bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B95: Targeting cancer cell metabolism: The combination of metformin and 2-deoxyglucose induces p53 dependent apoptosis in prostate cancer cells
Authors: Sahrab Issam Ben , Laurent Kathiane , Le marchand Brustel Yannick , Peraldi Sophie Giorgetti , Cormont Mireille , Auberger Patrick , Tanti Jean-François , Bost Frédéric 
Published: June 2012

Abstract
Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent exerts anti tumoral and antiproliferative action (1). In this study, we showed that the addition of metformin to 2 deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The association of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to up to 95% inhibition of cell viability in LNCaP prostate cancer cells and 65% decrease of tumor growth in a xenograft model. Similarly, combination of the drugs was very powerful to inhibit PC3 and DU145 (prostate cancer), breast and colon cancer cells viability, on contrary, a moderate effect was observed in normal prostate epithelial cells. At the cellular level, metformin arrested cell cycle in G0/G1 and 2DG induced autophagy. The addition of metformin to 2DG inhibited 2DG mediated autophagy, blocked cell cycle in G2/M and more importantly induced caspase 3 activity in LNCaP cells (p53 wild-type). The tumor suppressor p53 plays a major role in apoptosis and cell metabolism, we showed that metformin combined to 2DG arrested prostate cancer cells in G2/M independently of the p53 status of the cells. Importantly, metformin/2DG did not induce apoptosis in PC3 (p53 null) and DU145 (p53 mutated) cells. Expression of a functional p53 in these cells restored caspase 3 activity showing that metformin/2DG induced apoptosis is p53 dependent. Thus, our study reinforces the growing interest of metabolic perturbators in cancer therapy and emphasizes the potential use of the combination of metformin and 2DG.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B95.
Abstract C105: Preclinical evaluation of galectin-1 targeting antiangiogenic, antitumor peptidomimetics
Authors: Dings Ruud P.M , Miller Michelle C. , Loren Melissa L. , Mayo Kevin H. 
Published: June 2012

Abstract
We have showed previously that the peptide 33mer anginex targets galectin-1 (gal-1) thereby inhibiting tumor endothelial cell proliferation via anoikis and attenuating tumor angiogenesis and tumor growth. Gal-1 binds β-galactoside groups on various cell surface receptors and is highly upregulated in tumor-activated endothelial cells. Differential stromal elevation of gal-1 over the tumor parenchyma has been reported in several cancers, including cancer of the breast, colon, prostate and ovaries. The aim of the present study was to develop gal-1 targeting anti-angiogenic peptidomimetics and anti-tumor clinical candidates for use in the management of human cancers. Based on structure-activity relationships of anginex, a partial-peptide mimetic was designed, using dibenzofuran (DBF) as a β-turn mimetic to maintain the two key β-strands and the bioactive amphipathic β-sheet conformation of the peptide. The best DBF-based compound 6DBF7 (13mer) inhibited tumor angiogenesis and tumor growth in vivo better than parent anginex. Subsequently, by substituting natural and non-natural amino acids, new DBF-based analogues were generated and tested in vitro. The analogs with improved anti-angiogenic activity and pharmacokinetic profile were then tested in tumor mouse models in vivo. The pre-clinical development of these novel anti-angiogenic and anti-cancer peptidomimetics will aid in the development of small-molecule mimetics and subsequently hold great promise for the management of human cancers in the clinic.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C105.
Abstract C107: The antitumor activity of SCV-07 is attributable, in part, to an inhibitory effect on STAT3 driven responses
Authors: Tuthill Cynthia W. , Subbarao Krishna Prasad , Ramachandra Raghuveer , Nagabhushanam Vijaya , Ramachandran Murali , Reddy Jhansi 
Published: June 2012

Abstract
Introduction: In recent years, agents that boost the immune system to break through tumor-induced immunosuppression have gained importance. The dipeptide, SCV-07 (gamma-D-glutamyl-tryptophan) has been shown to be efficacious in reducing progression of renal and lung carcinoma as well as melanoma in mouse models. SCV-07 also induces the elaboration of Th1 cytokines. Because the dipeptide has an effect on a diverse range of tumors, it is possible that SCV-07 has a global, antigen-independent effect on the immune system. Because STAT3 is known to be upregulated in tumor microenvironments, and the effect of STAT3 driven gene expression is global immune suppression of anti-tumor responses, we conducted the following studies to determine whether SCV-07 modulates STAT3-induced responses as part of its mechanism in stimulation of an anti-tumor immune response.
Experimental design: In vitro studies were conducted using B16F0 melanoma cells, transiently transfected with a STAT3 responsive element driving luciferase expression. Cells were incubated with varying concentrations of SCV-07, and luciferase expression was measured after 24 hours of incubation. In in vivo studies Balb/c mice were injected with B16 melanoma cells and the mice were either left untreated or were treated with SCV-07 at 5 mg/kg. Tumors were harvested on day 11 and were analyzed by flow cytometry for the presence of P-STAT3-positive cells.
Results: SCV-07 inhibited expression of STAT3 driven luciferase expression to the extent of ∼70 – 80%, depending on concentration of SCV-07. Further studies showed that SCV-07 additionally inhibited the translocation of STAT3 into the nucleus of HeLa cells. SCV-07 increased survival and inhibited the progression of melanoma growth in the B16 mouse model, and this inhibition was accompanied by reduced phosphorylated STAT3 staining at the tumor site as well as an influx of natural killer cells.
Conclusions: These results provide support that SCV-07 acts in an antigen independent manner to reduce STAT3 driven gene expression and potentiate anti-tumor immune responses.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C107.
Abstract C114: The KidsCancerKinome: Validation of CDK2 as potential drug target in pediatric tumors
Authors: Molenaar Jan J. , Westerhout Ellen M. , Boer den Monique L. , Clifford Steve C. , Delattre Olivier , Geoerger Birgit , Lanvers Claudia , Pietsch Torsten , Serra Massimo , Shipley Janet , Vassal Gilles , Versteeg Rogier , Verschuur Arnauld C. , Caron Huib N. 
Published: June 2012

Abstract
The KCK consortium has validated CDK2 as potential drug target in six highly malignant pediatric tumor types (i.e Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL). The stepwise procedure started with the selection of genes that can be targeted using small molecule inhibitors. Drug target genes and signal transduction routes were studied using Affymetrix mRNA profiles of over 500 tumors and cell lines. CDK2 and cell cycle signal transduction genes showed expression patterns that were significantly different from reference tissues and expression was related to poor prognosis. The next step to evaluate the potential drug targets consisted of targeted knock down using RNA interference. Inhibition of CDK2 resulted in significant phenotypes in several pediatric tumor models. Cell lines from most tumor types showed growth inhibition and differentiation. Neuroblastoma cell lines showed extensive apoptosis. Highly interesting was the synthetic lethal relation between CDK2 and the driving oncogene MYCN. These findings warranted further evaluation using the CDK2 inhibiting small molecule Roscovitine. This compound was tested in the core panel of pediatric tumor cell lines and more extensive in tumor types that showed high sensitivity for the compound. Neuroblastoma cell lines were most sensitive with IC50 in the low uM range. Neuroblastoma, which showed high sensitivity for Roscovitine, are now being evaluated in in vivo mouse xenograft models.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C114.
Abstract C130: Plucked human scalp hairs: Potential utility as a surrogate tissue for the assessment of therapies targeting the androgen receptor
Authors: Growcott Jim , Brady Ged , Pickering Karen , Walker Jill , Lovick Susan , Chetty Raj , Kevill Helen , Prahladan Manoj , Grimes Emma , Harrison Elliott , Mefo Timothy , Hodgson Darren 
Published: June 2012

Abstract
Objective: Evaluate whether plucked human scalp or eyebrow hairs obtained from male elderly healthy normal volunteers (HNVs) are suitable for assessing RNA expression patterns linked to the androgen receptor.
Procedure: For each of 12 HNV subjects plucked eyebrow and scalp hairs were obtained at 2 time points. For each time point up to three individual anagen hairs were selected for RNA extraction and representative cDNA amplification. For each sample RNA quality was assessed by agarose gel electrophoresis and cDNA quality assessed by qPCR analysis of 3 reference or “housekeeping” genes. Expression levels of a panel of 20 androgen receptor regulated genes were measured by qPCR for samples passing both RNA and cDNA quality criteria.
Results : Of the 72 scalp hairs analysed 64 (89 %) passed both RNA and cDNA quality criteria with 23 out of 24 (96%) sample collection points yielding 2 or more analysable hairs. This high success translated into available data for both time points in 11 out of 12 HNVs (92 %). In contrast, for the 72 eyebrow hairs analysed only 2 (3 %) passed RNA quality criteria with none of the collection points yielded 2 or more analysable hairs. Of the 20 test genes qPCR analysis identified a short list of 7 genes with expression levels similar to “housekeeping” genes indicating that they should be reliably detected in the majority of scalp hairs. These results are in keeping with a previous HNV study of younger male and female donors and indicate that plucked scalp hairs may be of value in the early phases of clinical development of androgen receptor based therapies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C130.
Abstract C143: Expression profiles of miRNA, FFPE, and nonamplified samples for diagnostic tests using a supersensitive microarray
Authors: Sudo Hiroko , Ueda Yoji , Kuroda Toshihiko , Takizawa Satoko , Nomura Osamu , Akiyama Hideo , Nobumasa Hitoshi 
Published: June 2012

Abstract
We have developed a novel gene expression microarray system, 3D-Gene™, featuring micro-columnar structure on the platform made of black resin and micro-bead agitation for efficient hybridization. With these technological characteristics, 3D-Gene™ achieves dramatic reduction of background noise, exceptionally high sensitivity and reproducibility, and high correlation with qRT-PCR methodology particularly for genes with low expression. In addition to the general high performance, however, the medical devices in clinical settings must be versatile for a variety of biomarker types as well as sample types. Employing this microarray, we further developed a highly sensitive system to detect attomole-level miRNA which is reported to be a novel biomarker for some cancers. Moreover, we were able to detect gene profiles reproducibly and accurately from formalin-fixed paraffin-embedded (FFPE) tissue which is known to be stored worldwide in a large number for retrospective studies. Finally, we developed a RNA sample preparation protocol with no amplification process, resulting in a quick and cost-effective protocol with high accuracy. Taken together, we developed systems for gene expression detection using a high performance microarray suitable for a wide range of clinical applications. 3D-Gene™ could be a powerful tool for drug target discovery and clinical diagnostic for various diseases.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C143.
Abstract C155: External Qi of Yan Xin Qigong induces apoptosis and inhibits migration and invasion of estrogen-independent breast cancer cells by down-regulating Akt/NF-κB signaling
Authors: Yan Xin , Shen Hua , Jiang Hongjian , Hu Dan , Zhang Chengsheng , Wang Jun , Wu Xinqi 
Published: June 2012

Abstract
Background: The concept External Qi of Qigong refers to the technology and ability of “Qi deployment” therapy and health preservation of traditional Chinese medicine (TCM). External Qi therapy of TCM has long been one of the medical practices in China. Long-term clinical observations and ongoing studies have shown positive effects of external Qi of Yan Xin Qigong (YXQ-EQ) on cancer patients. Recently, the molecular and cellular mechanisms underlying YXQ-EQ's antitumor effects have begun to be addressed. In the present study we investigated YXQ-EQ's effects on growth, migration, invasion and apoptosis of estrogen-independent breast cancer MDA-MB-231 cells and the underlying molecular mechanisms.
Methods: Cytotoxic effects were evaluated by trypan blue exclusion assay, MTS assay and/or clonogenic assay. Apoptosis was assessed by DNA fragmentation and cleavage of caspases and poly(ADP-ribose) polymerase. Quantitative analysis of apoptosis and cell cycle distribution was carried out by flow cytometry. Migration and invasion assay was performed in Transwell Boyden chambers and Matrigel-coated Boyden chambers, respectively. NF-κB activity was determined by electrophoresis mobility shift assay. Akt phosphorylation and NF-κB target gene expression was evaluated by Western blot analysis.
Results: YXQ-EQ treatment of MDA-MB-231 cells induced a time-dependent reduction in viability, clonogenic growth inhibition, and apoptosis. Furthermore, YXQ-EQ blocked migration and invasion of MDA-MB-231 cells. Biochemically, YXQ-EQ markedly inhibited constitutive and EGF-induced Akt phosphorylation. YXQ-EQ also substantially repressed NF-κB activity, resulting in decreased expression of antiapoptotic Bcl-2, Bcl-XL, XIAP and survivin proteins.
Conclusion: Our findings suggest that YXQ-EQ may induce apoptosis and inhibit migration and invasion of MDA-MB-231 cells through the repression of Akt/NF-κB signaling.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C155.
Abstract C171: On- and off-target effects of telomere uncapping G-quadruplex ligands based on pentacyclic acridinium salts
Authors: Stevens Malcolm FG , Hutchinson Ian , McCarroll Andrew J. , Hummersone Marc , Williams Huw EL 
Published: June 2012

Abstract
Antitumor properties of the potent G-quadruplex ligand 3,11-difluoro-6,8, 13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) are driven by telomere uncapping events. RHPS4 has good selectivity for quadruplex DNA over duplex DNA as measured by surface plasmon resonance (Kquad 1.1 × 107 M−1); Kdup 3.4 × 105 M−1). In preclinical models of solid tumor xenografts RHPS4 potentiates the activity of camptothecins but good response is dependent on the timing of the drug sequence employed. These experiments teach how an agent of this novel class might be used clinically in combination with chemotherapeutic agents. Although RHPS4 has several ‘drug-like’ qualities (synthetic accessibility, water solubility, cellular uptake), a preliminary toxicological study revealed that the compound is a potent hERG inhibitor (IC50 0.2 M) and has additional receptor interactions, notably with muscarinic M1, M2 and M3 receptors. In an anaesthetized guinea pig cardiac model RHPS4 increased QTcB interval at doses of 5 and 10 mg/kg. Modifications to the peripheral substituents around the pentacyclic core have identified agents with differing on- and off-target effects. Removal of the N(13)-methyl group of RHPS4 to generate an uncharged molecule drastically reduced affinity for the target quadruplex DNA coupled with reduced pharmacological liabilities; increasing the size of the onium group at N(13) from Me to Et reduced affinity for quadruplex DNA (Kquad 0.6 × 106 M−1) and increased hERG inhibition (IC50 0.04 M). After a significant redesign program two isomeric compounds have been identified, 2- and 3-acetylamino-8,13-dimethyl-8H-quino[4,3,2-kl]acridinium iodides with ‘win-win’ profiles - better selectivity for quadruplex DNA and markedly reduced hERG liability (for the 2-acetylamino compound Kquad 2.4 × 107 M−1; Kdup 3.8 × 105 M−1; hERG IC50 3.7 M): for the 3-acetylamino isomer Kquad 2.5 × 107 M−1; Kdup 4.4 × 105 M−1; hERG IC50 18 M). Molecular modeling studies on the favored 3-acetylamino derivative indicate that the pentacyclic core acts as a surrogate K+ stabilizing the G-quadruplex structure with the acetylamino side-chain projecting into a quadruplex groove.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C171.
Abstract C185: Head and neck squamous carcinoma cells are susceptible to the attenuated vesicular stomatitis virus expressing suicide genes
Authors: Porosnicu Mercedes , Liu Jingfang , Lyles Douglas E. 
Published: June 2012

Abstract
Background: The predominant loco-regional progression of Head and Neck Squamous Cell Carcinoma (HNSCC) makes it suitable for testing oncolytic viruses. Recent work from several laboratories including ours has focused on developing vesicular stomatitis virus (VSV) as a replication-competent anticancer viral vector. Attenuated strains, such as M protein mutant VSV (M51R) are more likely to be promoted in clinical research. The major shortcoming of viral therapy is related to the large proportion of tumor cells remaining uninfected. We are addressing this limitation in two ways: the expression of the cytosine deaminase-uracil phosphoribosyltransferase (C:U) suicide gene by the rVSV vector, expected to produce a strong bystander effect and the exploitation of the radiosensitizing potential of the 5-fluorouracil (5-FU) chemo-drug produced intratumorally, as well as of the VSV virus itself.
Methods: We determined the susceptibility to oncolytic VSV in a collection of HNSCC cell lines and in patient HN primary tumor cells by measuring: 1) the level of GFP expression after infection with rVSV-GFP and M51R-GFP; 2) the viral production by plaque assay and 3) cell death by Trypan blue exclusion. The extent of defectiveness in interferon pathways was tested by employing pre-treatment with IFN and INF-blocking antibodies before the infection with the oncolytic VSV. We have generated the rVSV-C:U and M51R-C:U viruses and we tested our collection of HNSCC cell models to infection with these viruses in the presence and absence of 5-fluorocytosine. SQ20B cell line is a model of radiation resistant HNSCC. Regular SQ20B and SQ20B infected with low-dose M51R-VSV were evaluated by clonogenic assay.
Results: 1) All HNSCC cell models tested are susceptible to the infection with the rVSV but many present a degree of resistance to the attenuated M51R-VSV. 2) Human Primary HNSCC cells are more resistant than the HNSCC cell lines to the M51R-VSV; 3) The activation of IFN pathways is contributing to the resistance to M51R-VSV. 4) Addition of the suicide gene C:U to the attenuated VSV model significantly increased the oncolytic effect in vitro; 5) HNSCC cells infected with M51R-VSV become more radiation sensitive.
Conclusions: The decreased oncolytic effect of the attenuated M51R-VSV can be overcome by the expression of suicide genes such as the yeast C:U fusion model. The demonstrated radiosensiting potential of the M51R-VSV virus as well as the known radiosensitizing effect of the generated chemotherapeutic 5-FU can be further exploited against the loco-regional HNSCC tumors. Finally, we have important new information, both from cell lines and patient tissues, for proof-of-principle that cancers can down-regulate antiviral responses.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C185.
Abstract C188: Nanoantibodies and other engineered antibody domains as candidate cancer and infectious disease therapeutics
Authors: Vu Bang K. , Gong Rui , Xiao Xiaodong , Chen Weizao , Dimotrov Dimiter S. 
Published: June 2012

Abstract
Engineered single antibody domains are small (sizes about 12–14 kDa i.e. about 10-fold smaller than the size of a typical full-size antibody) and can access targets and epitopes that are not accessible by larger molecules. We have constructed two large (size 2×1010) VH-based libraries of high diversity (Chen et al, JMB, 2008, and submitted) from which several high affinity domain antibodies against HIV and cancer-related proteins were identified and characterized with potential use as therapeutics (Chen et al, PNAS, 2008, and unpublished). We have also engineered human antibody constant domains (CH2) as scaffolds which are highly stable, soluble, and express at high levels (Rui et al, JBC, 2009, and unpublished). Based on these new scaffolds several libraries have been constructed, and binders were selected and characterized (Xiao et al, BBRC, 2009; Bang et al, unpublished). Further engineering to confer additional functions (nanoantibodies) is in progress.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C188.
Abstract C193: Biological evaluation of novel multi-targeted Aurora-B kinase inhibitor TAK-901 in xenograft models
Authors: Satou Takashi , Hoshino Takashi , Farrell Pamela , Zhang Lilly , Elliott Sarah , Fabrey Robyn , Lee Bumsup , Paraselli Bheema , Ishino Seigo , Nomura Toshiyuki , Teratani Mika , Ohta Yoshikazu , de Jong Ron 
Published: June 2012

Abstract
Aurora kinases play an essential role in cell division, specifically orchestrating several intricate steps during the mitotic phase of the cell cycle. The human genome encodes for 3 Aurora kinase genes, designated Aurora A, B, and C. Aurora A localizes to centrosomes and spindle poles and is required for mitotic spindle assembly, whereas Aurora B is a chromosome passenger protein required for phosphorylation of histone H3, chromosome segregation, and cytokinesis. Expression levels of Aurora A and B kinases are frequently elevated in human cancers making them attractive targets for therapeutic intervention. TAK-901 is an Aurora B kinase inhibitor with multi-targeted inhibitory activity against other kinases important in malignancy. In the present study, we investigated the pharmacodynamic effects and in vivo activity of TAK-901 in human tumor xenograftmodels. In solid tumor xenograft models, potent dose-dependent antitumor activity was observed against HCT116 (colon), H460 (large cell lung) and A2780 (ovary) cancer models by twice daily intravenous dosing on 2 consecutive days per week for 3 cycles. TAK-901 also displayed potent activity against several leukemia models such as subcutaneously implanted MV4-11 and HL60 (AML). In the A2780, HCT116, and HL60 models, TAK-901 induced tumor regression at higher dose levels, including complete regression of A2780 tumors at 30 and 45 mg/kg/injection. When dosed in combination with chemotherapeutic agents, such as irinotecan in the HCT116 model or daunorubicin in the HL60 model, TAK-901 produced additive effects. Following intravenous administration of 20 and 40 mg/kg TAK-901 in the A2780 xenograft model, histone H3 phosphorylation was completely suppressed for at least 6 hours and in the 40 mg/kg treated tumors did not return to control levels during the 12 hour time course. After multiple doses of TAK-901, polyploidy was observed in the tumor samples. TAK-901 drug levels remained constant throughout the time course in tumor tissues whereas plasma levels declined steadily. These in vivo biomarker studies demonstrate that TAK-901 induces pharmacodynamic responses consistent with Aurora B kinase inhibition, which correlates with effective retention of TAK 901 in tumor tissues. Taken together, these preclinical data emphasize the therapeutic potential of TAK- 901 in the treatment of diverse human malignancies. TAK-901 is currently under investigation in Phase I clinical trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C193.