bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 699: Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti-Trop-2 antibody
Authors: Santin Alessandro D. , Cocco Emiliano , Varughese Joyce , Richter Christine E. , Casagrande Francesca , Bellone Stefania , El-Sahwi Karim , Bellone Marta , Todeschini Paola , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter E. , Rutherford Thomas J. , Pecorelli Sergio 
Published: February 2011

Abstract
Purpose:
To evaluate the expression of human trophoblast cell-surface marker (Trop-2) and the potential of hRS7, a humanized monoclonal anti-Trop-2 antibody, as a novel therapeutic strategy against Uterine Serous Papillary Carcinoma (USPC), a biologically aggressive and chemotherapy resistant variant of endometrial cancer.
Methods:
Trop-2 expression was evaluated by real time-PCR and flow cytometry in six primary uterine serous papillary carcinoma cell lines recently characterized in our laboratory. Sensitivity to hRS7 antibody-dependent-cellular-cytotoxicity (ADCC) was tested in standard 5-hrs 51Cr release-assays against primary USPC cell lines expressing different levels of Trop-2. Finally, to investigate the effect of interleukin-2 (IL-2) on hRS7-mediated ADCC, 5-hrs 51Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50-100 IU/ml).
Results:
Trop-2 mRNA transcript was significantly overexpressed in 3 out of 6 USPC primary cell lines when compared to normal human endometrial-cells (NEC) [p=0.005]. Consistent with RT-PCR data, high surface expression of Trop-2 was detected by flow cytometry in Trop-2 overexpressing cell lines [i.e., percentage of positive cells = 100% in all 3 positive cell lines, median (minimum-maximum) MFI (mean fluorescence intensity) of 184.2 (62.5-276.2)]. Importantly, while these USPC cell lines were found highly resistant to natural killer dependent cytotoxicity in the absence of the hRS7 antibody (range of killing 1.1% to 12.4%), they showed high sensitivity to hRS7-mediated ADCC in vitro (range of killing 28.2% to 64.4%) (P&lt; 0.001). Incubation with IL-2 in addition to hRS7 further increased the cytotoxic activity against USPC cell lines overexpressing Trop-2 (p= 0.01).
Conclusion:
Primary USPC cell lines may overexpress Trop-2 at mRNA and protein level and are highly sensitive to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel, potentially highly effective therapeutic strategy in patients harbouring advanced, recurrent or metastatic USPC refractory to standard treatment modalities.
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 699.
Abstract 70: Mitochondrial localization of adiponectin receptor 1 (AdipoR1) induces apoptosis in cancer cells
Authors: Lu JianPing , Hou ZheFeng , Beatty Laura K. , Pinthus Jehonathan H. 
Published: February 2011

Abstract
INTRODUCTION
Previous studies by us and others demonstrated tumor suppressive effects of adiponectin, an adipocyte derived hormone. Adiponectin signaling occurs through two distinct membrane receptors; AdipoR1 and AdipoR2. There is paucity of data how their activation leads to tumor suppression. Here we present data indicating localization of AdipoR1 to the mitochondria and its role in apoptosis of cancer cells.
MATERIALS AND METHODS
Human kidney (RCC1932) and cervical (HeLa CCL-2) cancer cells as well as human embryonic kidney cells (HEK 293) were used as models. Full length AdipoR1 and its N-terminal (ligand binding) and C-terminal (intracellular moiety) truncated mutants (mutAdipoR1) ORFs were subcloned into YFP expressing vectors (pEYFP- AdipoR1, pEYFPmutAdipoR1). Cells were seeded onto glass cover slips in multi-well culture plates and transfected with vectors through Lipofectamine-2000 (Invitrogen) method 24 h after seeding. The effect of adiponectin (BioVendor) supplementation was also tested. Immunocytochemistry staining were with MitoTracker labeling or anti-MnSOD (mitochondria), anti-Stearoyl-CoA desaturase (SCD-1, ER), anti-Reb5, anti-manose-6-phosphatase receptor (M6P, endosome); or anti-Catalase (peroxisome). Images of the cells were collected with DM IRB Deconvolution Microscope (Leica) or Confocal microscope LSM510 (Carl Zeiss). Apoptosis was determined by sub-diploid population detection and or annexin binding using flow cytometry.
RESULTS
Over-expression of AdipoR1 in the cells induced apoptosis which was further augmented by adiponectin treatment. This was evident only in cells expressing full length AdipoR1. Furthermore, cells expressing mutAdipoR1 had different intracellular distributions with loss of mitochondrial localization of the receptor and pro-apoptotic activity.
CONCLUSIONS
This is the first report showing that AdipoR1 can be localized in the mitochondria. Adiponectin induce apoptosis in cancer cells through mitochondrial localization related mechanism that requires both ligand and signaling domains of AdipoR1.
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 70.
Abstract 705: Crosstalk with stromal fibroblasts contributes to EGFR inhibitor resistance in colorectal cancer cells
Authors: Liska David , Chen Chin-Tung , Ding Pei-Rong , Weiser Martin R. 
Published: February 2011

Abstract
The mechanism for resistance to EGFR targeted therapies in colorectal cancer (CRC) with intact KRAS is still unknown. Host stromal cells contribute to tumorigenicity; however their effect on the sensitivity to EGFR targeted therapies has still to be determined. We hypothesized that crosstalk between stromal fibroblasts and CRC cancer cells contributes to cetuximab resistance via activation of the HGF/MET axis.
Primary CRC associated fibroblasts (CAFs) were isolated and expanded from five surgical specimens. Fibroblasts were enriched by magnetic activated cell sorting (MACS®) and activated fibroblast lineage was confirmed by alpha smooth muscle actin (SMA) immunofluorescence. Supernatant HGF content and cellular mRNA expression levels in primary CRC CAFs, an embryonic lung fibroblast cell line (MRC-5), and a normal colon fibroblast cell line (CCD18) were determined by ELISA and quantitative RT-PCR. The effect of fibroblasts or HGF (75ng/ml) on the CRC cell lines LIM1215 and DiFi treated with cetuximab (5nM) for 72 hours was determined by co-culture using Transwells and WST-1 cell proliferation assays. Alterations in proliferation were compared by ANOVA.
Mean fibroblast HGF secretion (8.3 ng/ml) and relative mRNA expression (2.0) could be augmented by co-culture with conditioned media (CM) from the CRC cell LIM1215 (14.1 ng/ml and 4.1, respectively) (Table). Further, co-culture of CRC cells with HGF, CCD18 cells, or primary CAFs reversed cetuximab-induced growth inhibition. LIM1215 proliferation was inhibited by cetuximab (55.3 ± 14.4%) which could be reversed by co-culture with either HGF (93.1 ± 10.2%) or CCD18 cells (107.2 ± 10.8%) (p&lt;0.01 for both).
Stromal-tumor interactions may play an important role in CRC resistance to cetuximab via the HGF/MET axis. Inhibition of both EGFR and MET may be necessary to realize the full potential of EGFR targeted therapies in CRC.Supernatant HGF levels and relative mRNA expression in fibroblasts treated with LIM1215 CM LIM1215 (Control)MRC5CCD18CAF3CAF4CAF5CAF6HGF (ng/ml) Ctrl&lt;0.11.217.310.97.24.08.9LIM1215-CM&lt;0.10.840.015.08.45.015.5 HGF mRNA Ctrl00.81.82.63.01.6 LIM1215-CM01.07.65.44.91.8
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 705.
Abstract 708: A novel hedgehog signaling inhibitor blocks hedgehog-mediated carcinogenesis
Authors: Xie Jingwu , Fan Eric Qipeng , Schelgel Chelsea , Zhang Xiaoli , Garrisson Massound , He Miao 
Published: February 2011

Abstract
The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. We have developed a novel hedgehog signaling inhibitor Cyc-T, which has better solubility and higher efficacy in inhibiting hedgehog signaling. In analyses of motor neuron differentiation and osteoblast differentiation, we found that Cyc-T is very effective in preventing hedgehog-mediated functions. Using a mouse model based on keratin 14 promoter-driven expression of an activated form of SMO, SmoM2, we found that a cyclopamine derivative cyc-T are effective in shrinkage of Smo-mediated tumors. K14cre/R26SMOm2yfp mice develop skin dysplasia on postnatal day 3 and BCC-like tumors by day 15. We performed topical application of cyclopamine or its derivatives CPA006, Cyc-T on the skin of K14cre/R26SMOm2yfp mice daily for seven days with the solvent ethanol as the control. The effects of these reagents on the tumors were examined by histological examination of skin biopsies and expression of Hh target genes. In comparison with the control group, we found that 6 out of 9 mice treated with cyclopamine reduced tumor mass and decreased expression of Hh target genes. The mice with no effects by cyclopamine and its derivatives had no changes in Hh target gene expression. In an orthotopic mouse model of pancreatic cancer, we measured the tumor progression following drug treatment and obtained promising results. Taken together, we discovered that Cyc-T are an effective inhibitor for Hh signaling-mediated carcinogenesis.
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 708.
Abstract 716: CXCR4 antagonist, CTCE-9908, inhibits PC-3 cell invasiveness and metastasis
Authors: Chinni Sreenivasa R. , Kandagatla Pridvi , Wong Donald , Korz Walter 
Published: February 2011

Abstract
Chemokines and their receptors function in the migration and homing of cells to target tissues. Current evidence suggests that cancer cells activate chemokines and their receptors during dissemination and metastasis formation at secondary sites. Previously, in prostate cancer cells, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 induced signaling events leading to MMP-9 expression, migration and invasion. CXCL12/CXCR4 transactivation of epidermal growth factor family receptors in lipid raft membrane microdomains on cell surface mediates these invasive signaling events and subsequent expansion of the skeletal metastatic deposits. Herein, we tested the efficacy of CXCR4 antagonist CTCE-9908 in prostate cancer cell growth, invasion, and metastasis. Methods: We used in vitro growth and invasion assays and in vivo orthotopic model system to asses the tumor growth and metastasis. Results: We found that (a) CTCE-9908 treatment resulted in no significant change in the growth of PC-3 cells; (b) CTCE-9908 compound at 50 μg/ml inhibited CXCL12 mediated invasion of PC-3 cells; (c) in vivo CTCE-9908 compound did not significantly altered the growth of primary tumors as measured by calipers and (d) the total tumor burden in the animal including the growth of prostate and soft tissue metastases to lymph node and distant organ tissues were significantly decreased upon CTCE-9908 administration. Histological analysis showed that CTCE-9908 treatment resulted in tumor necrosis in primary prostate tumors. Conclusions: These data suggest that CXCR4 inhibition by CTCE-9908 compound decreased the invasive signaling and metastatic spread of tumor cells without apparently affecting the primary tumor growth in animal model. Hence, CTCE-9908 is an efficacious antagonist for CXCL12/CXCR4 signaling pathway mediating invasive spread of tumor cells in secondary metastasis formation. Studies of CTCE-9908 in phase II are planned.
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 716.
Abstract 717: The diterpenoid lactone andrographolide (andro) induces apoptosis in all- trans-retinoic-acid (ATRA) resistant acute promyelocytic leukemia (APL) cell lines: Potential therapeutic implications
Authors: Yang Shuo , Evens Andrew M. , Prachand Sheila , Singh Amareshwar T.K. , Bhalla Savita , Platanias Leonidas , Gordon Leo I. 
Published: February 2011

Abstract
Andro is a diterpenoid lactone isolated from Andrographis paniculata, an important herbal medicine used in Asia to treat a range of diseases, (respiratory infection, fever, diarrhea). Andro is the major bioactive component extracted from Andrographis paniculata. The three hydroxyls at C-3, C-19 and C-14 are responsible for its biological activities. Recently, the anti-cancer properties of Andro have been recognized, and we found that Andro results in mitochondrial-mediated apoptosis in lymphoma cell lines and fresh malignant cells from patients with lymphoma. Based on the mechanism of action of this novel diterepenoid lactone and a prior report (Manikam et al Journal of Pharmacy and Pharmacol 2009, 61:69), we hypothesized that Andro may have activity in APL. The cell differentiation inducing agent all-trans retinoic acid (ATRA) combined with chemotherapy has become standard first-line treatment for APL through a mechanism that involves cell differentiation, but recent data suggest that ATRA alone or ATRA and arsenic trioxide, which induces apoptosis by degradation of the chimeric fusion protein PML-RARα, may replace ATRA/chemotherapy as initial treatment. Because Andro appears to work through a different mechanism than ATRA, we utilized ATRA-sensitive NB4, ATRA-resistant NB4 (NB4-007/6 and NB4-306) cell lines to test the in-vitro anti-leukemia effect of Andro on APL cells by measuring cell viability (MTT assay), apoptosis (Annexin V-FITC/PI, FACS), mitochondrial membrane potential (MMP) (TMRE/ FACS), cell differentiation (CD11B staining/FACS) and signaling pathways (Western blot). We found that Andro reduced APL cell viability, MMP and increased apoptosis in a time & dose-dependent manner. Moreover ATRA-resistant NB4-007/6 or NB4-306 cell lines were more sensitive to Andro compared with the ATRA-sensitive NB4 cell line. We found that the mechanism of Andro activity is not related to cell differentiation as measured by CD11b. In order to interrogate signaling pathways involved, we studied p27kip1 and FasL expression and found that Andro resulted in up-regulation of both. One of the forkhead box O (FOXO) proteins, FOXO1, a transcription factor, also demonstrated increased phosphorylation at Thr24 at 1h, 3h, and 24h Andro, but reduced phosphorylation at Thr24 at 6h and 16h. Taken together, these data suggest that Andro may have activity in patients with ATRA-resistant APL by a mechanism of action that is distinct from ATRA. Thus, further studies of diterpenoid lactones in APL are warranted.
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 717.
Abstract 726: Targeting the extracellular and intracellular interfaces of CXCR4
Authors: Meier Jason B. , Jala Venkatakrishna R. , Bodduluri Haribabu , Trent John O. 
Published: February 2011

Abstract
CXCR4 is a G protein coupled receptor that has multiple critical functions in normal and pathologic physiology that include regulation of the metastatic behavior of mammary carcinoma, and utilization as a coreceptor for infection by T-tropic strains of HIV-1. We have targeted CXCR4 via an interdisciplinary approach including molecular dynamics simulations of partial and fully constitutively active, and inactive forms of CXCR4 performed in a solvated lipid bilayer to reproduce the microenvironment of this integral membrane protein. We have discovered that it is the partially activated form that can interact with the G-protein complex. We have used in silico virtual screening to select possible CXCR4 inhibitors. Two sites were chosen to disrupt CXCR4 function. The extracellular site was targeted to interfere with the natural ligand for CXCR4, SDF-1. The intracellular site was targeted to interfere with the G-protein: CXCR4 interface. The ranked lists of compounds were tested for their ability to alter chemotaxis, an in vitro model for metastasis, and calcium flux, a measure of CXCR4 signaling capability. Several small molecules were found to inhibit these functions of CXCR4. The presented approach combines computational studies with molecular biological data and provides a powerful tool in the search for new inhibitors.
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 726.
Abstract 727: Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a diaryl template
Authors: Woo L. W. Lawrence , Jackson Toby , Putey Aurelien , Cozier Gyles , Leonard Philip , Acharya K. Ravi , Chander Surinder K. , Purohit Atul , Reed (Deceased) Michael J. , Potter Barry V. l. 
Published: February 2011

Abstract
Designing single agents that act against multiple biological targets are of increasing interest and prominence. In recent years, an increasing volume of work has been published exemplifying the successful use of this strategy. Estrogen deprivation has been an effective therapeutic intervention for hormone-dependent breast cancer (HDBC). One established and clinically proven approach involves the inhibition of the aromatase enzyme, although the inhibition of steroid sulfatase (STS) is an emerging new strategy as demonstrated by the promising results of STX64 (BN83495),1 the first STS inhibitor that entered clinical trials. While both aromatase and STS are targets for treating HDBC, it is reasoned that estrogen deprivation may be more comprehensively achieved by dual inhibition of both enzymes. To this end, the reversible aromatase inhibitory pharmacophore, which is principally a heme-ligating nitrogen-containing heterocycle, was thus introduced into a known sulfamate-based STS inhibitor to give a series of dual aromatase-sulfatase inhibitors (DASIs). Several compounds were found to be good aromatase or STS inhibitors individually. However, two compounds show exceptional dual in vitro potency in JEG-3 cells, inhibiting aromatase with IC50 values of 0.5 and 2.0 nM, and STS with IC50 values of 5.5 and 35 nM. Both compounds share the common structural feature of having a sulfamate group on one aryl ring, and a heterocycle and a H-bond acceptor on the other. At 1 mg/kg p.o., both DASIs reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. One of the compounds was found to be non-estrogenic and potently inhibit human carbonic anhydrase II (hCAII IC50 = 86 nM). A complex of hCAII with the inhibitor was crystallized and solved by X-ray crystallography. This class of DASI should encourage further development towards multi-targeted therapeutic intervention in HDBC.
Ref 1: a) Stanway, S. J. et al. Clin. Cancer Res. 2006, 12, 1585-1592. b) Stanway, S. J. et al. Oncologist 2007, 12, 370-374.
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 727.
Abstract 73: Mitochondrial 10-formyltetrahydrofolate dehydrogenase: A novel enzyme in folate metabolism
Authors: Dubard Marianne E. , Strickland Kyle C. , Oleinik Natalia V. , Krupenko Natalia I. , Krupenko Sergey A. 
Published: February 2011

Abstract
Cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH, Aldh1L1) is an important regulator of intracellular folate pools, which displays antiproliferative effects in cancer cells. We have identified a gene at the chromosome locus 12q24.11 in the human genome, the product of which has 87% sequence similarity with cytosolic FDH. This protein has an extra amino-terminal sequence of 22 amino acid residues enriched in arginines, which is predicted to be a mitochondrial translocation signal. The mitochondrial targeting function of the leader has been confirmed in Cos7 cells: green fluorescent protein (GFP)-tagged at the amino-terminus with the leader, localizes to mitochondria. Transfection of Cos7 or A549 cell lines with a construct, in which GFP has been introduced between the leader sequence and the rest of the putative mitochondrial FDH (mtFDH), has also shown mitochondrial localization, suggesting that the identified gene encodes a mitochondrial enzyme. To evaluate the abundance of mtFDH, we have measured its mRNA levels in a wide array of human tissues by real-time PCR, and compared them to the levels of mRNA that encode cytosolic FDH. While cytosolic FDH mRNA is highest in liver, kidney and pancreas, mtFDH mRNA is most highly expressed in pancreas, heart and brain, but not in liver or kidney. In contrast to the cytosolic enzyme, which is non detectable in human cancer cell lines, the presence of mtFDH mRNA was demonstrated in A549 and PC3 cells by conventional and real-time PCR. The presence of the endogenous enzyme in mitochondria of A549 cells has been further confirmed using specific polyclonal antibody generated against purified recombinant mtFDH. We have also shown that recombinant mtFDH, similar to the cytosolic enzyme, catalyzes NADP+-dependent oxidation of the 10-formyltetrahydrofolate to tetrahydrofolate and CO2. Thus, the enzyme is a likely source of CO2 production in mitochondria and we propose that it plays an essential role in distribution of one-carbon groups between cytosolic and mitochondrial compartments of the cell.
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 73.
Abstract 730: Targeting colchicine binding site in tubulin for the treatment of advanced melanoma
Authors: Li Wei , Wang Zhao , Chen Jianjun , Lu Yan , Li Chien-Ming , Dalton James T. , Miller Duane 
Published: February 2011

Abstract
Inhibition of tubulin dynamics has been a fruitful drug target for cancer treatment. Out the three ligand binding sites in tubulin, drugs targeting taxane binding site (e.g. taxol and epithilones) and vinca alkaloids binding site (e.g. vinblastine) are clinically very successful drugs. However, no FDA-approved cancer drugs targeting the colchicine binding site in tubulin currently exist. In our ongoing efforts to search for effective drugs for the treatment of advanced melanoma that are highly resistant to all existing cancer treatment, we have discovered a new class of compounds that are not substrates of P-glycoprotein (Pgp) and are highly efficacious against human melanoma tumors in A375 xenograft models. At relatively low doses (5∼15 mg/kg), these compounds inhibit melanoma tumor growth more effectively than DTIC (the gold standard drug for advanced melanoma) at 60 mg/kg. Extensive biological and molecular modeling studies suggest that these compounds work by competitively binding to the colchicine site in tubulin. Further optimization of these compounds hold great promise in providing an effective agent for the treatment of advanced melanoma.
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 730.