bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1363: Development of novel anticancer agents based on fusarochromanone
Authors: Mahdavian Elahe , Boston Dakota , Grimes Reid , Williams-Hart Tara , Furmanski Brian , Clifford John , Salvatore Brian 
Published: June 2012

Abstract
The primary goal of this research is to develop novel anti-cancer agents based on fusarochromanone (FC101a), a natural mycotoxin with potent anti-angiogenic and direct anti-tumor activity. This research may lead to new cancer chemotherapeutic agents that are more potent and less toxic than conventional chemotherapy. Like most other bioactive natural compounds, the potency of FC101a is compromised in-vivo, suggesting unfavorable bioavailability, distribution, and/or metabolism. Development of FC101a as a chemotherapeutic drug requires the completion of its total synthesis, as well as the synthesis of a series of structural analogs with greater in-vivo potency than the lead compound.
Progress towards both the chemical and biological synthesis of FC101a will be presented. We have employed a new pathway for synthesizing the unique multifunctional four-carbon side chain in the parent compound. We have also been successful in synthesizing the 6-iodo-4-chromanone, a key intermediate that is needed for the coupling reaction with the side-chain. Additionally, we have synthesized two novel acetal analogs of FC101a and will present the rational for choosing these structural analogs for devising structure activity relationships for this series of compounds.
For the biological synthesis, we have obtained a highly fluorescent metabolite from the rice culture of two Fusarium strains (#4482 and #8508) that resembles FC101a, based on TLC analyses. We have also developed an efficient HPLC purification protocol to obtain samples of this compound with high purity. We are currently working to scale up this separation and confirm the structure of this compound through 1H, 13C-NMR as well as high-resolution mass spectrometry analyses.
We will report our preliminary results on the inhibition effects of FC101a on the growth of human aggressive skin cancer carcinoma (SCC) both in-vitro and in-vivo. We have also investigated the mechanism of the biological function of FC101a. We will report our results on the expression levels and phosphorylation states of key proteins involved in cell proliferation signaling pathways, cell sorting profiles, and FACS analyses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1363. doi:10.1158/1538-7445.AM2011-1363
Abstract 1364: Design, synthesis and evaluation of potent antiproliferative and cytotoxic antifolates with selective FRs and PCFT transport over RFC and potent GARFTase inhibition
Authors: Wang Lei , Cherian Christina , Desmoulin Sita Kugel , Hou Zhanjun , Matherly Larry H. , Gangjee Aleem 
Published: June 2012

Abstract
Lack of selectivity for folate transporters is one of the major causes of toxicity and chemotherapy failure with clinically used antifolates. 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. We recently reported potent inhibition of cell proliferation by a classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine with a thienoyl for benzoyl-substituted side chain and a 4-carbon bridge (AG71). AG71 was selective for transport by FRs and PCFT over RFC and inhibited glycinamideribonucleotide formyl transferase (GARFTase) in de novo purine biosynthesis. In SCID mice with KB tumors, AG71 was highly active against both early and advanced stage tumors. A series of five thienoyl regioisomers of AG71 with [1,3] (AG117 and AG118) and [1,2] (AG114, AG115, AG116) thienoyl substitutions by the 4-carbon bridge and the L-glutamate were synthesized. Analogs were evaluated for anti-proliferative activities in engineered Chinese hamster ovary (CHO) cells expressing RFC, FR, or PCFT to determine the optimum structures for selective transport by FRs and/or PCFT. Additional studies were performed in KB and IGROV1 tumor cells, using inhibition of cell proliferation or colony formation as metrics. Like AG71, none of the novel thienyol regioisomers were substrates for RFC. AG117 and AG118 were potently active toward FR- and PCFT-expressing CHO cells and toward KB and IGROV1 tumor cells, equivalent or exceeding levels for AG71. In colony-forming assays in KB cells, AG117 and AG118 were cytotoxic. AG114, AG115, and AG116 were substantially less active or completely inert. AG117 and AG118, like AG71, were high affinity ligands for FRα by competitive ligand binding with 3H-folic acid, and were potent substrates for PCFT by direct competition 3H-methotrexate transport. By protection assays, AG71 and AG117 preserved potent anti-proliferative activity even in the presence of 50 nM leucovorin; adenosine and 5-imidazole-4-carboxamide were completely protective, establishing the de novo purine biosynthetic pathway and GARFTase as the principal intracellular targets. GARFTase inhibition was confirmed by in situ GARFTase metabolic assays with 14C-glycine as a radiotracer. Our results identify 6-subsituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers of AG71 as potent anti-proliferative and cytotoxic antifolates, reflecting selective transport by PCFT and FR over RFC and inhibition of GARFTase.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1364. doi:10.1158/1538-7445.AM2011-1364
Abstract 137: MicroRNA-200c restores anoikis sensitivity in breast and gynecological cancers
Authors: Richer Jennifer K. , Howe Erin N. , Cochrane Dawn R. 
Published: June 2012

Abstract
Background: MicroRNA-200c directly targets ZEB1, an epithelial to mesenchymal (EMT)-inducing transcriptional repressor of E-cadherin and other key determinates of epithelial identity and polarity. Therefore, restoration of miR-200c results in repression of ZEB1, dramatic reduction in migration and invasion, and increased sensitivity to microtubule targeting chemotherapeutics. We hypothesized that in addition to ZEB1, miR-200c targets additional genes that contribute to its myriad effects on maintaining the epithelial phenotype by repressing mesenchymal genes.
Results: We performed microarray analysis following restoration of miR-200c to aggressive endometrial cancer cells and identified 18 genes that were both significantly repressed and predicted to be direct targets of miR-200c. These genes, including fibronectin 1 (FN1), class III beta-tubulin (TUBB3), neurotrophic tyrosine receptor kinase type 2 (NTRK2 or TrkB), leptin receptor (LEPR), moesin (MSN1) and Rho GTPase activating protein 19 (ARHGAP19), are all typically expressed only in non-epithelial cells, such as fibroblasts or neurons. Utilizing luciferase reporter assays and mutational analysis, we validate each of these genes as direct targets of miR-200c. We also demonstrate that restoration of miR-200c leads to a dramatic decrease in mRNA and protein levels of these targets. Further we find that restoration of miR-200c restores anoikis sensitivity to suspended cells, leading to over a 1.5 fold increase in cell death. TrkB is a potent suppressor of anoikis in breast and ovarian cancer models. Addition of TrkB lacking the miR-200c binding site reversed the ability of miR-200c to suppress anoikis. Interestingly, neurotrophin 3 (NTF3), a ligand for TrkB, contains 2 putative miR-200c binding sites and is down regulated upon restoration of miR-200c. Thus, loss of miR-200c in carcinoma cells allows inappropriate translation of both TrkB and NTF3, setting up an autocrine loop that results in anoikis resistance.
Conclusions: Our data demonstrate that miR-200c serves as a “guardian of the epithelial phenotype” and suppressor of EMT by directly targeting and repressing a program of genes that should not be on in differentiated epithelial cells. We identify a novel function of miR-200c, the ability to suppress anoikis resistance, an important yet understudied step in the metastatic cascade.
Funding source: DOD Breast Cancer Program Idea Award BC084162 to JKR
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 137. doi:10.1158/1538-7445.AM2011-137
Abstract 1378: Identification and characterization of small molecule inhibitors targeting Eya phosphatase activity for anti-breast cancer therapy
Authors: Krueger Aaron , Dehdashti Seameen , Southhall Noel , Patnaik Samarjit , Marugan Juan , Zheng Wei , Ford Heide , Zhao Rui 
Published: June 2012

Abstract
Eya proteins are transcriptional co-activators of the homeobox gene Six1 and are also unique protein tyrosine phosphatases. Six1 and Eya2 are required for normal development but are down-regulated in most adult tissues. However, Six1 and Eya are over-expressed in a large number of breast tumors and play a causal role in the initiation and development of these tumors. The phosphatase activity of Eya was shown to be important for the transformation, migration, invasion, and metastasis of breast cancer cells. Eya's phosphatase activity therefore provides an attractive enzymatic target for anti-breast cancer therapy. In addition, Eyas also direct cells to a DNA-damage-repair pathway instead of an apoptotic pathway upon DNA damage through the dephosphorylation of histone H2AX. Inhibiting Eya phosphatase activity can therefore potentially sensitize tumor tissue to radiation or chemotherapy treatment. We developed an HTS assay to identify small molecule inhibitors of Eya's phosphatase activity. In collaboration with the NIH Chemical Genomics Center, we have screened over 300,000 compounds and identified several promising lead compounds. These hits are currently being evaluated for their potency, specificity, and mechanism of action using biochemical, structural, and cell-based assays. We believe that Eya is a significant target for cancer therapy through sensitizing cancer cells to radiation and chemotherapy and through the inhibition of Six1-mediated tumorigenesis and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1378. doi:10.1158/1538-7445.AM2011-1378
Abstract 1382: Use of polarized light spectroscopy (CD) to study STAT3 folding and STAT3:ligand interactions
Authors: Rahman Khondaker M. , Palmer Jonathan , Essex Samantha , Nkansah Edwin , Zinzalla Giovanna , Wilderspin Andrew F. , Bui Tam T.T , Drake Alex F. , Thurston David E. 
Published: June 2012

Abstract
STAT3 is a homodimeric transcription factor that is over-expressed in variety of solid tumours. It is known to trigger transcription of a range of genes associated with tumour growth and metastasis. In order to use the STAT3/STAT3 dimer for drug discovery, the factors affecting dimerisation of the monomeric protein and the interaction with ligands must be understood. In this study, we have demonstrated that Circular Dichroism (CD) can be used as a tool to study these processes. We have found that formation of the dimeric STAT3/STAT3 complex results in an induced CD signal which is absent in monomeric protein. Thus, CD can be used to optimize conditions for the production and storage of un-phosphorylated (un-P-) and phosphorylated (P-) STAT3. A similar induced signal was observed when a small molecule (or peptide ligand) interacted with either un-P- or P-STAT3 due to chiral perturbation of the protein structure or electron rearrangements. Crucially, the intensity of the induced CD signal was found to depend on the strength and geometry of the interaction of the binding partner. CD was also used to determine the secondary structure of un-P- and P-STAT3. HIS- and FLAG-tagged STAT3 were examined using the far-UV spectral region (190-250 nm), and the regular folded environment of the peptidic bonds was used to determine the alpha-helix, beta-sheet, and random coil content of different batches of STAT3 protein. For batches of P-STAT3, the composition was found to be 28.3% α-helix, 22.3% β-sheet and 49.4% random coils. For un-P-STAT3, the β-sheet content was slightly higher (23.2%) while the α-helix content was lower (26.8%). Next, protein:ligand interactions which alter the conformation of the protein were studied. Titration of un-P-STAT monomer with different small-molecule inhibitors produced a significant change in the CD spectrum consistent with modification of secondary structure due to altered folding. In particular, significant effects on the secondary structures of both un-P- and P-STAT3 were observed upon binding of the natural peptidic ligands LKTKF and LPQTV. Crucially, the different complex geometries adopted by the proteins upon interaction with ligands could be used to determine the stoichiometry of interaction and the orientation of the ligands in the binding pocket of the protein. These results demonstrate that CD spectroscopy can be used to evaluate STAT3 structure and ligand interactions at the molecular level, and thus represents a useful analytical tool in the development of small molecule inhibitors for potential therapeutic use.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1382. doi:10.1158/1538-7445.AM2011-1382
Abstract 1385: Real-time imaging of paxillin-GFP expression in breast cancer cells in vitro and in vivo
Authors: Suetsugu Atsushi , Digman Michelle , Gratton Enrico , Moriwaki Hisataka , Saji Shigetoyo , Bouvet Michael , Hoffman Robert M. 
Published: June 2012

Abstract
Paxillin is involved in the assembly of focal adhesions. In this study, we describe real-time imaging of paxillin-GFP expression in breast cancer cells (MDA-MB-231) in vitro and in vivo. In vitro, round cancer cells had greater paxilin movement than stretched cancer cells as seen by fluorescence imaging. When paxillin-GFP breast cancer cell (1×106) were injected in the epigastric cranials vein, round cancer cells had GFP-expressing protrusions. Many paxillin-GFP-expressing breast cancer cells stretched. The cancer cells extravasated and subsequently grew around the outer surface of the blood vessel after one week. Migration of single cells in vivo was observed by fluorescence microscopy. Two weeks after cell injection, paxillin-GFP breast cancer cells migrated along the vessel wall. Most of paxillin-GFP cancer cells were stretched and were not mobile. With anti-VEGF treatment, paxillin was observed in round structures rather than stretched structures and paxillin movement within the cell were arrested. The results show that paxillin-GFP allows the imaging of the role of paxillin in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1385. doi:10.1158/1538-7445.AM2011-1385
Abstract 1392: CTGF inhibits cell motility in oral cancer cells through reducing COX-2 expression
Authors: Yang Wan-Yu , Tang Chih-Hsin , Chuang Jing-Yuan 
Published: June 2012

Abstract
Oral squamous cell carcinoma (SCC) has a striking tendency to migrate and metastasize. Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin synthase, has been implicated in tumor metastasis. Connective tissue growth factor (CTGF), a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells. However, the effect of CTGF on migration activity and COX-2 expression in human oral cells is mostly unknown. Here we found that CTGF reduced the migration and expression of COX-2 in human oral cancer cells. αvβ5 monoclonal antibody (mAb), phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002 and wortmannin) and Akt inhibitor reversed the CTGF-inhibited the migration and COX-2 down-regulation of oral cancer cells. CTGF stimulation decreased the phosphorylation of focal adhesion kinase (FAK), PI3K and Akt. In addition, c-Jun siRNA also antagonized the CTGF-inhibited migration and COX-2 expression. Moreover, CTGF decreased the binding of c-Jun to the AP-1 element on the COX-2 promoter. Taken together, our results indicated that CTGF inhibits the migration of oral cancer cells by decreasing COX-2 expression through the αvβ5 integrin receptor, FAK, PI3K, Akt, c-Jun and AP-1 signal transduction pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1392. doi:10.1158/1538-7445.AM2011-1392
Abstract 1394: Beta-cryptoxanthin suppresses cancer cell motility and angiogenesis via inhibiting alpha 7-nicotinic acetylcholine receptor-mediated PI3K pathway
Authors: Miao Benchun , Wang Xiang-Dong 
Published: June 2012

Abstract
Epidemiologic studies show that increased dietary intake or higher blood levels of one specific carotenoid, beta-cryptoxanthin (BCX), is strongly associated with a reduced risk of lung cancer. However, the biological activities and molecular targets by which BCX functions as a chemopreventive agent against lung cancer are poorly understood. Recent studies show that both nicotine and nicotinic acetylcholine receptors (nAChRs) play crucial roles in cancer cell survival, proliferation, migration, invasion and angiogenesis. In particular, alpha 7-nAChR is the main subunit mediating the effects of nicotine in lung carcinogenesis. Here we report that BCX suppresses cancer cell motility and angiogenesis by inhibiting the expression of alpha 7-nAChR and its mediated PI3K pathway in vitro. Similar to MG624, an alpha 7-nAChR-specific antagonist, BCX significantly inhibited migration and invasion of alpha 7-nAChR positive lung cancer cells and endothelial cells in both transwell and wound healing assays, but both MG624 and BCX were inactive in alpha 7-nAChR negative cells. Moreover, BCX and MG624 were synergized in suppressing cell migration due to the fact that BCX, but not MG624, is effective at suppressing alpha 7-nAChR at both mRNA expression and protein levels. Furthermore, the inhibition of cell migration by BCX was attenuated in PTEN-deficient U87MG cells or MCF-7 cells which express constitutively active PI3K. BCX also effectively inhibited nicotine and PNU282987, an alpha 7-nAChR-specific agonist-stimulated cell migration, endothelial cell tube formation and microvessel outgrowth in an aortic ring model. Immunocytochemistry analysis showed that BCX effectively suppressed actin reorganization, lamellipodia and stress fiber formation induced by overexpression of wild type PI3K downstream molecules Rac and Rho, while constitutively active Rac and Rho attenuated the inhibition of cell migration by BCX. Moreover, BCX suppressed activities of matrix metalloproteinase (MMP)-2 and MMP9, two downstream molecules of alpha 7-nAChR/PI3K. Conclusively, these data demonstrate that BCX can inhibit cancer cell motility and angiogenesis by suppressing alpha 7-nAChR expression and its downstream PI3K pathway. This could be one of the potential mechanisms for the chemopreventive effect of BCX against lung cancer (Supported by NIH R01CA104932).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1394. doi:10.1158/1538-7445.AM2011-1394
Abstract 1398: IFIT2 depletion promotes migration through atypical PKC signaling in oral squamous cell carcinoma
Authors: Lai Kuo Chu , Liu Chung Ji , Lee Te Chang 
Published: June 2012

Abstract
Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is one of most responsive interferon-stimulated genes to interferons, viruses, and a variety of agents. However, the biological functions of IFIT2 are poorly understood. Our previous study showed that IFIT2 overexpression was frequently found in tumor tissues of oral squamous cell carcinoma (OSCC). Besides, enhanced IFIT2 expression was inversely associated with poor patient survival. In cultured cell system, we demonstrated that depletion of IFIT2 expression in OSCC cell lines significantly enhanced the motility of cells. In this study, experiments were conducted to explore the underlying mechanisms by which IFIT2 depletion enhanced migration of OSCC cells. We first established stable IFIT2 knockdown and non-silencing control cells by lentivirus transduction system. Our results showed that stable IFIT2 knockdown cells displayed elongated spindle-like morphology, F-actin reorganization, and loss of epithelial markers, such as E-cadherin and keratin 18, as compared to control cells, suggesting the involvement of IFIT2 in epithelial-mesenchymal transition and F-actin cytoskeleton organization. While stable IFIT2 knockdown cells exhibited enhanced cell motility and invasion as compared to control cells, we found that PI3K/Akt or PKC inhibitors significantly inhibited migration of stable IFIT2 knockdown OSCC cells. Notably, PKCζ pseudosubstract significantly abolished IFIT2 depletion-induced migration. Furthermore, atypical PKC phosphorylation (Thr410/403) was enhanced in IFIT2-silencing cells compared to that of control cells. Furthermore, among 25 metastatic OSCC patients, the median survival was 57.4 months in patients expressed high levels of IFIT2 (IFIT2 ≥ 50), whereas the median survival drastically reduced to 13.6 months in patients expressed low IFIT2 (IFIT2 &lt; 50). Taken together, our results revealed that atypical PKC signaling may involve in enhanced migration of IFIT2 knockdown OSCC cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1398. doi:10.1158/1538-7445.AM2011-1398