bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1366: Computer-modeled novel cancer targeting peptides for therapy and imaging
Authors: Wang Sheng-Hung , Chen I-Ju , Chang Nai-Chuan , Wu Han-Chung , Yu Alice L. , Yu John 
Published: June 2012

Abstract
We have recently developed practical software programs for optimization of cancer targeting peptides, including combinatorial construction of 3D peptide library (Buildpep), binding pocket analyzer (PscanMS) and high accuracy protein-ligand scoring program (HotLig). Based on these programs, a strategy of structure-based optimization of cancer targeting peptides in silico is developed to target human GRP78 which consists of 654 amino acids. The homology modeling of human GRP78 was constructed through aligning amino acid sequence and 3D structure with its homologs. This protein contains two major structural domains, the peptide-binding domain and the ATPase. Based on the results from the molecular modeling, new peptide analogs were designed and examined for optimized binding to the targeted GRP78 through in silico analysis. We had thus delineated the pharmacophore description of binding motif targeting peptide-binding domain of GRP78 as Pro-X1-Leu-X2. Peptides possessing this motif can be applied in cancer-targeted drug delivery system. We have thus designed several new tumor-targeted peptides [P-12, P-13, and P-6]. Their ability to bind target protein was confirmed in subsequent in vitro binding through Biacore analysis. We next examined their capacity to target cancer cells in the in vitro binding with various cancer cells, and in vivo tumor imaging and targeted chemotherapeutic studies. The results indicate that these peptides exhibit promising therapeutic potential by their selective binding to cancer cells, but not normal cells. Notably, these peptide analogs can bind to breast cancer stem cell (CSC) population in xenografts of primary breast cancer suggesting that they can target breast CSC enriched subpopulation. The microSPECT/CT molecular imaging of a primary human breast tumors, BC0244, xenograft with 188Re-liposome-PEG-P12 or P13 peptide showed significantly more uptake of radioactivity as compared to 188Re- liposome-PEG-L-peptide in the BC0244 breast tumors in NOD/SCID mice at 6, 24 and 48 h after intravenous injection, and even greater difference was found as compared to that of 188Re-liposome alone. To further compare P12 labeled liposome with L-peptide labeled liposome for therapeutic efficacy, mice bearing BC0244 xenografts were distributed into 4 groups for treatment with P12-Lipo-Dox, L-peptide-Lipo-Dox, Lipo-Dox, and PBS. The tumor growth of P12-lipo-Dox group was 1.57-fold slower than that of the L-peptide group; both of them showed significant increase in the therapeutic efficiency than Lipo-Dox control. These optimized cancer targeting peptides may be useful for imaging and targeted therapy of cancers.
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 1366. doi:10.1158/1538-7445.AM2011-1366
Abstract 1367: Substituted Pyrimido[4,5-b]indoles with single agent combination chemotherapeutic potential
Authors: Gangjee Aleem , Zaware Nilesh , Kisliuk Roy L. , Ihnat Michael A. 
Published: June 2012

Abstract
Combinations of cytotoxic agents with antiangiogenic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We previously identified two compounds with a 5-(thioaryl)-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor-beta (PDGFR-β) for antiangiogenic effects and remarkably also inhibit human thymidylate synthase (hTS) for cytotoxic effects. In a COLO-205 xenograft mouse model one of these analogs demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. Thus, these compounds afford combination chemotherapeutic potential in single agents. In an effort to optimize the structural requirements for antiangiogenic effects and hTS inhibition, six additional compounds were synthesized. Electron withdrawing (3,4-diClPh, 4-ClPh), electron donating (2,5-diOMePh, 4-OMePh) and bulky (1-naphthyl, 2-naphthyl) thioaryl groups in the 5-(thioaryl)-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold were selected to establish optimum activity. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-bromo-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. A novel four step synthetic scheme to the common intermediate was developed which is more efficient relative to the previously reported six step synthesis. Biological evaluation of these compounds in various RTKs indicated that in the VEGFR-2 assay the 2,5-diOMePh substituted compound was equipotent to the standard SU5416 used in this assay. In the hTS assay, the 2-naphthyl, 4-OMePh, and 4-ClPh substituted compounds were nanomolar inhibitors and were 3-fold better than or equipotent to the standard TS inhibitor raltitrexed.
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 1367. doi:10.1158/1538-7445.AM2011-1367
Abstract 1368: Fragment-based design, synthesis and biological evaluation of a series of novel PDK1 inhibitors
Authors: Sharma Sunil , Venkataswamy Sorna , Warner Steven L. , Call Lee T. , Bearss David J. , Vankayalapati Hariprasad 
Published: June 2012

Abstract
The PDK1 is a monomeric serine/threonine kinase and a promising oncology target of significant current interest for drug development due to its central role in the PI3K/AKT/mTOR pathway. It phosphorylates highly conserved Ser or Thr residues in the activation loop of several AGC super family kinases including PKC, SGK, PKB/Akt, p70S6K, and PDK-1 itself. Approximately, 40-50% of all tumors involve mutations in the PTEN protein, which results in elevated levels of PIP3 and enhanced activation of PKB/AKT, p70S6K, and SGK. It has been proposed that inhibitors of PDK-1 could provide a valuable therapeutic approach to targeting cancer, particularly those with PTEN deficiencies. Using a fragment-based design strategy, we screened a collection of 1100 low molecular weight (&lt; 250 MW) fragments against the PDK1 kinase and identified 9 fragments with moderate inhibitory activity against PDK1 (IC50 values from 45-82 μM).
Of these fragments, those based off of a 5-Br,4-I-1H-indazol-3-amine scaffold seemed the most promising based on initial activity and in keeping with the “rule of 3” for fragment-based drug design. Subsequent molecular docking studies using a crystal structure of PDK1 allowed for the structural rationalization of how these fragments bound in the ATP-binding pocket (hydrogen bonding to S160/A162 hinge residues) and provided insight for further optimization. Concurrently, we carried out scaffold-hopping searches at 2-site points for hydrophobic and solvent pocket fragments. With the addition of one fused heterocyclic ring, the potency increased to 8.8 and 10.9 μM. Our systematic fragment based workflow led to the preparation of target molecules in 4 steps beginning with the condensation, cyclization, and reduction and finally installing the hydrophobic binding site fragments under normal amide coupling. Subsequent SAR and follow-up screening led to the discovery of HCI-1680, a potent PDK1 inhibitor with an IC50 of 97 nM. Additional productive interactions sites with PDK1 were introduced to further improve both biochemical and cellular activities in panel of cancer cells. In cell-based assays HCI-1680 demonstrated enhanced activity in PTEN-deficient cell lines compared to PTEN-wild type lines. HCI-1680 and additional compounds from this series were also shown to inhibit the activation of AKT and other downstream signaling molecules. Kinase selectivity profiling, additional cell-based assays, and animal studies are ongoing. The details of these studies will be presented.
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 1368. doi:10.1158/1538-7445.AM2011-1368
Abstract 1372: A cell based high throughput screening assay for inhibitors of melanoma with high S100B
Authors: Wilder Paul T. , Gianni Kira , Green Deborah L. , Weber David J. 
Published: June 2012

Abstract
The calcium regulated S100B protein is over-expressed in many cancers including malignant melanoma where high levels of S100B correlate inversely with patient survival. It has been shown that increased S100B is not only a marker for cancer but may promote tumor survival by directly affecting the activity of several cell signaling proteins. For example, S100B has been shown to bind wild-type p53 in a calcium-dependent manner, sequestering it, and resulting in the loss of p53-dependent tumor suppression activities, and transient knockdown of S100B with siRNA has been shown to reverse this affect in melanoma cell lines. Therefore, the discovery of compounds that specifically inhibit the growth of melanoma cells with high levels of S100B may provide a useful therapeutic strategy. We have developed a cell based high throughput screening assay where the effect of small compounds on the growth of MALME-3M and WM115 melanoma cells with a stable shRNA to knockdown S100B is compared to the isogenically matched cell control containing a stably expressing a scrambled shRNA. Out of the greater than 15,000 compounds screened many inhibited growth of the melanoma cells, some had selectivity inhibiting the growth of the S100B high cells, and inversely high S100B was found to overcome the growth inhibition caused by several compounds. Previously, many S100B inhibitors found using an in vitro screening assay were found to function by chemically modifying Cys84 in S100B, so S100B might act as a sink to sequester some of the cysteine reactive compounds protecting cells from these compounds in some cases.
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 1372. doi:10.1158/1538-7445.AM2011-1372
Abstract 1396: Bradykinin enhances cell migration in human prostate carcinoma cells via bradykinin B2 receptor, PKCdelta, c-Src and NF-kappaB signaling pathways
Authors: Yu Hsin-Shan , Tang Chih-Hsin 
Published: June 2012

Abstract
Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. In addition, bradykinin has been found in many tumor cell lines and has been shown to be involved in carcinogenesis and cancer progression. Prostate cancer is the most common cancer excluding skin cancer in men and usually metastasizes to the particular organs in the late stages of cancer processes. The matrix metalloproteinase (MMP) play an important role in tissue remodeling associated with various physiological and pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis and metastasis. In this study, we found that bradykinin increased the migration and the expression of MMP-9 in human prostate cancer cells (PC3,DU145 and LNCaP). Bradykinin-mediated migration and matrix MMP-9 up-regulation was attenuated by bradykinin B2 receptor antagonist (HOE140), protein kinase Cdelta (PKCdelta) inhibitor (Rottlerin), c-Src inhibitor (PP2), NF-kappaB inhibitor (PDTC), and IkappaB protease inhibitor (TPCK). Transfection of cells with bradykinin B2 receptor and protein kinase Cdelta (PKCdelta), siRNA or dominant-negative mutant of c-Src, IkappaBalpha kinase alpha(IKK alpha) and IkappaBalpha kinase beta(IKK beta), also inhibited the potentiating action of bradykinin. Stimulation of PC3 cells with bradykinin induced PKCdelta, c-Src, IKK alpha/beta, IkappaB and p65 phosphorylation, and kappaB-luciferase activity. In addition, BKR2 PCKdelta and c-Src pathways are involved in bradykinin-induced NFkappaB activation. Taken together, our results suggest that bradykinin enhances the migration of prostate carcinoma cells by increasing MMP9 expression through the bradykinin B2 receptor /PKCdelta/c-Src/NF-kappaB signal transduction pathways.
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 1396. doi:10.1158/1538-7445.AM2011-1396
Abstract 1400: Inhibition of cell migration by the synthetic triterpenoid acetylenic tricyclic bis-(cyano enone)
Authors: Chan Eddie , Guglielmo John Di 
Published: June 2012

Abstract
Triterpenoids are a family of naturally occurring compounds that have multiple anti-tumorigenic effects, including the ability to induce cell differentiation, apoptosis and inhibit proliferation. Research in our lab has demonstrated that a synthetically derived 5 ring triterpenoid, 2-cyano-3, 12-dioxooleana-1,9-dien-28-oic acid-imidazolide (CDDO-Im), inhibits cell migration (To et al., 2008, J. Biol. Chem. 283:11700), which is essential in numerous physiological processes including tumor metastasis. Recently, a smaller 3 ring compound containing the same active functional groups as CDDO-Im has been derived; acetylenic tricyclic bis-(cyano enone) [(+/-)-(4aa,8aa,10ab)-1,2,4a,6,8a,9,10,10a-octahydro-8a-ethynyl-1,1,4a-trimethyl-2,6 dioxophenanthrene-3,7-dicarbonitrile] (TBE-31). Here we examined the effect of TBE-31 on cell migration. Using scratch assays with Rat2 fibroblasts we demonstrated that concentrations of TBE-31 above 0.75 µM were effective in inhibiting fibroblast migration. To elucidate the mechanism(s) for this inhibition we examined different components of the cytoskeleton and the polarity complex, which are both crucial for cell migration. To examine cell polarity, we used immunofluorescence microscopy to assess the localization of two proteins involved in the polarization of migrating cells, IQGAP1 and RAC1. Similar to CDDO-Im, TBE-31 was observed to reduce the elongation and polarity of cells, however unlike CDDO-Im, IQGAP1 and RAC1 in TBE-31 treated cells were localized in punctate fashion around the cell perimeter instead of at the leading edge. Using immunofluorescence imaging, the cytoskeleton of Mv1Lu mink lung cells or COS7 cells treated with TBE-31 were analyzed. The microtubule network of treated cells displayed a unique cross-hatched phenotype and were resistant to nocodazole depolymerization. In addition, the intermediate filament cytoskeleton was observed to retract towards the nucleus. Lastly, in vitro actin polymerization assays revealed that TBE-31 inhibits linear but not branched actin polymerization. We conclude that TBE-31 is an effective inhibitor of cell migration and further research will shed light on the mechanisms that TBE-31 uses to modulate the cell migration machinery.
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 1400. doi:10.1158/1538-7445.AM2011-1400
Abstract 1409: Overexpression of inhibitor of DNA (Id-1) correlates with the invasiveness of colon cancer cells
Authors: Pandey Ambarish , Oh Michael , Sengupta Shiladitya 
Published: June 2012

Abstract
Background: Id-1 gene expression has been shown to be involved in carcinogenesis in several types of human cancers. It belongs to a family of helix loop helix proteins that has been shown to induce cell proliferation, increase DNA synthesis and changes in gene expression to promote tumor growth and metastasis. In this Study we look into the expression of Id-1 in human colon cancer cell lines and its effect on the invasive potential of the cancer cells.
Methods: Id-1 gene expression in human colon cancer cell line HT-29 was analyzed by real time Polymerase chain reaction. The expression of Id-1 protein in colon cancer tissue array samples was examined by immunohistochemical assay and its relationship with the clincopathological staging of the tumor was analyzed. Id-1 gene knockdown was carried out in HT-29 cells using siRNA transfection and the knock down cells were subjected to matrigel invasion assay.
Results: A significant overexpression of id-1 gene was observed in the colon cancer cell line HT-29 as compared to normal epithelial cells. Immunohistochemical analysis showed that id-1 protein expression in malignant tissue was significantly more than the normal variant and there was a significant correlation between the degree of Id-1 expression and the stage of the colon cancer. Knockdown of Id-1 in the cancer cells significantly decreased the invasiveness potential in the matrigel after 72 hours as compared to the controls.
Conclusion: The level of id-1 expression is correlated to the malignant potential of colon cancer cells and its expression seems to be critical for the invasiveness and more aggressive behavior of the tumor 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 1409. doi:10.1158/1538-7445.AM2011-1409
Abstract 1412: Two-photon imaging of cancer cell extravasation in live mice
Authors: Digman Michelle A. , Aguilar Jose S. , Gratton Enrico , Suetsugu Atsushi , Hoffman Robert M. 
Published: June 2012

Abstract
MDA-MB-231 breast cancer cells were engineered to express cytoplasmic paxillin-GFP and nuclear H2B-mCherry. In order to image extravasation, the cancer cells were injected in the blood stream of nude mice. Using 2-photon excitation microscopy we can simultaneously excite the two probes and also visualize the autofluorescence of tissues. A skin flap was opened to visualize blood vessels and recognize the position of the cancer cells. Two-photon imaging showed that after an initial phase in which the cells are non-adherent, some cells spread on the internal surface of the capillaries. Days later some cells started to appear on the external side of the capillary. The extravasated cells extend very long protrusions into the tissue. The goal was to determine if at the end of the long protrusion, if it is possible to observe the formation of focal adhesions by imaging paxillin-GFP. Preliminary results show that when cells start to adhere to the blood vessel wall they form focal adhesions as determined by the characteristic elongated features observed in the paxillin-GFP channel. New approaches will allow the tracking of the tip of the protrusion to determine if focal adhesions are forming there as the cells extravasate. This is important in establishing the mechanism of cell extravasation and migration in tissues.
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 1412. doi:10.1158/1538-7445.AM2011-1412
Abstract 1414: Lysophosphatidic acid-induced Cyr61 is associated with prostate cancer progression
Authors: Terada Naoki , Zeng Yu , Kulkarni Prakash , Getzenberg Robert H. 
Published: June 2012

Abstract
Lysophosphatidic acid (LPA) is a serum phospholipid that has been associated with progression in several types of cancer. Cysteine-rich angiogenic inducer 61 (Cyr61) is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling. We have reported that Cyr61 expression in benign prostate cells is regulated by LPA (Endocrinology 2004). Furthermore that Cyr61 expression is significantly up-regulated in prostate cancer (PCa) and that the expression levels correlate with Gleason score (J Urol 2010). The aim of this study was to determine if LPA-induced Cyr61 up-regulation is associated with PCa progression. BPH1 was utilized as a benign prostate cell line and PC3 as a PCa cell line. In real-time PCR of untreated BPH1 and PC3 cells, Cyr61 expression ratios to TBP were 0.5 and 5.1, and these ratios after 2 hours of 1uM LPA under serum-free medium treatment were 1.8 and 44.3, respectively. These results indicated that the Cyr61 expression levels and their increase by LPA stimulation were higher in PCa cells than in benign prostate cells. To examine whether LPA promotes cell invasion, Matrigel invasion assays were performed for 72 hours with or without 1uM of LPA in the lower chamber. LPA stimulation increased the invaded cell number from 0.3±0.5 to 12.6±2.5 (p&lt;0.001) in BPH1 cells and from 31.9±20.9 to 55.2±14.8 (p=0.005) in PC3 cells. These results indicate that LPA promotes cell invasion in both benign prostate and PCa cells. To examine whether LPA-induced Cyr61 is associated with cell invasion, the Cyr61 was knocked down by siRNA in PC3 cells. Invaded cell numbers were changed by 48 hours of LPA stimulation after scramble siRNA from 2.2±1.3 to 12.3±10.2 (p=0.002) and after Cyr61 targeting siRNA from 1.8±2.6 to 2.7±2.7 (p=0.235), respectively, revealing that Cyr61 down-regulation suppresses LPA induced cell invasion. To investigate the association between Cyr61 up-regulation and prostate carcinogenesis, Cyr61 over-expressing BPH1 cells (BPH1-Cyr61) were established and their cell proliferation was compared with vector only transfected BPH1 cells (BPH1-mock) by MTS assays. The cell proliferation ratio of BPH1-mock and BPH1-Cyr61 cells after 48 hours of incubation in serum-free medium was 1.24±0.05 and 1.40±0.02 (p=0.043), respectively, indicating that Cyr61 over-expression promoted cell proliferation of BPH1 in vitro. In conclusion, LPA induced Cyr61 up-regulation was suggested to be associated with PCa progression.
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 1414. doi:10.1158/1538-7445.AM2011-1414