bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2612: Inhibiton of phospholipase C γ 1 enhances senstivity of glioblastoma multiforme to cisplatin and biochanin A
Authors: Jain Aditi , Bhardwaj Vikas , Lai James C. K. , Bhushan Alok 
Published: February 2011

Abstract
Glioblastoma multiforme (GBM), the most prevalent primary brain tumors, is characterized by its invasiveness and poor prognosis of the patients with this disease. Due to its rapid and aggressive nature, it is difficult to treat with conventional therapies. Several new agents have been tested and used for treating glioblastoma but with limited success. Phospholipase C γ 1 (PLC γ 1) is at the point of convergence of many signal transduction pathways and plays an important role in regulating intracellular calcium mobilization and promote cell motility, differentiation and invasion. Inhibition of PLC γ 1 is known to be associated with blocking invasion in gliomas, prostate, breast and bladder carcinomas. In glioblastoma the significance of PLC γ 1 inhibition has been implicated due to its effect on cell motility and invasion. Our laboratory has been investigating the anticancer properties of Biochanin A, a natural isoflavonoid. Biochanin A induces apoptosis, causes cell cycle arrest affecting cellular signaling in several cancers. Previous studies in our laboratory have shown that Biochanin A inhibits invasion in GBM cells. In GBM several signaling pathways are upregulated leading to tumor progression and thus designing targeted therapies is still a major challenge. In this study we investigated the cytotoxic potential of PLC γ 1 inhibitor (U73122) in combination with Biochanin A or with Cisplatin on U87 MG cells (human glioblastoma cell line). We hypothesized that the combinations would enhance the anti-proliferative and anti-invasive properties of the two compounds. We performed a dose response assay using these compounds alone and in combination. At 5µM, U73122 is effective in decreasing cell survival. We also found that U73122 is effective in enhancing the cytotoxic potential of Biochanin A and Cisplatin. Further, we determined the effect of U73122 (5μM) alone and in combination with either of the two compounds on cell signaling, invasive processes and transcription factors. Western blot analysis shows a decrease in the protein expression of p-AKT, NFκ-β, uPAR. Our results implicate that inhibition of PLC γ 1 can augment the cytotoxic potential of Biochanin A and Cisplatin and decrease progression of GBM. These findings have a therapeutic implication in GBM treatment.
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 2612.
Abstract 2616: Thioredoxin reductase 1 modulates methylseleninic acid-induced redox status effects in A549 human lung cancer cells
Authors: Poerschke Robyn L. , Moos Philip J. 
Published: February 2011

Abstract
Thioredoxin reductase (TR1) is a selenoprotein that is involved in cellular redox status control and deoxyribonucleotide biosynthesis. Many cancers, including lung, overexpress TR1, making it a potential cancer therapy target. TR1 is hypothesized to be involved in the mechanism of selenium in cancer etiology. Also of interest is the selenocompound methylseleninic acid (MSA). MSA is a known substrate of TR1 and previous work has shown that TR1 knockdown enhances MSA toxicity and redox status effects in human colon cancer cells compared to those with endogenous TR1 levels. However, it is unknown if TR1 knockdown produces similar effects of MSA in human lung cancer cells. To further elucidate the role of TR1 in the mechanism of MSA in lung cancer, a lentiviral microRNA delivery system to knockdown TR1 expression in A549 adenocarcinoma cells (A549 miR-TR1) was utilized. Redox status after 24 hr MSA treatment was assessed by measuring reactive oxygen species (ROS) generation, mitochondrial membrane depolarization, and total glutathione (GSH) concentration. Although the toxicity of MSA was not increased in A549 miR-TR1 cells at 24 hrs, changes in redox status parameters were observed. TR1 knockdown alone had no effect on mitochondrial membrane depolarization or ROS, but did increase ROS and mitochondrial membrane depolarization generated by MSA. Total GSH concentration was increased by TR1 knockdown alone, the majority of which was reduced glutathione. MSA decreased total GSH concentration and TR1 knockdown further enhanced this MSA-induced attenuation in total GSH. These results indicate the ability of TR1 to modulate the redox status effects of MSA in human lung cancer cells. Potential use of MSA as a cancer treatment in combination with TR1 inhibitors is also of interest.
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 2616.
Abstract 262: Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through NF-κB activation
Authors: Li Shau-Hsuan , Hawthorne Valerie S. , Neal Christopher L. , Sanghera Sartaj , Xu Jia , Yang Jun , Guo Hua , Steeg Patricia S. , Yu Dihua 
Published: February 2011

Abstract
ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers including breast carcinomas. NGAL can inhibit erythroid cell production leading to anemia. Anemia usually occurs in cancer patients and negatively impacts quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we demonstrate that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor kappa B (NF-κB) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by an NF-κB inhibitor and an ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-κB activation is involved in cancer-related anemia, and ErbB2, NF-κB, NGAL pathway may serve as potential therapeutic targets for cancer-related anemia.
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 262.
Abstract 2621: Telomere length in peripheral blood mononuclear cells (PBMNC) predicts for leukopenia, neutropenia and mucositis in colorectal cancer patients treated with 5FU
Authors: Sakoff Jennette A. , Garg Madhu B. , Adler Kim , Scorgie Fiona E. , Lincz Lisa F. , Ackland Stephen P. 
Published: February 2011

Abstract
Defining the parameters contributing to variability in clinical toxicity is necessary to optimise cancer treatment. Some variability is accounted for by variations in 5FU pharmacokinetics, differences in co-morbidity (liver & renal), pre-disposing factors (gender & age). But a considerable amount remains unexplained. This study aims to identify various factors contributing to such toxicity in colorectal cancer patients receiving 5FU. The variables chosen for study include those that control 5FU metabolism including measures of dihydropyrimidine dehydrogenase (DPD) activity which is critical for 5FU catabolism, together with polymorphic analysis of thymidylate synthase (TS), methyltetrahydrofolate reductase (MTHFR) and methionine synthase (MS) activity. The addition of pharmacodymamics and the ability of end-organs to respond to drug treatment further refined the predictive model, particularly the ability to identify those patients most likely to experience severe myelosuppression in response to chemotherapy. In this regard, the replicative capacity of bone marrow progenitors was determined by measuring telomere length (TL) in peripheral blood mononuclear cells (PBMNC). Clinical toxicity was determined in 42 colorectal patients receiving 5FU. Toxicity (≥ grade 2) included neutropenia (n=25), leukopenia (n=14), mucositis (n=19) and diarrhea (n=5). While the severity of toxicity significantly correlated with the magnitude of the insult, ie 5FU dose, the analysis also showed that toxicity significantly correlated with TL, with short telomeres predicting for higher toxicity. Univariate analysis showed TL significantly correlated with leukopenia (r=-0.461, P=0.009), neutropenia (r=-0.413, P=0.021) and mucositis (r=-0.341, P=0.048). Multivariate analysis further confirmed the significant role of TL in these clinical toxicities. Collectively, these results support the link between TL and progenitor replicative capacity. In conclusion, PBMNC TL may be exploited to tailor chemotherapy schedules for colorectal cancer patients receiving 5FU.
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 2621.
Abstract 2623: Induction of Bmf and Bim in Vorinostat-induced apoptosis in mantle cell lymphoma
Authors: Xargay-Torrent Silvia , Roue Gael , Lopez-Guerra Monica , Campo Elias , Colomer Dolors 
Published: February 2011

Abstract
OBJECTIVES: Mantle cell lymphoma (MCL) is an incurable B-cell neoplasm harboring the t(11;14)(q13;q32) which leads to the overexpression of cyclin D1, with the consequent cell cycle deregulation. Usually, MCL is characterized by bad prognosis and an aggressive course of the disease. Current therapies have shown limited efficacy. Recently, Histone Deacetylase Inhibitors (HDACis) have been successfully introduced for the treatment of several cancers, including hematological malignancies. Accordingly, tumor suppressor genes are frequently epigenetically silenced in these entities, due to histone deacetylation in their promoters. Therefore, our purposes were to evaluate the antitumoral properties of the HDACi suberoylanilide hydroxamic acid (Vorinostat; Merck & Co) in MCL, and to describe the molecular mechanisms involved in HDACi signaling in this disorder.
METHODS: MCL cell lines and primary MCL cells were used. HDAC activity was measured using a colorimetric HDAC Assay Kit. Flow cytometry was used to determine sensitivity to Vorinostat through measurement of AnnexinV binding, and to analyze apoptosis features. Vorinostat anti-tumoral signaling was evaluated by RQ-PCR determination of gene transcription, western blot analysis and acetyl Histone H4 ChIP assays.
RESULTS: Vorinostat exhibited a heterogeneous cytotoxic effect among MCL cell lines, with a median LD50 of 6.6 μM after 24-hour incubation. Nevertheless, cytotoxicity increased notably after 48h of exposure to the drug with LD50 ranging from 0.4 to 5.3 μM. Interestingly, 7 out of the 10 MCL primary samples tested were extremely sensitive to the compound (with a median LD50 of 2.2 μM after 24-hour incubation). Vorinostat increases the acetylation of H3 and H4 histones, as well as inhibits global HDAC activity in just 1 hour of incubation. The drug notably decreases cyclin D1 protein levels while induces upregulation of the proapoptotic BH3-only proteins Bmf and Bim, triggering the mitochondria-dependent cell death and activation of the caspases cascade. Acetyl Histone H4 ChIP assays showed that Vorinostat increases acetylation of BMF and BIM gene promoters, consequently up regulating Bim and Bmf mRNA levels.
CONCLUSIONS: This study suggests that Vorinostat could define a new and attractive therapeutic approach for the treatment of MCL. We identify BMF and BIM as possible crucial target genes of HDAC inhibitors in MCL cells, promoting the induction of mitochondria-mediated apoptosis.
GRANTS: This work is supported by Ministerio de Ciencia e Innovación SAF 06-8850; S. X-T is a fellow from Ministerio de Ciencia e Innovación (FPU predoctoral fellowship).
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 2623.
Abstract 2633: Adenosine analog enhances actions of 17-AAG
Authors: Cervantes-Gomez Fabiola , Nimmanapalli Ramadevi , Gandhi Varsha 
Published: February 2011

Abstract
Heat shock protein 90 (HSP90) is a molecular chaperone that regulates the functional stability of client oncoproteins, which is driven by the binding and hydrolysis of ATP. The geldanamycin analog, 17-AAG, binds to the ATP pocket of HSP90 leading to the degradation of client proteins. However, 17-AAG also induces transcription of antiapoptotic HSP70 and HSP27 resulting in cell death resistance. The nucleoside analog 8-Chloro-Adenosine (8-Cl-Ado), currently in clinical trial, is a transcription inhibitor that gets metabolized into its cytotoxic form 8-Cl-ATP causing a parallel decrease of the cellular ATP pool. Based on its mechanisms of action we hypothesize that the combination of 17-AAG and 8-Cl-Ado will result in a favorable effect on cytotoxicity. % Cell Death Annexin V / 7-AAD TreatmentsHrsMM.1S8226-RPMIU2661)17-AAG 0.5 µM85452)17-AAG 0.5 µM202463)8-Cl-Ado 10 µM125324)8-Cl-Ado 10 µM2022825)17-AAG→8-Cl-Ado8→12 = 201511106)8-Cl-Ado→17-AAG12→8 = 205515197)8-Cl-Ado+17-AAG20421434
As shown in the Table, simultaneous or sequential combination (rows 6 and 7) were more than additive in multiple myeloma cell lines. With 17-AAG alone, there was a transcriptional induction of HSP90α, HSP90β, HSP70, HSC70 and HSP27 as measured by real time RT-PCR. With the drug combinations, there was no reduction of the 17-AAG-induced HSPs mRNA levels, rather a several fold increase was observed for the stress-inducible HSP70 and HSP27. In accordance, the protein levels of the HSPs were also increased when treated with 17-AAG but remained the same when 8-Cl-Ado was added. This suggests that the transcription inhibition by 8-Cl-Ado was not able to abrogate 17-AAG-mediated HSP induction. The transcript levels for client proteins (STAT3, Akt and c-Raf) remained at endogenous levels when treated with the drugs alone or in combination. However, the combination treatments resulted in a greater decline of the protein expression of STAT3 (1-60%), Akt (42-78%), and Raf-1 (25-85%). This may be due to the reduction in intracellular ATP levels after 8-Cl-Ado treatment, MM.1S (57%), 8226-RPMI (24%), and U266 (56%). Taken together, the increased cytotoxicity of 17-AAG and 8-Cl-Ado combination is mediated by the actions of 8-Cl-Ado on the cellular ATP pool and not due to its effect on transcription.
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 2633.
Abstract 2636: Preclinical evaluation of the Hsp90 inhibitor KW-2478 in combination with bortezomib as a treatment for multiple myeloma
Authors: Ishii Toshihiko , Nakashima Takayuki , Seike Toshihiro , Shudo Aiko , Akinaga Shiro , Soga Shiro , Shiotsu Yukimasa 
Published: February 2011

Abstract
KW-2478 is a novel Hsp90 inhibitor with a new chemical structure and is under clinical investigation in multiple myeloma patients. Our previous study revealed that KW-2478 bind to N-terminal ATP/ADP pocket and thus inducing apoptosis in myeloma cells. Others have reported that bortezomib, a proteasome inhibitor, induces apoptosis of myeloma cells through increase of ER stress mediator protein such as Noxa. Since Hsp90 inhibition can also causes cellular stress, combining Hsp90 inhibitor and bortezomib may be of therapeutic benefit. In this study, we assessed the combined effect of KW-2478 with bortezomib using human myeloma cell lines. In OPM2/GFP cells, KW-2478 enhanced caspase activation of bortezomib in vitro and this effect was revealed to be mediated through synergistic induction of Noxa. Interestingly KW-2478 reduced bortezomib-induced level of another ER stress mediator, Puma in the same cells. To see if this in vitro effect is translated into in vivo setting, we evaluated combined anti-tumor activity of KW-2478 with bortezomib in s.c. inoculated NCI-H929 human myeloma model. In this model, twice weekly treatment of KW-2478 at the dose of 50 mg/kg (1/4 of MTD) showed synergistic anti-tumor effect with 1 mg/kg bortezomib, without significant body weight loss. Our previous studies showed that KW-2478 showed anti-tumor activity in bone marrow environment, the combined effect of KW-278 with bortezomib was further evaluated using an orthotopic myeloma model in which OPM2/GFP cells were i.v. inoculated. The combination of KW-2478 with bortezomib showed synergistic reduction of myeloma cells in bone marrow and this effect was reflected in a significant decrease in serum M protein level. Our results strongly suggested that combination of KW-2478 with bortezomib may exhibit the enhanced anti-tumor activity against human myeloma than bortezomib alone. Clinical study for combination of KW-2478 with bortzomib in myeloma patients is 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 2636.
Abstract 2652: Formulation and pharmacokinetics of Lazaroid U-74389G (LAZ) liposomes in rats
Authors: Ibrahim Fady Makram L. , New Pamela , Chow Diana S-L 
Published: February 2011

Abstract
Purpose Lazaroid U74389G (LAZ) is a 21-aminosteroid that has a radioprotective and antioxidant effects. It prevents the damage in the tissues after radiation by a selective action on vascular endothelium cells in normal tissues. The aim of this study is to develop liposomal formulations of LAZ with favorable pharmacokinetic (PK) profiles for potential therapeutic merits in an animal model.
Methods Conventional (LipoB) and pegylated (LipoG) liposomes were prepared with various phosphatidylcholine: cholesterol ratios and lipid: LAZ ratio of 10:1. The liposomes were characterized with the size, charge and release profile. The PK study was performed in Sprague-Dawley rats. The rats were randomized into 3 groups (n=4 each) prior to the dosing of the formulations (LAZ solution, LipoB and LipoG) at a dose of 1 mg/kg by injection through the cannula at jugular veins. At pre-determined time points, blood samples were collected from the tail vein. The LAZ concentrations in plasma were quantified by a validated UPLC/MS/MS assay using Daidazine as the internal standard, with a lower limit of quantification (LLOQ) of 4 ng/ml for LAZ. The PK profiles were constructed by plotting the plasma concentration versus time and the PK parameters were derived using compartmental models of WinNonlin Ver 3.3 software.
Results The liposomal preparations with the least amount of cholesterol had the lowest Encapsulation Efficiency (EE=26%). However, an increase of cholesterol ratio up to 20% increased the EE up to 58%. The size of the liposomes was in the range of 90-118 nm. In in-vivo study, the plasma profile of the solution fits 1-compartment model while the liposomal formulations fit 2-compartment model. The solution group yielded a higher Cmax and faster clearance (4.27 μg/ml and 546 ml/hr) than those of LipoB and LipoG (0.97 and 2.03 μg/ml and 380 and 216 ml/hr, respectively). The t1/2's of LAZ from LipoB and LipoG were 5 folds of that from the solution (0.64 and 0.52 hr vs 0.10hr). The solution showed a significantly smaller AUC compared to those of LipoB and LipoG (0.56 μg.hr/ml vs. 0.79 and 1.42 μg.hr/ml, respectively). The volume of distribution was small for the solution compared to LipoB and LipoG (73 ml vs. 1173 and 589 ml, respectively). The half-lives of distribution and elimination, t1/2 α and t1/2 β, were comparable between LipoB and LipoG (0.22 vs. 0.16 hr and 3.17 vs. 2.55 hr, respectively).
Conclusion The liposomal formulations modified the pharmacokinetics of LAZ solution. The liposomal formulations resulted in a slower clearance and wider distribution of LAZ in-vivo compared to the solution. LAZ systemic exposures in rats after administration of LAZ liposomes were 1.4 −2.5 folds higher than that of solution.
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 2652.
Abstract 2654: Transferrin receptor targeting PRINT® nanoparticles: Chemotherapeutic-free nanomedicine for B-cell lymphoma
Authors: Tian Shaomin , Wang Jin , Petros Robby A. , Napier Mary E. , DeSimone Joseph M. 
Published: February 2011

Abstract
Transferrin receptor (TfR, CD71) is an essential protein involved in cellular iron uptake and regulation of cell growth. This study is to convert PRINT® nanoparticles to targeted drug delivery system by conjugating TfR ligands to particle surface, taking advantage of TfR overexpression on many types of malignant tissues. 200 nm × 200 nm cylindrical PRINT nanoparticles with poly(ethylene glycol)-based composition were fabricated and labeled with transferrin receptor antibody (mouse anti-human TfR mAb, clone OKT-9) or human transferrin (hTf) via biotin-avidin binding or direct chemical conjugation strategies. Nanoparticles coated with OKT9 or hTf, but not isotype control mouse IgG1 or bovine transferrin (bTf), showed highly specific TfR-mediated uptake by all human tumor cell lines tested in this study, including solid tumors and disseminating B cell lymphomas. Non-cancerous HEK293 cell that expresses low level of surface TfR, in contrast, took up particles at much lower rate during short exposure to TfR-targeting particles. The targeting efficiency was dependent on particle concentration, ligand density, particle dosing time and cell surface receptor level.
Interestingly, the PRINT nanoparticles coated with OKT9 or hTf showed little cytotoxicity on all solid tumor cell lines tested but were toxic to Ramos B-cell lymphoma. More than 70% of the Ramos cells were killed by OKT9 or hTf coated nanoparticles at a concentration of 100 µg/mL. In contrast, free OKT9 or hTf did not induce death of Ramos cells. There was a strong correlation between TfR ligand density on particle surface and cell viability. Elevated caspase 3 activity indicates the activation of apoptosis pathways upon particle treatment. Iron supplementation suppressed toxicity of NP-OKT9 but not NP-hTf, suggesting different mechanisms by which hTf and OKT9 exerts cytotoxicity on Ramos cells. Further study of cell death mechanism through DNA microarray analysis is under way.
Overall, we have shown that human transferrin and transferrin receptor antibodies can be useful targeting ligands for nanoparticle delivery to tumors. More importantly, non-toxic transferrin and TfR antibodies can be turned into a potential chemotherapeutic-free medicine for B-cell lymphoma through multiplexing with PRINT nanoparticles.
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 2654.