bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-184: Differential effects of sulforaphane and related isothiocyanates on HDAC turnover and the DNA damage response in colon cancer cells
Authors: Rajendran Praveen , kidane Ariam I. , Yu Tian-Wei , Dashwood Wan-Mohaiza , Ho Emily , Williams David E. , Dashwood Roderick H. 
Published: August 2012

Abstract
Protein acetylation is mediated by histone deacetylases (HDACs) and acetyltransferases, which influence chromatin dynamics, protein turnover, and the DNA damage response. HDACs overexpressed in cancer cells have been implicated in protecting against genotoxic insults, whereas HDAC inhibitors circumvent this protection (Rajendran et al. Clin Epigenetics 2011,3:4). Here, we show in human colon cancer cells that sulforaphane and related isothiocyanates (ITCs) inhibited HDAC activity and increased HDAC protein turnover, with the potency directly proportional to alkyl chain length. Under these conditions, DNA damage signaling was triggered by ATR kinases, leading to increased double-strand breaks and histone (H2AX) phosphorylation. Activation of checkpoint kinase-2 was followed by growth arrest and cell death. HDAC inhibition by ITCs enhanced the acetylation of repair proteins, like CtIP, leading to their degradation. Notably, cancer cells were more susceptible than normal cells, the latter exhibiting efficient double-strand-break processing and repair. Thus, dietary ITCs preferentially exploit the HDAC turnover pathways, faulty DNA repair mechanisms, and genomic instability in cancer cells. Supported by NIH grants CA090890, CA65525, CA122906, CA122959, CA80176, and ES007060.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-184. doi:1538-7445.AM2012-LB-184
Abstract LB-185: Cytokinesis-blocked micronuclei Assay (CBMN) as a biological cancer risk assessment tool
Authors: Lloyd Stacy M. , Lopez M , El-Zein Randa 
Published: August 2012

Abstract
Lung cancer is the leading cause of all cancer-related deaths in the US. Given the lack of effective of screening modalities, the need to develop more accurate cancer risk assessment tools is imperative to improve the ability to identify individuals that are at greatest risk of developing this disease. The Cytokinesis-Blocked Micronuclei Assay (CBMN) presents a sensitive, specific, and rapid method of assessing DNA damage, a hallmark of cancer. We have previously reported that this assay is extremely sensitive to genetic damage caused by the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and that the binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds in lymphocytes (chromosome damage endpoints measured by the assay) are strong predictors of lung cancer risk. To further identify the specific chromosomes involved in lung carcinogenesis, we conducted Spectral Karyotyping (SKY) on a population of n=116 cases and n=126 controls on whom CBMN data are available. SKY was performed on both baseline and NNK-treated blood lymphocytes. After adjusting for age, gender, race/ethnicity, smoking status, pack years (intensity), and smoke years (duration), we observed consistent significant results for damage on chromosomes 1, 3, 4, 9, 13, 16, 17, 19, 22, and X (all p's ≤ 0.05) and lung cancer risk. Several of these identified chromosomes are well known to harbor critical genes involved in lung carcinogenesis, such as the FHIT gene (chromosome 3), p16/CDKN2A (chromosome 9), PADPRP (chromosome 13) and TP53 (chromosome 17). Our results support the utilization of CBMN as a cancer risk assessment tool, and when used in conjunction with other cytogenetic methodologies can increase our ability to identify specific regions of DNA damage, thereby improving our understanding of the underlying mechanisms involved in individual cancer predisposition. This work was supported by the following: Kellogg Health Scholars Program (W.K. Kellogg Foundation P0117943) NIMHS P60 MD000503 CA129050 NIHS P30 ES007784
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-185. doi:1538-7445.AM2012-LB-185
Abstract LB-187: Modulation of redox status: An alternative approach for prevention and treatment of prostate cancer
Authors: Das Trinath P. , Suman Suman , Gulappa Thippeswamy , Kurisetty Vittal , Vadodkar Aditi Shirish , Lakshmanaswamy Rajkumar , Damodaran Chendil 
Published: August 2012

Abstract
Radical prostectomy, radiation treatment, and/or hormone ablation therapy are the first lines of treatment for prostate cancer (CaP). Despite initial sensitivity to these treatments, CaP eventually progresses to castration-resistant CaP (CRPC), which is both aggressive and refractory to current therapeutic options. Accordingly, there is a tremendous need for a novel agent that can either retard or prevent the emergence of CRPC. Changes in reactive oxygen species (ROS) play a pivotal role in these processes. For example, a moderate increase in ROS promotes cell proliferation, but excessive amounts of ROS can induce apoptosis in cancer cells. Hence, it is possible to manipulate the redox (oxidative stress) system to selectively kill cancer cells. Psoralidin (Pso), a natural bioactive compound derived from Psoralea Corylifolia which is extensively used in Asian and African medicines, is an orally bioavailable dietary agent. We are the first group to demonstrate that Pso is non-toxic to normal prostate epithelial cells but specifically targets CaP cell lines (PC-3, DU-145, LnCaP and C4-2B) by inhibiting Akt and its downstream pro-survival signaling pathways. While dissecting the upstream events of Akt, we found that Pso generates ROS production and inhibits Akt mediated pro-survival signaling in both cell cultures and animal models of CRPC. Importantly, over expression of antioxidants, genetically (SOD/Catalase) or pharmacologically N-acetylcysteine (NAC) or treatment with ROS inhibitors Rotenone (mitochondrial) or Diphenylenel iodonium DPI (extra mitochondrial) inhibited Pso induced oxidative stress (both Intracellular and NADPH oxidase mediated) in CaP cells. Further, Pso in combination with anti-oxidants/ROS inhibitors significantly decreased the migratory and invasive property of CaP cell lines. Currently, we are delineating the role of Pso induced non-mitochondrial ROS generation, by analyzing expression patterns of NADPH oxidase and their subunits. We will apply genetic and/or pharmacological approaches to determine the key Pso target in CaP cell lines. Further, our chemopreventive and chemotherapeutic studies of Pso in both xenograft models and pilot experiments in transgenic adenocarcinoma of mouse prostate (TRAMP) model showed that Pso inhibits prostate tumor growth. These studies may suggest modulation of redox status could be a novel and powerful approach to chemoprevention and/or treatment of CaP.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-187. doi:1538-7445.AM2012-LB-187
Abstract LB-198: Ryl hydrocarbon receptor agonist Aminoflavone disrupts mammosphere formation via alpha 6 integrin inhibition
Authors: Brantley Eileen J. , Yee Michael , Quitugua Ashley , Zylstra Dain , Soto Ubaldo 
Published: August 2012

Abstract
Introduction: Emerging evidence has suggested that cancer stem cells (CSCs) play a prominent role in the initiation and dissemination of a myriad of malignancies including breast cancer. CSCs have the capacity to self-renew within heterogeneous tumor cells. Currently available therapeutic options for breast cancer are incapable of suppressing CSC growth. Alpha 6 integrin contributes to CSC growth while aryl hydrocarbon receptor (AhR) activation impedes CSC proliferation. AhR agonist Aminoflavone, a synthetic flavonoid, is currently undergoing clinical evaluation for the treatment of breast cancer. We hypothesize that Aminoflavone alters the integrity and formation of cell suspension clusters initiated by breast cancer stem cells (mammospheres) by modulating alpha 6 integrin expression in an AhR-dependent manner Experimental Procedures: Mammospheres derived from MCF-7 breast cancer cells were exposed to Aminoflavone at varying times. We also treated mammospheres with Tamoxifen an anticancer agent frequently used in the treatment of breast cancer. Following Aminoflavone treatment, cells were analyzed microscopically to evaluate alterations in mammosphere structure. In addition, the expression of molecular targets associated with CSC growth in addition to alpha 6 integrin were evaluated by Western blotting and quantitative RT-PCR analysis. Results: We observed that Aminoflavone, but not Tamoxifen, disaggregates MCF-7 mammospheres. In contrast, Aminoflavone did not affect mammospheres produced from AhR defective MCF-7 (AHR100) cells. Aminoflavone abrogated the ability of secondary mammospheres to form. In addition, alpha-6-integrin expression was abolished following Aminoflavone treatment in MCF-7 but not AHR100 cells. The expression of several genes whose products regulate alpha-6 integrin expression were also modulated following Aminoflavone treatment in MCF-7 cells. Conclusion: These data suggest that Aminoflavone disrupts mammosphere formation via AhR signaling activation that results in alpha 6 integrin inhibition. These findings support continued efforts to develop novel AhR ligands with efficacy against breast CSCs as a viable therapeutic strategy for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-198. doi:1538-7445.AM2012-LB-198
Abstract LB-199: ZEB factors link IL-1β-induced EMT and stem cell phenotypes in colon cancer
Authors: Wang Lei , Li Yijing , Beckley Amy , Pappan Loretta , Shi Jishu 
Published: August 2012

Abstract
Up-regulation of inflammatory cytokines such as IL-1β in tumor microenvironment has been associated with progression of human colorectal cancer. However, the exact molecular mechanisms by which inflammatory cytokines promote colon tumor growth are still unclear. Cancer stem cells (CSCs), a distinct subpopulation with self-renewal ability, drug resistance and high oncogenic potential, are thought to be responsible for tumor initiation and progression. Epithelia-mesenchymal transition (EMT), characterized by the repression of E-cardherin expression and increased cell mobility, is associated with enhanced metastasis. The objective of this study is to determine whether IL-1β may promote cancer progression by inducing EMT and colon CSC development. Here, we showed that IL-1β promoted E-cadherin repression in both human colon cancer cell line HCT-116 cells and primary colon cancer cells. Expression of E-cadherin transcription repressors ZEB1 and ZEB2 was up-regulated in IL-1β-treated HCT-116 and primary colon cancer cells, respectively. In addition, IL-1β-treated HCT-116 cells exhibited higher cell migratory ability. Moreover, IL-1β induced the expression of stem-cell marker Bmi-1 in both HCT-116 cells and primary colon cancer cells. IL-1β increased these cells’ ability of sphere formation in serum-free conditions and chemo-resistance; properties associated with colon CSCs. Taken together, these results indicate that IL-1β can induce EMT and promote generation of colon CSCs. More importantly, we found that ZEB1 and ZEB2, but not other E-cadherin transcriptional repressors (such as Snail and Twist), were consistently up-regulated in HCT-116 cells and primary colon cancer cells, respectively, during both processes of IL-1β-induced EMT and sphere formation. This suggests that ZEB factors may mediate IL-1β-induced EMT and generation of colon CSCs. Currently, this hypothesis is under evaluation using shRNAs to knock down ZEB1 in HCT-116 cells. Understanding the role of ZEB factors in IL-1β-mediated EMT and CSC development may lead to the identification of novel molecular targets for colon cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-199. doi:1538-7445.AM2012-LB-199
Abstract LB-2: Structure-based design of G-quadruplex ligands leads to enhanced potency against pancreatic cancer cells
Authors: Micco Marialuisa , Collie Gavin , Gunaratnam Mekala , Ohnmacht Stephen A. , Reszka Anthony P. , Neidle Stephen 
Published: August 2012

Abstract
Certain small molecules can sequester the single-stranded overhang of human telomeric DNA into higher-order quadruplex structures. Such quadruplex-ligand complexes interfere with telomerase activity and inhibit its ability to maintain telomere integrity in many cancer cell types. This approach to selectivity interfering with cancer cell viability has been demonstrated for several classes of quadruplex-binding molecules in cells and in xenograft experiments. We have previously described a series of tetra-substituted naphthalene diimide (ND) compounds with high affinity for human telomeric quadruplex DNA. These also have high potency for growth inhibition in a panel of cancer cell lines, concomitant with telomerase inhibition. Those compounds with N-methyl-piperazine (NMP) end-groups have shown exceptional potency in a pancreatic cancer cell line panel, with the lead compound having typical IC50 values of 100-200 nM. It has significant anti-tumor activity in a pancreatic cancer xenograft model, with a 50% reduction in tumor volume on ip administration, along with inhibition of telomerase activity. We report here a structure-based design study in which the four positive charges of the tetra-NMP compound have been modulated by substituting NMP groups on two of the four side-arms of the ND core with more weakly basic groups, in order to improve drug-like features. A diminution in the highly cationic nature of these ND compounds may improve cellular uptake and tumor distribution properties, while retaining quadruplex affinity. The morpholine group has been used because it is less basic than the NMP group. We hypothesized that the presence of four NMP groups is non-essential in order to retain effective quadruplex binding, since the morpholine group is of equivalent size and so could be bound in the same way. Three co-crystals structures of NMP and morpholino-containing ND compounds with a human telomeric quadruplex have been determined. These show that the morpholino group binds in quadruplex grooves in a closely-similar manner to the NMP group and has the same hydrogen-bonding. Accordingly, several hybrid morpholino-NMP ND compounds have been synthesized and shown high quadruplex affinity, exceptional potency in selectively inhibiting growth in pancreatic cancer cell lines, with IC50 values of &lt;10 nM, together with potent telomerase inhibition in these cells. Lead compounds from this study are currently being taken into further in vivo evaluation, with a view to identifying a compound suitable for pre-clinical development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-2. doi:1538-7445.AM2012-LB-2
Abstract LB-31: USP15 stabilizes the TGF-β receptor I and promotes oncogenesis through the activation of the TGF-β signal in glioblastoma
Authors: Eichhorn Pieter J. , Rodon Laura , Gonzalez-Junca Alba , Baselga Jose , Seoane Joan 
Published: August 2012

Abstract
In advanced cancer including glioblastoma, the TGF-β pathway acts as an oncogenic factor and is considered a therapeutic target. Using a functional RNA-interference screen, we have identified the deubiquitinating enzyme USP15 as a critical component of the TGF-β signaling pathway. USP15 binds to the SMAD7-SMURF2 complex and deubiquitinates and stabilizes the TGF-β receptor I leading to an enhanced TGF-β signal. Importantly, we find that the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer and that USP15 gene amplification confers poor prognosis in glioblastoma patients. Furthermore we demonstrate that downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β signaling. Our results show that USP15 regulates the TGF-β pathway and is a critical factor in glioblastoma pathogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-31. doi:1538-7445.AM2012-LB-31
Abstract LB-315: Suppression of tumor invasion and metastasis by inhibition of c-MET and VEGF signaling together
Authors: Sennino Barbara , Ishiguro-Oonuma Toshina , Williamson Casey W. , Wei Ying , Chapman Harold A. , Christensen James G. , Aftab Dana T. , McDonald Donald M. 
Published: August 2012

Abstract
Treatment with inhibitors that block vascular endothelial growth factor (VEGF) signaling can make tumors more aggressive in preclinical models. The mechanism underlying this form of resistance is not fully understood, but vascular pruning, intratumoral hypoxia, and increased expression of c-MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), could be contributing factors. We found that treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody or with sunitinib, a receptor tyrosine kinase inhibitor that blocks VEGFR and related receptors, reduced tumor burden and vascularity but increased intratumoral hypoxia, HIF-1alpha, and expression and activation of c-MET. Invasion into the exocrine pancreas and metastasis to the liver also increased. Importantly, administration of either of two c-MET inhibitors, PF-04217903 or crizotinib (PF-02341066), together with anti-VEGF therapy reduced tumor growth and vascularity and also significantly decreased local invasion and liver metastasis. Similar benefits were found after treatment with cabozantinib (XL184), a multitargeted tyrosine kinase inhibitor that simultaneously blocks c-MET and VEGF receptors. Together, these results indicate that inhibition of VEGF signaling can promote vascular pruning, intratumoral hypoxia, HIF-1alpha accumulation, and activation of c-MET. Concurrent inhibition of c-MET and VEGF signaling not only can slow tumor growth but also can reduce invasion and metastasis. Inhibition of c-MET and VEGF signaling pathways together combines the favorable tumor growth-slowing effects of inhibiting angiogenesis with suppression of invasion and metastasis, despite the intratumoral hypoxia due to vascular pruning.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-315. doi:1538-7445.AM2012-LB-315
Abstract LB-33: Identification of two unrecognized acute myeloid leukemia (AML) subtypes based on cell by cell analysis of leukemic blasts
Authors: Hsu Faye , Nolan Garry P. , Chen Tiffany , Goltsev Yury 
Published: August 2012

Abstract
Single cell multiparametric flow cytometry studies have previously shown that G-CSF-mediated intracellular signaling responsiveness of blast cell subsets stratified clinical outcomes of AML patients. 13 AML samples were stimulated with G-CSF, fixed, and permeabilized with a technique we developed that preserves mRNA integrity in a manner suitable for microarray-based expression analysis. From the microarray profiles we identified surface markers that could be prospectively used to separately enrich G-CSF Responsive Cells (GRCs) and non-G-CSF Responsive Cells (NGRCs) from each sample. The results demonstrate that two previously unrecognized subtypes of AML could be discerned, as portrayed by the proteomic and molecular characteristics of the GRC and NGRC subsets. First, GRC cells had a higher colony formation capacity as well as being more reactive to cytokines secreted by NGRCs In one discovered AML subtype, patients present with bone marrow that had higher percentages of GRCs (20-50%), with the remainder being NGRCs. The molecular signatures of both the GRCs and NGRCs in this subtype had a hematopoietic progenitors mRNA signature (HPMS). In the second subtype of AML there were lower percentages of GRCs (0.5-10%, which had the HPMS) but in these cases the NGRC mRNA signatures were distinct resembling those of a more differentiated myeloid phenotype. Therefore, in most AML patients tested, two blast cell populations inevitably appear, and each of these blasts represented a distinct level of hematopoietic maturity, or cytokine responsiveness. The common thread between the two subtypes is that the GRCs in each patient were more capable of colony formation, enabled by a potentially more “stem-like” phenotype. Critically, each population would be clinically termed “blast” cells and would therefore be considered malignant and a potential target for chemotherapy. These results lead to two important conclusions. The first is that the blast phenotype can exist independently of the apparent cell maturation stage. This raises the questions of whether each blast subtype is equally susceptible to standard chemotherapy, whether a strategy of defining the molecular players that drive the formation of each of these blast types should be pursued, and finally whether such information can be used to better combat these aspects of the leukemic disease spectrum.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-33. doi:1538-7445.AM2012-LB-33