bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1520: CDX2 regulates Multidrug Resistance 1 gene expression in malignant intestinal epithelium
Authors: Takakura Yuji , Hinoi Takao , Oue Naohide , Sasada Tatsunari , Kawaguchi Yasuo , Okajima Masazumi , Yasui Wataru , Ohdan Hideki 
Published: February 2011

Abstract
The intestine-specific caudal-related homeobox transcription factor CDX2 is important for intestinal development and differentiation. CDX2 heterozygous mice form colonic polyps, and loss of CDX2 expression is seen in some poorly differentiated colon carcinoma in humans. Conversely, ectopic CDX2 expression in the stomach of transgenic mice promotes intestinal metaplasia, and CDX2 expression is often seen in stomach and esophageal metaplasia. We sought to define CDX2-regulated genes to enhance the knowledge of CDX2 function. HT-29 colorectal cancer cells with minimal endogenous CDX2 expression were generated to express exogenous CDX2, and the gene expression changes were assessed by microarrays. Activation of CDX2 rapidly induced Multidrug Resistance 1 (MDR1/P-glycoprotein/ABCB1) gene expression in HT-29 cells, even in the presence of protein synthesis inhibitor, and RNA interference-mediated inhibition of CDX2 decreased MDR1 expression. In other colorectal cancer cell lines and human tissues, endogenous MDR1 expression was well correlated to CDX2 expression. Analysis with MDR1 reporter gene constructs and chromatin-immunoprecipitation assays suggested that CDX2 directly regulates MDR1 transcription. Overexpression of CDX2 in HT-29 cells revealed increased resistance to MDR1's known substrate, vincristine and paclitaxel, which was reversed by an MDR1 inhibitor, verapamil. These data indicate that CDX2 directly regulates MDR1 gene expression via binding to elements in the promoter region. Thus, CDX2 is probably important for basal expression of MDR1, regulating drug excretion and absorption in the lower gastrointestinal tract, as well as for multidrug resistance to chemotherapy reagent in CDX2-positive gastrointestinal cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1520.
Abstract 1531: BCR-Abl tyrosine kinase inhibitor Nilotinib (Tasigna®) reverses ABCB1/Pgp- and ABCG2/BCRP-mediated multidrug resistance
Authors: Tiwari Amit K. , Sodani Kamlesh , Wang Sirong , Kuang Ye-Hong , Deng Wen , Chen Xiang , Chen Kevin , Ashby Charles R. , Chen Zhe-Sheng 
Published: February 2011

Abstract
Over-expression of ABC transporters are involved in the extrusion of therapeutic drugs, leading to MDR, which can eventually produce cancer chemotherapy failure. Previously, it was shown that specific TKIs could modulate several human multidrug resistance (MDR) ATP-binding cassette (ABC) proteins. Recently discovered second generation, BCR-Abl tyrosine kinase inhibitor (TKI), Nilotinib was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia positive chronic myelogenous leukemia. Here, we report for the first time that nilotinib not only potentiates the cytotoxicity of widely used therapeutic substrates of ABCB1, such as colchicine, vincristine, and paclitaxel, but also that of ABCG2 substrates such as mitoxantrone and doxorubicin. Nilotinib also significantly enhances the intracellular accumulation of methotrexate (MTX) in cells transfected with ABCG2. Similarly, nilotinib significantly increases the accumulation of paclitaxel in cell lines overexpressing ABCB1. Furthermore, nilotinib produces a concentration-dependent inhibition of the ABCG2-mediated transport of MTX, as well as E217βG a physiological substrate of ABCG2. Uptake studies in membrane vesicles over-expressing ABCG2 have indicated that nilotinib inhibits ABCG2 similar to other established TKIs as well as fumitremorgin C. In addition, the kinetic analysis demonstrated that nilotinib is a potent competitive inhibitor of MTX transport by ABCG2 with a Ki value of 0.69+/-0.083 μM. To sum it up, our results indicate that nilotinib could reverse ABCB1- and ABCG2-mediated MDR by blocking the efflux function of these transporters. These findings may be useful in clinical practice for cancer combination therapy with nilotinib and may be vital to the design of present and future clinical trials with nilotinib, elucidating potential pharmacokinetic interactions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1531.
Abstract 1532: Stemofoline is a potent natural product modulator of the multidrug resistance-linked P-glycoprotein (ABCB1)
Authors: Ohnuma Shinobu , Chanmahasathien Wisinee , Ambudkar Suresh V. , Limtrakul Pornngarm 
Published: February 2011

Abstract
Stemofoline is a plant alkaloid isolated from Stemona, which is native to Eastern and Southeastern Asia and Northern Australasia. The extract from the tuberous roots of Stemona is used to treat respiratory disorders, including pulmonary tuberculosis and bronchitis, and different insect pests. P-glycoprotein (P-gp, ABCB1), a member of the ATP-binding cassette (ABC) transporter superfamily is implicated in multidrug resistance (MDR) in cancer cells. We investigated the effect of stemofoline on P-gp function aiming to overcome P-gp-mediated MDR. Stemofoline stimulated P-gp-mediated ATP hydrolysis (conc. required for 50% stimulation = 10-12 micro M). In addition, Stemofoline did not change the Km for ATP, suggesting that this alkaloid seems to interact with drug-binding site of P-gp. Consistent with this view, stemofoline inhibited the photo-crosslinking of P-gp with [125I]-iodoarylazidoprazosin (IAAP; IC 50 = 7 micro M), which is a transport substrate of P-gp. Interestingly, stemofoline instead of inhibiting substrate-stimulated ATP hydrolysis (such as verapamil and vinblastine), it further enhanced the ATPase activity suggesting that stemofoline and these drugs (verapamil and vinblasine) bind simultaneously to P-gp in the drug-binding pocket. In addition, the efflux of the fluorescent substrates such as calcein-AM and Bodipy-verapamil from P-gp expressing cells was blocked by stemofoline in a concentration-dependent manner. Furthermore, stemofoline was not cytotoxic to P-gp expressing KB-V1 or parental KB-3-1 cells up to 100 micro M concentration, but this compound at non-toxic concentration (1 − 5 micro M) sensitized KB-V1 cells to vinblastine. Stemofoline does not appear to interact with ABCG2 transporter, which is also linked to development of MDR. These studies indicate that stemofoline could be developed as a specific potent modulator to overcome P-gp-mediated MDR in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1532.
Abstract 1536: Characterization of tumor cell lines selected for resistance to the HDM2 antagonist Nutlin-3a
Authors: Wang Yaolin , Wang Xiaoying , Lipari Philip , Devlin David , Simon Jason , Chen Lei , Levitane Diane , Liu Suxing , Seidel-Dugan Cynthia , Hicklin Daniel J. , Bishop Walter Robert 
Published: February 2011

Abstract
The tumor suppressor p53 is activated in response to various cellular stress signals including DNA damage and oncogene activation. Activated p53 regulates the expression of multiple downstream target genes involved in cell cycle control, cell death and senescence. Dysfunction of the p53 pathway is the most frequent alteration in human cancers. HDM2 protein binds directly to p53 and acts as a major negative regulator of the p53 function. Nutlin-3a is an antagonist of the HDM2-p53 protein-protein interaction and restores p53 pathway function in tumors with wild-type p53. Nutlin-3a demonstrates anti-tumor activity both in vitro and in vivo. Emergence of resistance is frequently observed with many anti-cancer therapeutics. The goal of the current studies is to understand the mechanism of resistance to Nutlin-3a. Cancer cell lines were treated with Nutlin-3a for an extended period and resistant clones were isolated. We found using molecular profiling studies that the emergence of Nutlin resistance is primarily due to the inactivation of the p53 signaling pathway through either mutation of the p53 gene or loss of p53 protein expression. These Nutlin-resistant cells are also resistant to others antagonists of the HDM2-p53 protein-protein interaction. These results suggest that, following chronic treatment, resistance to HDM2 antagonists may occur in the clinic. It will be important to combine HDM2 antagonists with other anti-cancer drugs early on during the treatment cycle in order to minimize the emergence of resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1536.
Abstract 1539: Lovastatin sensitizes tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis through inactivation of NF-kB pathway and activation of JNK/p38 pathway in human glioblastoma cells
Authors: Liu Pi-chu , Li Jun , Chen George G. , Lu Gang , Poon Wai S. 
Published: February 2011

Abstract
Glioblastoma (GBM) is among the deadliest of all human cancers. Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) becomes a promising candidate for GBM therapy, not only for its strong antitumor activity in a wide range of cancer cell types, but also for its minimal cytotoxity to most normal cells. The main barrier in TRAIL-based therapies, however, is TRAIL resistance (including GBM-derived cell lines and primary cells). Methods overcome TRAIL resistance can largely enhance the effect of TRAIL-based therapy. In this regard, we have reported that lovastatin could sensitize GBM cells to TRAIL, but the underlying mechanism remains largely unknown. Our data suggested that lovastatin could up-regulate DR5 (TRAIL-R2) expression, which might contribute to the sensitization of GBM cells to TRAIL by lovastatin. Here we provide preliminary results suggesting that the mitogen-activated protein kinase (MAPK) signaling (p&lt;0.001) was significantly dysregulated after lovastatin treatment, by microarray pathway analysis in three GBM cell lines (A172, M059J and M059K). Furthermore, we demonstrated that lovastatin sensitized GBM cells to TRAIL by inhibiting ERK/MAPK and activating JNK/p38. In addition, NF-kB was reported to be involved in DR5 regulation. In this study, we further characterized the role of NF-kB signaling in TRAIL resistant GBM cell sensitization by lovastatin and especially its relation to TRAIL receptors. We have extended our study to investigate the mechanism of lovastatin sensitizing GBM cells to TRAIL. We first showed that lovastatin down-regulaetd cRelA/p65, one of the components of NF-κB subunit, which was reported to suppress DR-5 expression. This finding suggested that lovastatin might sensitize GBM cells to TRAIL by cRelA/p65 inactivation. Moreover, we found that the inactivation of cRelA/p65 was through down-regulation of its inhibitory IκB protein degradation and IKKα/ β after lovastatin treatment. In addition, we found that inhibition of NF-κB up-regulated DR5 expression. Findings obtained not only provides new insights into TRAIL resistant death signaling via both intrinsic and extrinsic pathways, but also is essential for developing new target-specific and safe strategy to overcome TRAIL resistance for future clinical application.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1539.
Abstract 1546: Effective co-targeting of tumor and tumor stroma for head and neck cancer treatment: making the right combination
Authors: Xing Rosie Hongmei , Wu Yongfei , Zhang Qingbei , Huang Yong , Shen Jikun , Fan Hanli , Li Jianrong , Xiao Hongyan , Lee Younghee , Weichselbaum Ralph , Lingen Mark , Lussier Yves A. 
Published: February 2011

Abstract
Successful cancer management has been hindered by the development of inherent or acquired resistance. Increasing evidence suggest that manifestation of comparable resistance phenotype may arise from different combinations of molecular lesions. Signal transduction pathways in cancer cells exhibit remarkable flexibility for re-wiring such that cancer cells of solid tumors are able of altering the targeting receptor tyrosine kinases (RTKs) such as EGFR, or using unaffected and co-expressed RTKs signaling, or manifesting gain-of-function changes of the downstream signaling molecules to sustain tumor growth and progression. However, The potential of a “pathway rewiring” strategy to more efficiently target a deregulated signaling network has not been effectively explored due to the lack of scientific framework. Furthermore, the effort of developing effective agents or combinations that can effectively co-target both cancer cells and tumor stroma is lagging behind the therapeutic development aiming at cancer cell targeting. In this report, we demonstrate the effectiveness of integrating predicative pathway analysis to identify mTOR as a key interacting signaling target for developing a rational “pathway-based” combination to overcome resistance to anti-EGFR therapies in squamous carcinoma of the head and neck (HNC). We show for the first time that HNC cancer cells can effectively exploit the molecular interactions between EGFR and mTOR to confer reciprocal resistance. In addition, network modeling and comparison of xenograft with human tumor specimens identifies the abundant presence of myofibroblasts specifically associated with cancer state. We subsequently show the dependence of the clonogenic survival of myofibroblast cells on mTOR signaling in vitro. In vivo, only concomitant inhibition of EGFR and mTOR signaling via erlotinib and rapamycin, respectively, achieves effective differential and co-targeting of cancer cells and myofibroblast and endothelial cell functions in tumor stroma, leading to tumor regression. Thus, we show a systems’ approach-guided biological investigation has the potential to identify resistance mechanisms that can be explored to design more effective combinations of targeted therapies capable of overcoming resistance via “pathway rewiring” and achieving tumor-tumor stroma co-targeting. Based on these observations, an NIH funded network Phase II human clinical trial, lead by the University of Chicago Cancer Center, is soon underway to evaluate the therapeutic efficacy of this combination therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1546.
Abstract 1547: Acquisition of resistance to the β1 integrin antagonist HYD1 correlates with decreased α4, α6, αV and β1 integrin expression and decreased adhesion to fibronectin, VCAM-1 and vitronectin
Authors: Emmons Michael , Nair Rajesh , McLaughlin Mark , Eschrich Steven , Cress Anne , Hazlehurst Lori 
Published: February 2011

Abstract
Our laboratory recently reported that the D amino acid-containing β1 integrin inhibitory peptide HYD1 causes caspase independent cell death in multiple myeloma (MM) cell lines as a single agent in vitro and in vivo (Nair et al Molecular Cancer Therapeutics, 2009). Exposure of MM cells to HYD1 induces autophagy, but autophagy was shown to contribute to survival following HYD1 treatment. HYD1 treatment induces cell death in MM cell lines indicative of necrosis. These characteristics included: (a) an increase in the levels of reactive oxygen species (ROS), (b) ATP depletion and (c) loss of mitochondrial membrane potential. To further characterize the mechanism of HYD1 induced cell death an isogenic drug resistant variant was developed. This variant, referred to as H929-60, was developed by chronically exposing parental H929 cells to increasing doses of HYD1. Acquired resistance correlated with decreased HYD1 induced TO-PRO-3 positivity, decreased levels of ROS, reduced ATP depletion and reduced mmp loss compared to the H929 cell line. Additionally, the drug resistant variant H929-60 cells displayed decreased cell surface binding of FAM-HYD1 compared to H929 cells. These data indicate that decreased expression of the binding target(s) of HYD1 may contribute to drug resistance. Gene expression profiling (GEP) was used as an unbiased approach to identify changes in gene expression that may contribute to HYD1 resistance. Differentially expressed genes were mined in silico using the pathway analysis programs Ingenuity and GeneGo. The integrin signaling hub showed substantial changes in gene expression in the drug resistant variant compared to the parental cell line. Specifically, α4, α6, αV and β1 integrins were all down regulated along with the integrin associated protein CD47 in the HYD1 resistant cell line. These changes were consistent with decreased protein expression of integrins on the cell membrane and decreased functional adhesion to fibronectin, vitronectin and VCAM-1. Reducing the expression of α4 integrin using shRNA in the parental H929 cell line conferred partial resistance to HYD1 induced cell death. Together our data show that the acquisition of resistance to HYD1 correlated with decreased integrin expression and functional binding to extracellular matrixes. Future studies aim to determine whether a decrease in α6, αV and β1 integrins on the cell surface contributes to HYD1 resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1547.
Abstract 1549: Oral inhibitors of macrophage migratory inhibitory factor (MIF) lead to reduced tumor burden in a murine model of invasive bladder cancer
Authors: Taylor John A. , Choudhary Shilpa , Hegde Poornima , Voznesensky Olga , de la Cruz Vidal F. , Pruitt James R. , Sielecki Thais M. , Pilbeam Carol 
Published: February 2011

Abstract
INTRODUCTION AND OBJECTIVES: MIF is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We have reported that absence of MIF in transgenic mice leads to decreased angiogenesis and invasion in the BBN model of bladder cancer. We evaluated the impact of 2 oral inhibitors of MIF (Cytokine PharmaSciences, King of Prussia, PA; CPSI) in the BBN model.
METHODS: 30, 3 mnth old male C57Bl/6 mice were treated with BBN 0.05% in drinking water for 22 wks. Mice (n=10/grp) received vehicle (PEG 300, methylcelluose), oral inhibitor CPSI-2705 or CPSI-1306 daily (25 mg/kg) by gavage from wks 16-22, corresponding to time of progression from CIS to invasive disease as determined in previous experiments. Animals were inspected daily for general health with weights recorded weekly. Bladders were weighed, fixed and assessed for tumor stage, grade, burden and associated angiogenesis.
RESULTS: In general, the group receiving CPSI-1306 appeared healthier during drug treatment. There was a 16% weight loss from the start of gavage in the control group vs 10-11% in the drug groups. Two animals each from the control and CPSI-2705 group died prior to study completion. The majority of control animals had evidence of upper tract obstruction with less noted in CPSI 2705 and none in the 1306 group. Average bladder weights were 0.5 ± 0.5 gm, 0.3 ± 0.3 gm and 0.2 ± 0.2 gm for control, 2705 and 1306 respectively which approached statistical significance for control vs 1306 (log transf p=0.06). There was a higher proportion of pT3 disease in the control (80%) vs inhibitor groups (60%). Tumor burden was markedly diminished in the drug groups (81% cntrl vs 62% 2705 vs 59% 1306, involvement invasive disease) with some bladders in these arms having only focal areas of invasion. Tumor grade trended lower in the drug groups as well.
CONCLUSIONS: The use of MIF oral inhibitors CPSI 2705 and CPSI 1306 in the BBN bladder cancer model resulted in less weight loss, improved general health, decreased tumor burden with a trend toward lower stage, grade and tumor associated angiogenesis. The results of this experiment warrant larger studies to validate and expand these findings with a goal of development for clinical use.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1549.
Abstract 1551: Benzimidazole as novel therapeutic agent for metastatic prostate cancer
Authors: Chung Ivy , Barrows Courtney , Wilson Arianne , Rummel Nathan , Badaruddin Shaikh , Mizokami Atsushi , Banyard Jackie , Zetter Bruce 
Published: February 2011

Abstract
While prostate cancer is among the most treatable disease when the tumor stays confined to the prostate, the prognosis is generally poor for patients whose cancer metastasizes to distant organs. Current chemotherapy is relatively limited for metastatic prostate cancer, and thus there is a demand for more efficacious treatments. Here, we described a novel screen of a library containing approved drugs, for compounds that selectively target metastatic prostate cancer cells. We identified that benzimidazoles, widely used as anti-parasitic agents, exhibit preferential toxicity in two paired of human prostate cancer cells with different metastatic potential and in an aggressive rat prostate adenocarcinoma model but showed minimal cell kill on normal prostate epithelial cells. As these drugs are highly water-insoluble, we improved the systemic bioavailability in mice using a micelle preparation. Benzimidazoles significantly extend the lifespan of tumor metastases-bearing mice (% increased life span, ILS 40-60 range), without severe toxicity to the host. Notably, these anti-tumor effects are comparable if not more effective than paclitaxel (%ILS 30). The selective cytotoxicity to the metastatic cells is mediated partly by inhibition of the microtubulin polymerization, leading to mitotic arrest and subsequently cell death. These cytotoxic effects are also observed in cancer cells with paclitaxel or multi-drug resistance, both in vitro and in vivo. The benzimidazoles may possess significant anti-tumor effects and a good safety profile that are desired in the long term treatment of men with late-stage prostate cancer and failed both hormone-deprivation and taxane-based therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1551.