bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4542: The design, synthesis and in vitro evaluation of selective FR α and β and PCFT substrates with potent GARFTase inhibitory activity as antitumor agents
Authors: Gangjee Aleem , Wang Lei , Cherian Christina , Desmoulin Sita Kugel , Hou Zhanjun , Kisliuk Roy L. , Matherly Larry H. 
Published: February 2011

Abstract
Three folate transporters, the reduced folate carrier (RFC), folate receptors (FR) and the proton-coupled folate transporter (PCFT) account for most of the folate influx activity in mammalian cells. Lack of selectivity for folate transporters is one of the major causes of chemotherapy failure with antifolate drugs. We recently reported the potent glycinamideribonucleotide formyltransferase (GARFTase) inhibitory activity of a series of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl for benzoyl-substituted side chain with FR and PCFT specificity over RFC. In an attempt to optimize for selective transport by FR and PCFT, and GARFTase inhibitory activity, a furan for benzoyl-substituted side chain analog with a 4-carbon bridge was synthesized. The target compound was tested against KB human tumor cells that express FR alpha, human RFC, and human PCFT using a fluorescence-based cytotoxicity screen, and showed remarkably potent subnanomolar inhibitory activity (IC50 of 0.29 nM). The furan analog was further tested in isogenic Chinese hamster ovary sublines, engineered to express human FR alpha (RT-16), FR beta (D4), hRFC (pC43-10), or hPCFT (R2/hPCFT4). The furan side chain compound again showed a subnanomolar IC50s for both FR alpha and FR beta expressing cells (IC50 of 0.16 nM for RT16, and 0.92 nM for D4). Thus, in comparison with the lead thienoyl side chain compound (IC50 of 2 nM for RT16, and 0.75 nM for D4), the furan analog exhibited similar activities toward FR beta, but a 12.5-fold increased activity toward FR alpha. For PCFT-expressing R2/hPCFT4 cells, the furan side chain compound (IC50 of 439 nM) was about 10-fold less potent than the thienoyl analog (IC50 of 43.4 nM). The furan analog was inactive against human dihydrofolate reductase (hDHFR) or human thymidylate synthase (hTS) (IC50 &gt;10−5 M), suggesting that neither hDHFR nor hTS is a principal target. Metabolite protection from in vitro cytotoxicity in KB cells showed that thymidine (10 μM) did not affect the growth inhibitory effects of the furan analog whereas adenosine (60 μM) and 5-amino-4-imidazolecarboxamide (320 μM) were completely protective, identifying GARFTase as the likely intracellular target. Our results indicate that the side chain heterocyclic ring may control the transport selectivity for both FR and PCFT of the pyrrolo[2,3-d]pyrimidines.
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 4542.
Abstract 4544: Novel indolequinone inhibitors of thioredoxin reductase are active against human pancreatic cancer
Authors: Yan Chao , Shieh Biehuoy , Regan Phillip , Zhang Zhiyong , Colucci Marie , Chilloux Aurélie , Newsome Jeffery , Siegel David , Chan Dan , Moody Christopher J. , Ross David 
Published: February 2011

Abstract
A series of indolequinones was previously developed in our lab as potential antitumor agents against pancreatic cancer. Three general classes of indolequinone consisting of 2-methyl, 2-hydroxymethyl and 2-unsubstituted derivatives with varying leaving groups at the indole 3- position exhibited marked activity against human pancreatic cancer both in vitro and in vivo. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and BxPC-3 were used to ensure effects were not cell line specific and growth inhibitory effects were measured using both the MTT and clonogenic assays. Indolequinones displayed growth inhibitory activity against pancreatic tumor cells in vitro and two specific classes of indolequinone, the 2-unsubstituted and 2-hydroxymethyl classes, were particularly active agents with IC50 values in the 20-200nM range. Indolequinones were also found to be efficient inducers of apoptosis in pancreatic cancer cell lines at concentrations which induced growth inhibition. Selected indolequinones were also screened against the NCI-60 cell line panel to reveal the pattern of activity across various tumor types and were particularly effective against colon, renal, and melanoma cancer cells. The spectrum of activity of indolequinones in the NCI-60 was similar to established inhibitors of thioredoxin reductase. Indolequinones of both the 2-hydroxymethyl and 2-unsubstituted classes were found to inhibit thioredoxin reductase in MIA PaCa-2 cellspancreatic cancer at concentrations equivalent to those inducing growth inhibitory effects. The mechanism of inhibition of thioredoxin reductase by the indolequinones was studied in detail in cell-free systems using purified enzyme and the C-terminal selenocysteine of thioredoxin reductase was found to be the primary adduction site of the indolequinones using LC-MS analysis. Inhibition of thioredoxin reductase by indolequinones in cells resulted in a change of thioredoxin redox state and activation of the P38/JNK signaling pathway which may result in downstream apoptosis. Our results demonstrate that thioredoxin reductase is a potential target of the indolequinones in pancreatic cancer cells. (Supported by CA11441).
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 4544.
Abstract 4545: Anticancer activity of elesclomol correlates with low LDH levels and active mitochondrial respiration
Authors: Nagai Masazumi , Blackman Ronald K. , Rao Patricia E. , Wada Yumiko , Koya Keizo 
Published: February 2011

Abstract
Elesclomol is a first-in-class investigational drug that exerts anticancer activity through the elevation of reactive oxygen species (ROS). Our previous studies revealed that elesclomol selectively chelates copper and generates ROS via reduction of Cu(II) to Cu(I). In a Phase 3 trial in metastatic melanoma, the level of baseline lactate dehydrogenase (LDH) in patients emerged as an important prognostic factor for treatment outcomes with elesclomol. Additional investigations were undertaken to evaluate the relation between elesclomol activity and LDH levels. Because the copper redox reactions necessary for elesclomol activity can be influenced by changes in cellular metabolic properties, we investigated whether elesclomol activity varies between normoxic conditions (active mitochondrial respiration, low LDH) and hypoxic conditions (decreased mitochondrial respiration, high LDH). To assess the influence of hypoxic conditions, we evaluated elesclomol activity under several situations in which cells express high levels of Hypoxia Inducible Factor-1α (HIF1α), a transcription factor that induces a complete set of glycolytic enzymes, including LDH, and switches off glycolytic carbon flow to mitochondria. First, an increase in the level of HIF1α protein was observed in M14 melanoma cells at low oxygen level or high cell density. Elesclomol showed decreased cytotoxicity under both of these conditions. Second, we evaluated lines within the same cancer phenotype but showing distinct levels of HIF1α, and found that the high-HIF1α-expressing Caki-2 renal cancer line was resistant to elesclomol, while lower-HIF1α-expressing renal cancer cell lines were sensitive to elesclomol. Third, we assessed HIF1α levels and elesclomol activity in cells treated with CoCl2, a chemical mimetic of hypoxia. High levels of HIF1α induction were present in M14 cells treated with CoCl2, and elesclomol was significantly less active in these cells. The addition of oxamate, which selectively inhibits LDHA and activates pyruvate entry into mitochondria, restored the activity of elesclomol in the CoCl2-treated cells. These results support the hypothesis that elesclomol is more active under normoxic conditions (low LDH) and less active under hypoxic conditions (high LDH), consistent with the clinical findings. The results may be important for identifying patient populations for future clinical development of elesclomol.
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 4545.
Abstract 4557: In vivo near-infrared fluorescent quantification of therapy-induced apoptosis using Annexin-Vivo 750
Authors: Zhang Jun , Cuneo Gary , Narayanan Nara , Delaney Jeannine , Kossodo Sylvie , Bao Bagna , Rajopadhye Milind , Peterson Jeffrey D. , Madden Karen , Gao David Z. , Moonen Peter , Reutelingsperger Chris 
Published: February 2011

Abstract
Drug-induced ex vivo apoptotic tests are widely used pre-clinically to monitor chemotherapeutic efficacy. Real-time non-invasive in vivo imaging and quantification of therapy-induced tumor apoptosis would impact drug discovery significantly. As a key apoptotic marker, phosphatidylserine (PS) translocated to the outer leaflet of the plasma membrane can be detected by fluorescent-labeled Annexin A5 specifically with high affinity. We synthesized an in vivo imaging contrast agent Annexin-Vivo 750 by conjugating a human recombinant Annexin A5 to a near-infrared fluorophore with em 770 nm. Fluorescence microscopy showed 4h anti-FAS Ab treatment significantly increased the number of Annexin-Vivo 750 positive Jurkat cells, confirming that the agent binds to PS on apoptotic cells. Similarly, flow cytometry showed anti-FAS Ab increased Annexin-Vivo 750 positive cells from 15% to 55%. TUNEL positive cells were increased from 0% to 65.14 ± 3.93% (p=0.0004) by anti-FAS antibody. The TUNEL data correlate very well with flow cytometry data and are consistent with the fluorescence microscopy data. In vivo imaging of Annexin-Vivo 750 was performed in nude mice implanted with human colorectal carcinoma HT-29 cells. Once tumors reached a volume of 142.36 + 8.3 mm3 mice were randomized and treated intraperitoneally with cyclophosphamide (170 mg/kg) or vehicle at time 0h. The agent was injected at 24h with a dose of 2.4 nmol/animal and the tumors were imaged at 26h with an FMT2500 quantitative tomography imager for in vivo real-time 3D Annexin-Vivo 750 quantification. Tumor fluorescence signal was 2.55 fold higher with than without cyclophosphamide (p=0.0002), while tumor volumes were the same (p=0.35). Fluorescent signal decreased significantly by 24h and returned to baseline at 48h post agent injection. Likewise, intratumoral injection of TNFα (2.5 μg) plus IFNγ subcutaneous injection (2500 units) also significantly increased HT29 tumor Annexin-Vivo 750 fluorescence (3 fold compared to control, p=0.0099, 24h after treatment, 2h post-agent injection). TUNEL positive HT-29 cells were increased from 11.16 ± 7.05 % to 41.77 ± 8.78 % (p=0.0004) by cyclophosphomide, indicating apoptosis. These results demonstrate that Annexin-Vivo 750 in vivo imaging can be used for detecting, quantifying and monitoring apoptosis following cancer treatments, underscoring its value in drug discovery and development in cancer and potentially in other clinically important areas, such as cardiovascular-, autoimmune-, inflammatory- and neurodegenerative diseases.
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 4557.
Abstract 457: Hypoxia-mediated upregulation of Pim-1 contributes to tumor survival
Authors: Chen Jian , Kobayashi Masanobu , Darmanin Stephanie , Qiao Yi , Gully Christopher , Zhao Ruiying , Kondo Satoshi , Wang Hua , Wang Huamin , Yeung Sai-Ching Jim , Lee Mong-Hong 
Published: February 2011

Abstract
Introduction: The proto-oncogene pim-1 regulates apoptosis and the cell cycle by phosphorylating target proteins. Overexpression of Pim-1 can cause genomic instability and contribute to lymphomagenesis. Tumor hypoxia directly promotes genomic instability and changes the responses of cancer cells to many chemotherapy agents, resulting in chemoresistance. It is not clear whether Pim-1 is involved in hypoxia-mediated tumor survival and drug resistance.
Result: (1) Hypoxia stabilize Pim-1 by preventing its ubiquitin-mediated proteasomal degradation and cause Pim-1 translocation from the cytoplasm to the nucleus. (2) Overexpression of Pim-1 increases NIH3T3 cell transformation exclusively under hypoxia, suggesting that Pim-1 expression under hypoxia may be implicated in the transformation process of solid tumors. (3) Introduction of dominant negative Pim-1 resensitizes pancreatic cancer cells to apoptosis induced by glucose-deprivation under hypoxia. Also, administration of siRNAs for Pim-1 resensitizes cancer cells to glucose deprivation under hypoxic conditions, while over-expression of Pim-1 causes solid tumor cells to become resistant to glucose deprivation. (4) Dominant negative Pim-1 reduces tumorigenicity and sensitizes tumors to chemotherapy in pancreatic cancer cells and HeLa xenograft mouse models.
Conclusions: Our studies indicate that Pim-1 plays a distinct role in solid tumor formation and chemoresistance, implying that Pim-1 may be a novel target for cancer 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 457.
Abstract 4573: Discovery of candidate biomarkers for colorectal cancer using mass spectrometry-based proteomic analysis of cell line conditioned media
Authors: Karagiannis George S. , Diamandis Eleftherios P. 
Published: February 2011

Abstract
Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths with approximately 655,000 deaths annually, worldwide. Specific biomarkers for early detection of CRC are needed, mainly because the currently applied serum biomarkers (CEA, CA 19.9) lack adequate sensitivity and specificity for screening purposes, while colonoscopy is invasive, with considerable cost, risks and inconvenience. In the present study, we utilized a mass spectrometry-based platform to analyze the proteome of the conditioned media from 12 CRC cell lines with diverse genetic profiles, to capture the disease heterogeneity. Proteins were trypsin-digested and fractionated by strong cation-exchange and reverse-phase liquid chromatography prior to mass spectrometric analysis with an LTQ Orbitrap instrument. The samples were run in triplicate and results were searched against the IPI human forward and reverse database, using MASCOT and X!Tandem search engines. We were able to identify approximately 2,000 unique proteins for each cell line, with reproducibility ranging from 71 to 82% among the triplicates. The efficiency of this approach was signified by the large number of known biomarkers, such as CEA, successfully identified in our list of candidates, as well as by the identification of internal control proteins, such as kallikreins 6, 7, 10, and 11, which were also quantified by ELISA in cancer cell supernatants. The acquired protein datasets were further subjected to bioinformatic analysis using Gene Ontology. The proteins were assigned a subcellular localization and 35-40% were classified as extracellular or plasma membrane proteins. Further mining of this vast database by using bioinformatics tools and experimental approaches (such as multiple reaction monitoring and ELISA) could lead to shortlists of proteins that may have utility as circulating CRC biomarkers.
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 4573.
Abstract 4575: Covalent incorporation of a new class of dye-based affinity baits in sieving hydrogel nanoparticles overcome roadblocks to cancer biomarker discovery
Authors: Luchini Alessandra , Tamburro Davide , Douglas Temple , Espina Benjamin H. , Lepene Benjamin S. , Zhou Weidong , Espina Virginia , Petricoin Emanuel F. , Liotta Lance A. 
Published: February 2011

Abstract
Cancer biomarker discovery and clinical application has been seriously hampered by low abundance, instability and complex formation with high abundance proteins (e.g. albumin). N-isopropylacrylamide (NIPA) based hydrogel particles, consisting of a bait-containing core and a protective shell, overcome these major issues associated to biomarker discovery and measurement. Particles perform in one step, in solution, a) total sequestration and concentration, b) size sieving and c) complete protection form degradation of LMW protein biomarkers in blood and urine. In this study, novel dye molecules were selected as affinity ligands for broad classes of biomarkers; dyes were chosen for their ability to bind proteins, glycoproteins and nucleic acid for tissue histology, to bind textile proteins for fabric staining or for their known property to bind allergens. Dyes containing primary amine group (e.g. Acid Black 48, Basic Red 9) were coupled to NIPA/acrylic acid (AAc) particles by condensation of the amine group the carboxylic group. The ability of particles to capture and concentrate analytes was tested against a panel of low abundance, labile tumor relevant biomarker that include angiogenic growth factors (bFGF, VEGF, PDGF), IGF-1 and IGF binding proteins, interleukins (IL-6, IL-8), chemokines (CXCL12, CCL24), pro-apoptotic Bcl-2 proteins (Bak, Bax), and nucleic acids. Technologies used to screen dye functionalized particles include 1 D gel electrophoresis, western blotting, immunoassay, and mass spectrometry.
Results showed that dye based baits have extremely high affinity for the target analytes so that particles capture all the analyte present in solution and that the affinity of biomarkers to the bait is unique and specific to the chemical structure of the bait molecule.
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 4575.
Abstract 4595: ERK/MAPK regulation of ERRγ in Tamoxifen resistant breast cancer
Authors: Mazzotta Mary M. , Liu Minetta C. , Clarke Robert , Riggins Rebecca B. 
Published: February 2011

Abstract
Breast cancer is a serious public health problem that is the second-most common cause of cancer-related death in women. Endocrine therapy, like Tamoxifen (TAM), has made significant contributions to the successful management of ER+ breast cancer but unfortunately 30-50% of these tumors may acquire endocrine resistance. However, not all ER+ breast cancers are the same. Two of the major classifications of breast cancer are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). In comparison to IDC, a significantly greater percentage of ILCs are estrogen receptor alpha-positive (ER+) and progesterone receptor-positive (PR+). Therefore, women diagnosed with this tumor subtype should be ideal candidates for endocrine or antiestrogen therapy. However, clinical studies differ as to whether ILC patients experience better or worse survival following antiestrogen treatment when compared to ER+ IDC patients.
In a model of TAM-resistance in ILC, we have shown that the orphan nuclear receptor estrogen related receptor gamma (ERRγ) plays a functional role in the resistant phenotype of LCCTam cells, ERRγ overexpression is sufficient to induce TAM resistance, and we show for the first time that ERRγ is serine-phosphorylated in TAM-resistant breast cancer cells in association with increased expression and activity of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK; ERK). We have also recently found an IDC-derived model of TAM-resistance to overexpress ERRγ. Therefore, we hypothesize that ERK regulates ERRγ transcriptional activity and is a critical determinant of ERRγ-induced TAM resistance in breast cancer.
To test this hypothesis, we used two antiestrogen-sensitive and -resistant breast cancer cell line pairs: IDC-derived RR cells and their sensitive controls MCF7, and the ILC-derived LCCTam cells and their sensitive controls SUM44. In both sensitive controls we found TAM alone to cause cell death. When we added the ERK inhibitor, U0126, to the TAM treatments, cell death increased. The resistant cell lines showed no effect with the addition of TAM alone, but the TAM treatment coupled with the inhibitor restored sensitivity and caused cell death. Additionally, we tested the transcriptional activity of ERRγ in the presence or absence of the ERK inhibitor. We found each of the four cell lines to show decreased ERRγ transcriptional activity in the presence of U0126.
Future studies include the identification of the serine residues on ERRγ being phosphorylated by ERK, and whether ERRγ overexpression is associated with increased ERK expression and activity, poor overall survival, and poor response to TAM in breast cancer patients treated with endocrine 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 4595.
Abstract 4606: An in vitro and in vivo evaluation of novel anticancer agents in a triple negative breast cancer model
Authors: Hawthorne Tamorah , Gallien Joseph , Gibbs Lee , Jones Janeque , Muir Shannon , Rhodes Lyndsay V. , Driver Jennifer , Khalili Hafez , Burow Matthew , Parker-Johnson KiTani A. 
Published: February 2011

Abstract
Patients diagnosed with triple negative breast cancer, which is the absence of the estrogen (ER), progesterone (PR), and Her2/neu receptor have a poor prognosis and there is a critical need to develop novel antineoplastic agents for this breast cancer sub-type. Therefore, the focus of this project is to identify novel anticancer agents with in vitro and in vivo antiproliferative activity in a triple negative breast cancer model. Previously, our laboratory synthesized a group of novel isochalcones called DJ compounds that demonstrated significant in vitro antiproliferative effects. Cell proliferation of MDA-MB-231 cells was measured using the alamar blue dye method and produced IC50 values of DJ52, DJ56, and DJ82 at 10−6M, 10−5M, and 10−5M, respectively. Binding studies have indicated that these agents do not bind the ER but appear to inhibit a phosphorylation step in the epidermal growth factor (EGFR) receptor pathway. In vivo studies were also conducted by implanting tumors derived from MDA-MB231 cells into SCID mice to determine tumor regression was measured over 20 days. DJ52 at 50mg/kg caused significant decrease (p value &lt;.05) decreased tumor volume by nearly fifty percent compared to the control with vehicle alone. Therefore, these data suggests that DJ52 has merit for further evaluation for potential intervention in patients diagnosed with triple negative breast cancer. Our laboratory continues our efforts to understand the mechanism of action of these agents to potentially provide alternative pharmacological options for these patients for better health outcomes.
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 4606.