (acute stage) or 13 weeks (late stage) after the last DOX injection. Cardiac function was measured with echocardiography and cardiomyocyte (CM) cell cycle was quantified using a tritiated thymidine incorporation assay. Results: Our results showed that CM cell cycle was increased in D2 mice as compared to NON-TXG mice (thymidine positive CM nuclei, 0.03±0.01% vs. 0.002±0.002 in acute stage, p&lt;0.01; and 0.03±0.01% vs. 0.001±0.001 in late stage, p&lt;0.01). In the absence of cell cycle activity, cardiac function remained depressed in late stage vs. acute stage (Fractional Shortening, FS, 41.4±3.1% vs. 44.0±3.2%, p&gt;0.05), whereas in the presence of CM cell cycle activity, cardiac function improved in late stage vs. acute stage (FS = 60.1±1.3% vs. 47.1±3.3%, p&lt;0.01). CM apoptosis (0.02±0.01/mm2 vs. 0.05±0.01/mm2, p&lt;0.01) and fibrosis (6.2±0.9% vs. 12.0±1.7%, p&lt;0.01) was reduced in D2 mice as compared to NON-TXG mice in late stage. Conclusion: For the first time, our data suggest activation of CM cell cycle in adult mice reverses DOX-induced cardiotoxicity.
Citation Format: Wuqiang Zhu, Mark H. Soonpaa, Wenjun Zhang, Weinian Shou, Mark Payne, Loren J. Field. Cyclin D2- mediated cardiomyocyte cell cycle activity reverses doxorubicin-induced cardiotoxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5602. doi:10.1158/1538-7445.AM2013-5602
Abstract 5603: Minocycline abrogates IL-6 signaling and inhibits migration, invasion and adhesion capacity of ovarian cancer cells.
Authors: Ataie-Kachoie Parvin , Morris David L. , Pourgholami Mohammad H. 
Published: August 2014

Abstract
Aims: Minocycline (7-dimethylamino-6-desoxytertracycline) has been recognized as a drug with interesting pleiotropic properties including suppression of pro-inflammatory cytokine levels. The beneficial effects of minocycline arisen from suppression of proinflammatory cytokines and in particular IL-6 have been elucidated in central nervous system. However, this drug has never been examined in cancers with aberrant IL-6 expression. Considering the key role of IL-6 and its signaling pathways in the growth and progression of ovarian cancer, we evaluated whether minocycline modulates IL-6, its receptor system and signaling pathways in ovarian cancer.
Methods: Expression of IL-6 in control and minocycline-treated ovarian cancer cell lines (OVCAR-3, SKOV-3 and CAOV-3) was determined by immunocytochemistry. ELISA was used to quantify the effects of minocycline on both constitutive and IL-1β or 4-OH-estradiol stimulated IL-6 expression in these cell lines. The effects of minocycline on IL-6R expression was assessed by immunocytochemistry and western blot. Activation of STAT3 and ERK1/2, two major pathways down-stream of IL-6 were evaluated by western blotting. To further characterize the influence of minocycline against IL-6 bioactivity, the effect of the drug on the functional status of SKOV-3 cells was examined by adhesion assay and transwell migration and invasion assay. Finally, to determine the effect of minocycline on IL-6 expression in vivo, female nude mice bearing intraperitoneal OVCAR-3 tumors were treated with a single 30 mg/kg dose of minocycline administered intraperitoneally for 4 and 24 h. The IL-6 expression in plasma and tumor samples excised from these animals was evaluated by ELISA and western blot.
Results: We found that minocycline was potent in suppressing both constitutive and stimulated IL-6 expression in vitro. Analysis of plasma and tumors also revealed substantial down-regulation of IL-6 in minocycline-treated mice in vivo. Moreover, minocycline blocked the expression of IL-6R and phosphorylation of STAT3 and ERK1/2 time-dependently. It was also found that minocycline-treated cells exhibit dose-dependent attenuation of cell adhesion, migration and invasion capacity.
Conclusion: These results demonstrated that minocycline effectively blocks IL-6 signaling in ovarian cancer. Blockage of IL-6 signaling may provide benefits for the treatment of this deadly cancer.
Citation Format: Parvin Ataie-Kachoie, David L. Morris, Mohammad H. Pourgholami. Minocycline abrogates IL-6 signaling and inhibits migration, invasion and adhesion capacity of ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5603. doi:10.1158/1538-7445.AM2013-5603
Abstract 5610: Electric-field assisted delivery of gemcitabine for the treatment of pancreatic cancer.
Authors: Byrne James , O'Neill Adrian , Jajja Raheel , Napier Mary , Luft James C. , Zamboni William , Yeh Jen Jen , DeSimone Joseph 
Published: August 2014

Abstract
Pancreatic cancer is the fourth leading cause of cancer death in the world, with an incidence rate approximately equivalent to the death rate. The very poor prognosis for pancreatic cancer can be attributed to late diagnosis and the ineffectiveness of drug delivery to the primary tumor. Poor tissue perfusion plays a substantial role in preventing adequate drug exposure to primary pancreatic tumors. The systemic administration of gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer, has shown limited efficacy for the treatment of pancreatic cancer, with only 5 to 10% of patients demonstrating an objective radiographic response at the primary tumor site. Furthermore, the toxicity associated with systemic chemotherapy has been found to reduce the quality of life of the patient and in extreme cases can be fatal. In an attempt to address the lack of effectiveness of systemically administered chemotherapy and associated toxicity, we have developed modalities for the localized delivery of chemotherapies to pancreatic tumors. These devices rely upon an applied electric potential difference between electrodes to drive chemotherapy into the tumor. This use of an electric potential for local delivery of chemotherapies offers the capability of overcoming considerable flow and pressure gradients. Significant work using an applied electric potential difference for drug transport has been performed in transdermal drug delivery. In the area of oncology, electric field-assisted delivery techniques have been proposed for skin and ocular cancers and have been clinically translated to the treatment of bladder cancers in the electromotive delivery of mitomycin C. This technique, combined with novel device approaches, is particularly well suited for the local treatment of the primary pancreatic tumor. Herein, we report the development of electric field-assisted delivery devices and the testing of these devices in a patient-derived orthotopic xenograft mouse model of pancreatic adenocarcinoma and a healthy canine animal model. The results show that our devices provide a significant increase in the local delivery of gemcitabine while limiting systemic toxicity.
Citation Format: James Byrne, Adrian O'Neill, Raheel Jajja, Mary Napier, James C. Luft, William Zamboni, Jen Jen Yeh, Joseph DeSimone. Electric-field assisted delivery of gemcitabine for the treatment of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5610. doi:10.1158/1538-7445.AM2013-5610
Abstract 5613: Enhanced treatment of lung metastasis of triple negative breast cancer by doxorubicin-mitomycin C co-loaded polymer lipid nanoparticles.
Authors: Prasad Preethy , Cai Ping , Rauth Andrew , Wu Xiao 
Published: August 2014

Abstract
Background: Treatment of triple negative breast cancer (TNBC) is a big challenge due to its aggressiveness, metastases, lack of therapeutic target and receptor proteins. Our laboratory has developed doxorubicin (Dox) -mitomycin C (MMC) co-loaded stealth polymer lipid hybrid nanoparticles (DMsPLN) and demonstrated their anti-cancer synergy in vitro and high efficacy in vivo. The purpose of this study is to evaluate the biodistribution, in vivo efficacy and safety of DMsPLN in a lung metastatic human TNBC model.
Method: Lung metastasis of breast tumor was established using MDA-MB 231-luc-D3H2LN, a luciferase expressing cell line that was derived from spontaneous lymph node metastasis. The cells were injected via tail vein to develop lung metastasis in SCID mice. The biodistribution and tumor accumulation of the nanoparticles were examined by whole animal optical imaging using near infrared fluorescence labeled nanoparticles. The efficacy and systemic toxicity of DMsPLN were evaluated against clinically used doxorubicin (Dox). DMsPLN and free Dox solution were administered intravenously at various equivalent Dox doses. The tumor burden was monitored weekly by bioluminescence imaging. The size and number of tumor nodules in the lungs were examined at different time points and the systemic toxicity was monitored by repeated measurement of body weight.
Results: A lung metastatic breast tumor model was successfully developed using the MDA-MB 231-luc-D3H2LN which allowed for non-destructive monitoring of tumor growth and metastases using bioluminescence imaging. Whole animal imaging demonstrated the accumulation of the fluorescent nanoparticles in the lung metastatic site. Treatment with free Dox (10 mg/kg) resulted in severe total body weight loss over 20% which is ruled as a toxic endpoint. However, the DMsPLN (10 mg/kg equivalent Dox dose) group did not show any systemic toxicity. Treatment with DMsPLN at various Dox doses resulted in a reduction in tumor burden compared to the saline and Dox-treated groups.
Citation Format: Preethy Prasad, Ping Cai, Andrew Rauth, Xiao Wu. Enhanced treatment of lung metastasis of triple negative breast cancer by doxorubicin-mitomycin C co-loaded polymer lipid nanoparticles. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5613. doi:10.1158/1538-7445.AM2013-5613
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.