bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 711: VEGF121/rGel inhibits prostate cancer-induced osteoblastogenesis by targeting osteoblasts and tumor neovasculature
Authors: Mohamedali Khalid A. , Li Zhi Gang , Starbuck Michael W. , Wan Xinhai , Yang Jun , Kim Sehoon , Zhang Wendy , Navone Nora M. , Rosenblum Michael G. 
Published: February 2011

Abstract
Prostate cancer metastasis to bone usually produces bone-forming lesions although an osteolytic component is present in most cases. We have previously shown excellent efficacy against prostate cancer growth in bone in an osteolytic model (PC-3) with VEGF121/rGel, a chimeric fusion toxin of VEGF121 and the plant toxin gelonin (rGel) that targets VEGFR-1 and VEGFR-2. In the current study, we demonstrate that VEGF121/rGel systemic administration is also effective in a model of prostate cancer that displays the bone-forming phenotype when growing in the femurs of immunodeficient mice. Both murine osteoblast precursor (MC3T3) cells and primary mouse osteoblasts (PMOs) were shown to express VEGFR-1 but not VEGFR-2. VEGFR-1 mRNA expression was shown to down-regulate during osteoblast (MC3T3) differentiation. In vitro, treatment with VEGF121/rGel showed cytotoxicity against osteoblast precursor cells (IC50 = 15 nM) that was substantially reduced (IC50 &gt; 1000 nM) after MC3T3 had been allowed to undergo differentiation. This suggests that the effect of VEGF121/rGel is specifically mediated by VEGFR-1. Furthermore, immunofluorescence microscopy showed that internalization of VEGF121/rGel into PMOs is VEGF121-receptor driven. In an ex vivo model of osteoblastic disease, 100 nM VEGF121/rGel significantly inhibited prostate cancer-mediated new bone formation in neonatal mouse calvaria. In vivo, systemic (iv, tail vein) administration of VEGF121/rGel significantly inhibited growth of the osteoblastic prostate cancer cell line MDA PCa 118b growing intrafemorally. Only 25% of VEGF121/rGel-treated mice showed the development of osteoblastic lesions compared to 90% of saline-treated mice. Micro-CT (µCT) analysis of isolated femurs demonstrated that intrafemoral growth of MDA PCa118b tumors caused a dramatic increase in bone volume and that treatment with VEGF121/rGel restored the bone volume fraction to normalized levels with no changes to the uninvolved contralateral femurs. H&E results confirmed that the osteoblastic growth of 118b cells was severely impeded. Our results clearly demonstrate that VEGF121/rGel administration may suppress the eventual development of skeletal prostate tumors and may have significant therapeutic effect against prostate cancer-mediated osteoblastic lesions in bone. Research conducted, in part, by the Clayton Foundation for Research.
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 711.
Abstract 735: Synthesis of substituted 1,2,3,4-tetrahydroisoquinolines as anticancer agents
Authors: Redda Kinfe Ken , Gangapuram Madhavi NA , Ardley Tiffany W. 
Published: February 2011

Abstract
The 1,2,3,4-tetrahydroisoquinoline moiety is commonly found in biologically active molecules of either natural or synthetic origin, making its derivatives excellent candidates as potential pharmaceutical agents. The tetraydroisoquinoline family of alkaloids includes potent cytotoxic agents that display a range of biological properties such as antitumor and antimicrobial activities studied thoroughly over the past 25 years, starting with the isolation of naphthyridinomycin in 1974. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) is considered to be a possible endogenous anti-parkinsonism agent that is present in the mouse, rat, monkey and human brain. Therefore, the discovery of novel and safer anticancer drugs represents a challenging goal for our research program. In the current investigation, we synthesized a few analogs maintaining the tetrahydroisoquinoline moiety with modifications on the phenyl ring by introducing groups with various electronic, steric and lipophilic properties.
The starting material, 2-aminoisoquinoliniumiodide was obtained by the reaction of hydroxylamine-O-sulfonic acid, water, and isoquinoline after heating at 90 oC for 2 h. The reaction mixture was cooled to room temperature, potassium carbonate added, and the water was evaporated. Ethanol was added to the solid residue and the insoluble potassium sulfate was filtered out. Hydroiodic acid was added to the filtrate, and the resulting solution was placed in a freezer for overnight. The precipitate was filtered out, washed with ethanol, and dried in vacuo. The crude product was used for the next step without further purification. Reaction of the 2-aminoisoquinoliniumiodide with substituted benzoyl chlorides/benzenesulfonyl chlorides in anhydrous tetrahydrofuran containing triethylamine gave stable benzoyl/benzenesulfonyl imino ylides. This was followed by reduction with sodium borohydride in absolute ethanol, which furnished the target compounds, 1-(substituted benzoyl/benzenesulfonylamino)-1,2,3,4-tetrahydroisoquinolines. These compounds were evaluated for their in vitro anti cancer activity on MCF-7, MDA-MB-231 and Ishikawa breast cancer cell lines. The cytotoxicity activities of the compounds were tested using tomaxifen as a control. The 1-benzoyl amino-1,2,3,4-tetrahydroisoquinoline showed most potent cytotoxicity with an IC50 values 0.23, 0.63, 0.74 µg/mL on Ishikawa, MCF-7 and MDA-MB-231, respectively.
This research was supported by NIH/RCMI Grant # G12 RR03020 and Pharmaceutical Research Center NIH/NCRR Grant 1 C06 RR12512-01.
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 735.
Abstract 737: Modeling of σ2 selective agonists for the development of new anticancer agents that utilize the celecoxib scaffold
Authors: Kinder David H. , Rhoades Derek J. , Mahfouz Tarek 
Published: February 2011

Abstract
Celecoxib has proved to be an enigma as a potential anticancer agent. COX-2 inhibition is not necessarily involved in its mechanism of cytotoxicity, and it induces a non-classical apoptotic pathway leading to cell death in some cell culture models. Because the classical pathways are not always induced by celecoxib, we hypothesized that celecoxib might be working as a σ2 receptor agonist as part of its cytotoxicity. In addition, published research has supported the therapeutic potential of σ2 receptor agonists in cancer chemotherapy. We have determined that celecoxib will inhibit the CRL-1620 cell line with an IC50 of 32 μM, and the 9L rat glioma model with an IC50 of 60 μM. Using a group of 41 high affinity σ2 receptor selective agonists and following a ligand-based drug design approach, we have developed a four-site pharmacophore model for σ2 receptor agonists. Upon aligning celecoxib to this model, it matched three of the four sites, further supporting our hypothesis that celecoxib might be working as a σ2 receptor agonist as part of its cytotoxicity. Additional compounds have been developed utilizing the celecoxib scaffold as σ2 receptor agonist anticancer agents. From the pharmacophore model we also developed an in silico model for the σ2 receptor binding pocket as it has not been cloned nor has its three dimensional structure been determined.
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 737.
Abstract 739: Targeting pancreatic cancers with a quadruplex-binding small molecule
Authors: Hampel Sonja , Gunaratnam Mekala , de la Fuente Maria , Schatzlein Andreas , Neidle Stephen 
Published: February 2011

Abstract
We have previously reported on a novel series of tetra-aminoalkyl substituted naphthalene diimide compounds that bind to quadruplex nucleic acids and have high potency against a panel of human cancer cell lines. We now report on a further sub-set of derivatives with piperidino end-groups, which show high selectivity for human telomeric quadruplexes and only low-level binding to duplex DNA. These compounds are similarly potent in the cancer cell line panel, and also show potency against several pancreatic cancer cell lines, with typical IC50 values &lt; 0.1μM. Telomerase activity is decreased in these cells on compound exposure, together with long-term growth arrest; this behaviour is consistent with a telomere targeting mechanism of action. These compounds also have &gt; 40-fold selectivity over several normal fibroblast cell lines.
We report on preliminary in vivo studies in this series, using the pancreatic cancer MiaPaCa-2 xenograft model. Starting doses for the compounds have been established in a dose ranging study. The compounds are relatively well-tolerated at doses well above the IC50 values, suggesting a sufficient therapeutic window exists to explore their therapeutic potential. The compounds show evidence of anticancer activity in the form of growth delay when established MiaPaCa-2 xenografts were dosed once daily by intraperitoneal injection.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 739.
Abstract 741: Lactic acid, hyperacidic media, and hypoxia diminish 4-hydroxyanisole-induced toxicity in melanoma cell lines
Authors: Moridani Majid , Kudugunti Shashi , Samala Rama Krishna 
Published: February 2011

Abstract
Lack of in-vitro in-vivo correlation in drug efficacy is a major problem in anticancer drug discovery, which may be attributed to hypoxia and lactic acid production in tumor. In current work, we evaluated the effect of hypoxia, lactic acid and hyper-acidic condition on efficacy of 4-hydroxyanisole (4-HA) as an anti-melanoma prodrug in human SK-MEL-28 cells. Lactic acid concentrations and pH were determined in tumor and compared with liver, lung, kidney and serum in skin melanoma tumor model in mice.
The pH of tumor and blood was measured using pH meter. The lactic acids were measured by a microdialysis analyzer. Modular incubator chamber was used to maintain hypoxic condition. MTT assay was used for IC50 (48h) determination and cell viability measurement. Male C57BL/6 mice (n=3) were inoculated s.c. at right flank with 1×106 B16-F0 melanoma cells.
The pH of tumor and serum was 6.8-6.9 and 7.4-7.6, respectively, indicating that pH was significantly lower in tumor. The lactic acid concentrations in tumor increased from 10.8 to 19.4mM during day 8 through 13 post melanoma cell inoculation, whereas in serum, liver, lung and kidney remained within 5.5-7.8mM, 11.1-14.4mM, 3.5-6.9mM and 6.6-7.5mM, respectively. Normoxia results: The IC50 (48h) of 4-HA in SK-MEL-28 was 50µM. Lactic acid demonstrated a concentration dependent toxicity towards melanoma cell lines with an IC50 (48h) of 20mM. 4-HA (50µM) led to 50% toxicity in the presence of lactic acid (5-20mM) as well. A decrease in pH of the media was observed with an increase in lactic acid concentration. Hypoxia results: The IC50 (48h) of 4-HA remained 50µM in hypoxia. Lactic acid was less toxic to the cells under hypoxia. 4-HA (50µM) showed no toxicity in presence of lactic acid (5-20mM) under hypoxic condition. The effect of pyruvic acid, HCl and NaCl on 4-HA toxicity were also investigated in normoxia and hypoxia conditions.
Our results suggest that lactic acid, hyper-acidic media and hypoxia may play major roles in diminishing 4-HA toxicity in melanoma cells, however, the role of hypoxia was found to be more prominent. Lactic acid provided protective effect against 4-HA induced toxicity under hypoxic condition.
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 741.
Abstract 75: Electron transport chain-dependent oxygen consumption in metastatic breast cancer cells
Authors: Al-Mehdi Abu-Bakr , Patel Mita , Reed Darla 
Published: February 2011

Abstract
Although mitochondrial ATP-production deficiency has been historically implicated to account for the Warburg effect or “aerobic” glycolysis in cancer cells, recent observations indicate the presence of functionally competent mitochondria in cancer cells. We hypothesized that a lung-metastatic breast cancer cell line with intact mitochondrial membrane potential would exhibit mitochondria-dependent oxygen consumption. A murine breast cancer cell line (4T1) was used to evaluate mitochondrial membrane potential by JC-1 fluorescence microscopy. Oxygen consumption by cancer cells in suspension was determined using a dissolved oxygen meter. Fluorescence microscopy of JC-1 red aggregates indicated the presence of highly polarized mitochondria in 4T1 cells, suggesting that these cells are capable of oxidative phosphorylation. Oxygen consumption rate of 4T1 cells suspended in 10 mM glucose-containing medium equilibrated with 21% oxygen (258 µM dissolved oxygen) at 25°C was 2.98 nmol/min/million cells (Control). Oxygen consumption was significantly enhanced by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), a mitochondrial uncoupler (7.88 nmol/min/million cells, p&lt;0.05 vs. Control). Myxothiazol (a respiratory chain complex III inhibitor) inhibited the oxygen consumption (0.75 nmol/min/million cells; p&lt;0.05 vs. Control), indicating the presence of a functional electron transport chain. A nitric oxide donor also inhibited oxygen consumption (0.84 nmol/min/million cells; p&lt;0.05 vs. Control). These data indicate the presence of oxidative phosphorylation-competent mitochondria in breast cancer cells. We conclude that cancer cells possess respiration-capable mitochondria and their “aerobic” glycolysis may not reflect a compensatory mechanism for ATP generation.
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 75.
Abstract 753: Novel, potent and selective small molecule inhibitors of 3-phosphoinositide-dependent kinase (PDK1)
Authors: Murphy Sean T. , Alton Gordon , Bailey Simon , Baxi Sangita , Burke Ben , Ermolieff Jacques , Greasley Samantha , Kablaoui Natasha , Kath John , Kohls Darcy , Kothe Michael , Kupchinsky Stan , Lingardo Laura , Marx Matthew A. , Richter Dan , Tran Khanh , Vernier William , Yin Min-Jean 
Published: February 2011

Abstract
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a crucial role in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of PI3Kα or loss-of-function of the tumor suppressor PTEN, have been closely linked to the development and progression of a wide range of cancers. Inhibition of the key targets in the pathway, PI3K, AKT, mTOR & PDK1, may provide an effective treatment of cancer. In an effort to discover compounds that inhibit PDK1, we have developed a series of 3-Carbonyl-4-Amino-Pyrrolopyrimidine (CAP) compounds that are selective and potent PDK1 inhibitors. Early screening led to a viable starting point, PF-03772304, (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(6-methylamino-pyrazin-2-yl)-methanone, which has an IC50 of 94 nM for PDK1 and a ligand efficiency of 0.42. While potent, this lead was not selective against PI3K. Using structure-based drug design, this lead was modified to expand into the selectivity pocket of PDK1 (under the G-Loop), leading to the identification of a potent and pathway-selective compound, PF-05017255 ((4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-{6-[(3S,4R)-4-(4-fluoro-phenyl)-tetrahydro-furan-3-ylamino]-pyrazin-2-yl}-methanone). PF-05017255 has a Ki of 0.6 nM for PDK1 and is more than 400-fold selective against other PI3K pathway kinases: PI3Kα, AKT, S6K and mTOR. For even greater kinase selectivity, we sought to lower the clogP of our lead (clogP for PF-05017255 is 3.0) to reduce the contribution from the hydrophobic effect. These efforts led to PF-05168899 (1-{(2R,3R)-3-[6-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyrazin-2-ylamino]-2-phenyl-pyrrolidin-1-yl}-ethanone) with a Ki of 0.4 nM for PDK1, a clogP of 2.1, and greater than 1000-fold selectivity against PI3Kα, AKT, S6K, mTOR, CDK2, CHK1 and PAK4. PF-05168899 also showed little inhibitory effect (&lt;50% at 1 uM) against 33 of 35 kinases in a broader panel, demonstrating significant inhibition only against CHK2 (94%) and AuroraB (54%). In addition, the most potent analogs (e.g. PF-05168889) inhibited the phosphorylation of AKT at the residue threonine 308 (IC50 40-200 nM) in a variety of cancer cell lines (e.g. H460, A549). The design, synthesis and SAR of this chemical series will be described.
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 753.
Abstract 766: Downregulation of MUC4 in pancreatic cancer cells by thymoquinone: A promise for pancreatic cancer therapies
Authors: Torres Maria P. , Ponnusamy Moorthy P. , Chakraborty Subhankar , Arafat Hwyda A. , Batra Surinder K. 
Published: February 2011

Abstract
Pancreatic cancer remains one of the most lethal cancers in the world. Currently, the existing therapies have not been optimized and the survival of pancreatic cancer patients remains under 5% after being diagnosed. The high molecular weight glycoprotein Mucin-4 (MUC4) contributes to the regulation of differentiation, proliferation, and metastasis of pancreatic tumor cells. As it is not expressed in normal pancreatic epithelial cells, MUC4 is a promising target for novel cancer therapeutics. Among the natural derived drugs that are being investigated, the extracts from the seeds of the plant Nigella sativa, particularly thymoquinone (TQ), possess multiple benefits, including anti-tumorigenic properties. The main objective of this study was to evaluate the effect of TQ on pancreatic cancer cells and determine the role of the drug on MUC4 expression by analyzing the cytotoxicity, protein and gene expression, and metastatic properties on the MUC4-expressing pancreatic cancer cell line FG/COLO357. Experimental techniques used included western blot, polymerase chain reaction (PCR), transient gene silencing, confocal, and flow cytometry analyses, among other functional assays. The results indicated a decrease in cell viability at increasing concentrations of TQ that correlated with MUC4 downregulation, which occurred thru the proteasomal degradation pathway. The genes that were regulated in FG/COLO357 cells after treatment with TQ were determined by microarray analysis and the results were confirmed by functional assays. It was found that TQ activated the Jun N-terminal Kinase (JNK) and p38 Mitogen-Activated Protein Kinase (MAPK) pathways. As the activation of these pathways is directly related to a decrease in proliferation, survival, and invasion of cancer cells, these results indicate the direct involvement of TQ on the induction of apoptosis of pancreatic cancer cells. The results present evidence that TQ induces the apoptosis of pancreatic cancer cells and the downregulation of MUC4 is related to the apoptotic effect of the drug. In conclusion, TQ, which has a role in downregulation of MUC4 among other anti-tumorigenic properties, represents promise for the development of novel therapies against pancreatic cancer.
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 766.
Abstract 783: High microsatellite instability predicts good prognosis in intestinal type gastric cancers
Authors: Song Meiying , An Ji Yeong , Noh Sung Hoon , Shin Sung Kwan , Lee Yong Chan , Kim Hoguen , Hyunki Kim 
Published: February 2011

Abstract
A subset of gastric cancers shows high microsatellite instability (MSI-H). The reported clinicopathologic features of MSI-H gastric cancers are heterogeneous, and specific factors associated with prognosis have not been identified. We analyzed the clinicopathologic characteristics and prognostic factors in a large series (161 cases) of MSI-H gastric cancers, and compared the results to 315 cases of microsatellite stable or low MSI gastric cancers. The frequency of MSI-H gastric cancers was 9.0% (161/1786). MSI-H gastric cancers have distinct clinicopathologic features including female gender, older age, antral location, protruded gross type (Borrmann typeIand type II), well to moderate differentiation, intestinal type of Lauren classification, expanding type of Ming classification, non signet ring cell component, presence of mucinous component, moderate to severe lymphoid stromal reaction, and lower tumor stage. The MSI-H phenotype was associated with better prognosis (P = .044), and male gender (P = .035, HR: 0.23), intestinal/mixed type of Lauren classification (P &lt;.001, HR: 0.09) and lower tumor stage (1 and 2) (P = .001, HR: 0.08) were independently favorable prognostic factors. With unique clinicopathologic features, the intestinal type MSI-H gastric cancers are associated with good prognosis and can be classified as a different subset of gastric cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 783.