bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5382: Etoposide enhances TRAIL cytotoxicity by increase of TRAIL-R2 expression via a NF-κB pathway in neuroblastoma cells
Authors: Lee Myoung Woo , Kim Hye Ryung , Kim Dae Seong , Noh Yoo Hun , Kim Hye Jin , Lee Soo Hyun , Cheuh Hee Won , Yoo Keon Hee , Sung Ki Woong , Koo Hong Hoe , Jung Hye Lim 
Published: February 2011

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which induces apoptosis in tumor cells while not in normal cells. TRAIL binds with two types of receptors which are apoptosis-inducing death receptors (TRAIL-R1 and TRAIL-R2) and non-apoptosis-inducing decoy receptors (TRAIL-R3 and TRAIL-R4). TRAIL has been considered as a promising agent for selective cancer therapy, although some cancer cells show resistance to apoptosis induction by this ligand. In this study, we examined whether combination treatment of chemotherapeutic drugs with TRAIL induces synergistic cell death in neuroblastoma cells. We showed that pre-treatment with sublethal concentrations of etoposide followed by exposure to TRAIL synergistically enhanced apoptotic cell death compared to treatment with etoposide or TRAIL alone in SK-N-MC cells (28 ± 2% versus 12 ± 3% or 2 ± 2% apoptotic cell death in 48 h), while not in IMR-32 cells (26 ± 4% versus 26 ± 7% or 0.5 ± 0.6% apoptotic cell death in 48 h). These synergistic cell death was inhibited by addition of fusion chimera protein (recombinant human TRAIL-R2: Fc), which can block TRAIL binding to TRAIL-R1 or TRAIL-R2. In addition, pre-treatment with sublethal concentrations of etoposide in SK-N-MC cells induced degradation of IκBα, resulting in NF-κB activation and up-regulation of TRAIL-R2 expression. The increase of TRAIL-R2 expression resulted in TRAIL-induced synergistic cell deaths, which were effectively inhibited by exposure to NF-κB inhibitor. Moreover, we showed that combination treatment significantly decreased the Mcl-1 expression and increased caspase-3 activation compared to treatment with etoposide or TRAIL alone. Our data suggest that pre-treated etoposide activates NF-κB by down-regulation of IκBα, and then NF-κB up-regulates TRAIL-R2 expression enhancing TRAIL-induced apoptosis in neuroblastoma cells.
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 5382.
Abstract 5384: Tanshinone IIA synergizes with arsenic trioxide to promote human NB4 promyelocytic leukemia cell differentiation and apoptosis
Authors: Wang Zhibo , Johnson Daniel E. , Cui Naiqiang , Wu Xianzhong , Herberman Ronald , Ferrone Soldano , Wang Wenjun 
Published: February 2011

Abstract
Background: Tanshinone IIA (TIIA), a natural compound isolated from Salvia Miltiorrhiza, has been used for hematological malignancies as an adjunctive therapy in combination with arsenic in other countries. However, the molecular mechanism of TIIA as an adjunctive therapy has not been well documented. The goal of this study is to develop novel strategies to treat human promyelocytic leukemia.
Methods: Purified TIIA was used for this pilot study; and purified arsenic trioxide (ATO) was purchased from Sigma. Western blotting and flow cytometry were employed to evaluate biomarker expression in human NB4 promyelocytic leukemia cells prior to treatment and 2-5 days after treatment.
Results: TIIA induced NB4 cell apoptosis at the concentrations above 0.75 µM, a concentration that is below plasma concentrations that can be achieved in vivo. TIIA was not toxic to peripheral blood mononuclear cells (PBMC) from healthy individuals at 3 µM, the highest concentration tested. TIIA also promoted NB4 differentiation at and above 0.75 µM. TIIA up-regulated the percentage of CD11b+ NB4 cells, as well as increasing the percentage of NBT+ cells. In addition, There were not significant differences between TIIA (1µM) and ATRA (1 µM), in terms of their impact on NB4 cell differentiation, as assessed by NBT and CD11b assays. TIIA also inhibited NB4 cell colony formation in CFU-L assays. Western blotting demonstrated that TIIA down-regulated c-Myc expression in NB4 cells. The combination of ATO and TIIA increased NB4 cell death when compared with single drug treatment (TIIA or ATO). In addition, the combination of TIIA and ATO had stronger impact on the induction of NB4 cell differentiation, as assessed by CD11b expression.
Conclusion: TIIA is a potential novel adjunctive agent to be considered in combination with ATO for the treatment of human promyelocytic leukemia.
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 5384.
Abstract 539: Endosialin (TEM1) is a tumor stroma marker and receptor for the metastasis-related Mac-2 binding protein
Authors: Wieland Matthias , Becker Renate , Vijayshankar Sivanandam , Mogler Carolin , Besemfelder Eva , Christian Sven , Augustin Hellmut G. 
Published: February 2011

Abstract
Endosialin is a heavily sialylated C-type lectin. It is a single transmembrane molecule that was identified by two independent studies as an angiogenic endothelial specific marker. However, recent high resolution confocal expression studies by our and other laboratories have revealed that Endosialin is not expressed by endothelial cells but instead by angiogenic blood vessel associated pericytes. Detailed tissue array-based expression profiling validated Endosialin as an oncofetal gene product of the mesenchymal lineage that is hardly detectable in normal tissues but abundantly expressed by tumor vessel-associated pericytes and tumor stromal fibroblasts (myofibroblasts). As such, Endosialin was not just identified as a marker of activated pericytes but based on its exclusive tumor-associated expression also as a novel therapeutic tumor stroma target. Cytokine induction experiments identified Endosialin as a major downstream target of TGFß stimulation. Cellular siRNA-based loss-of-function experiments unravelled a role of Endosialin in the regulation of mesenchymal cell adhesion, migration and proliferation. These findings prompted experiments aimed at identifying the extracellular ligand of Endosialin. Using Endosialin-Fc as an affinity probe, the metastasis associated molecule Mac-2BP/90K was identified as high affinity extracellular Endosialin ligand. As Endosialin, Mac-2BP/90K displays an exclusive tumor progression associated expression pattern. However, in contrast to the stromal expression of Endosialin, Mac-2BP/90K is strictly expressed by the tumor cell compartment. The mutually exclusive expression pattern suggests a repulsive interaction between Endosialin and Mac-2BP/90K which was confirmed in cellular experiments. Ongoing experiments are aimed at mechanistically studying the role of the Endosialin - Mac-2BP/90K interaction in controlling the crosstalk between the tumor cell and the stromal cell compartments during tumor progression and metastasis.
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 539.
Abstract 5397: Crocetin, a carotenoid compound derived from Saffron, enhances antitumor effects of paclitaxol and cisplatin in pancreatic cancer
Authors: Dhar Animesh , Wiegmann Peter S. , Reed Greg , Gutheil William , Veldhuizen Peter Van 
Published: February 2011

Abstract
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and no significant treatment is at present available. Although there are an increasing number of therapeutic options available for patients with advanced disease, their efficacy is time limited and non-curative. Presently approximately 50-60% of cancer patients in the United States utilize therapies derived from plants, herbs, flowers, or nutrients (complementary and alternative medicine [CAM]), exclusively or concurrently with their traditional therapies such as chemotherapy or radiation therapy. One such CAM therapy is “crocetin”, a carotenoid compound isolated from the saffron plant. Recent studies demonstrated that crocetin has a significant antitumorigenic effect in both in vitro and in vivo on pancreatic cancer. Two conventional chemotherapeutic agents, paclitaxol (a microtubule-targeted agent) and cisplatin (a platinum based anticancer drug binds to DNA), have been demonstrated significant reduction of growth and proliferation in pancreatic cancer. Therefore, the aim of the series of experiments was to determine whether crocetin enhances paclitaxol or cisplatin induced proliferation in pancreatic cancer. MIA-PaCa-2 and BxPC3 cells were treated with crocetin and paclitaxol or cisplatin together at different doses and a proliferation assay was utilized using Click-it Edu flurorometric assay. Paclitaxol or cisplatin alone at higher doses (50-100nM) inhibited proliferation in both MIA PaCa2 and BxPC3 cells but crocetin (200μM) in combination of paclitaxol or cisplatin showed significant additive effect even at lower doses (10 and 25nM) of paclitaxol or cisplatin. The combinational effect is more pronounced in BxPC3 cells. Paclitaxol or cisplatin alone at higher doses (50-100nM) stimulated apoptosis using Deadend flurorometric TUNEL apoptosis assay in MIA PaCa2 and BxPC3 cells and apoptosis is more pronounced at lower doses in combination with crocetin. This study indicated that crocetin in combination with lower doses of paclitaxol or cisplatin inhibited proliferation and stimulated apoptosis in pancreatic cancer. The antitumorigenic effect is more pronounced in BxPC3 cells and paclitaxol is more effective than cisplatin at lower doses in combination with crocetin.
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 5397.
Abstract 5400: Targeting the PI3K pathway improves the effect of PARP-1 inhibition in BRCA1-null breast cancer cells
Authors: Kimbung Siker S. , Berglund Pontus , Gruvberger-Saal Sofia , Hedenfalk Ingrid A. 
Published: February 2011

Abstract
The development of targeted therapies has greatly improved the prognosis for many women affected by breast cancer. Unfortunately, tumors with a triple-negative, ‘basal-like’ phenotype do not express the targets of these agents and remain a treatment challenge. New approaches to specifically target these groups of breast tumors are in need. The majority of BRCA1 mutated tumors display a triple-negative phenotype and are characterized by homologous recombination defects. They frequently harbor mutations in the PTEN gene leading to activation of the PI3K pathway. The absence of BRCA1 and PTEN expression both confer sensitivity to poly-(ADP-ribose) polymerase 1 (PARP-1) inhibitors whilst the activated PI3K signaling most likely promotes cell survival and resistance to apoptotic cues. The therapeutic effects of PARP-1 inhibitors in BRCA1 deficient cells and tumors have been investigated. Even though pre-clinical and clinical studies show promising results, further ways to improve and broaden the scope of application of this therapeutic approach is warranted. We have investigated the possibility of improving the response of BRCA1 mutated cells to PARP-1 inhibition by co-targeting the PI3K pathway. The BRCA1 and PTEN mutated human breast cancer cell line MDA-MB-436 was treated with the PARP-1 inhibitor AG14361 (1-(4-dimethylaminomethyl-phenyl)-8-9-dihydro-7H-2,7,9a-benzo[cd]azulen-6-one) and the PI3K inhibitor LY294002 (2-(4-morpholinyl)-8-phenyl-chromone), both as single agents and in combination and the effects on cell growth, cell cycle phase distribution and DNA integrity were analyzed. Our results confirm that PARP-1 inhibition alone induces DNA damage conferring a G2/M arrest and a profound decrease in cell growth. LY294002, at the low concentrations used, had less pronounced effects on both cell cycle phase distribution and cell growth. Importantly, combining AG14361 and LY294002 resulted in reduced G2/M accumulation concomitant with an even greater growth inhibition compared to AG14361 alone (p&lt;0.01). These observations could indicate a combination specific upregulation of apoptosis. Our results suggest that the combination of PARP-1 and P13K inhibitors is superior over PARP-1 inhibition alone and may represent an improved selective targeted treatment strategy for triple-negative breast cancers with DNA repair defects and activated PI3K signaling.
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 5400.
Abstract 5403: Akt inhibitor MK-2206 combined with Dasatinib synergistically inhibits the growth of sarcoma cells
Authors: Cubitt Christopher L. , Menth Jillaina L. , Dawson Jana L. , Sullivan Daniel M. 
Published: February 2011

Abstract
The number of effective drugs available for the treatment of soft tissue and bone sarcomas is limited to a small group of antineoplastic agents. Previously, we have identified synergistic anti-tumor activities of the Akt inhibitor, Triciribine, when combined with the Src family inhibitor Dasatinib. The goal of this study was to determine the effectiveness of MK-2206, a newly developed inhibitor of Akt, when combined with Dasatinib in a panel of nine sarcoma cell lines. CT-Blue cell viability experiments were performed to test dilutions of MK-2206 alone and in combination with Dasatinib at a 1:1 constant molar ratio. IC50s for MK-2206 alone ranged from 3 to 12.5 µM in the nine cell lines (Table). Using CI analyses (effective dose levels of 0.7, 0.9 & 0.95), a synergistic or strongly synergistic reduction in cell viability (CI &lt;0.7 or &lt;0.3 respectively) was observed in all cell lines. Synergy was observed over a wide dose range and remained synergistic when as little as 0.8 µM of each drug was combined.
Table. IC50s and Chou and Talalay Combination Index (CI) Synergy Analysis. Inhibitory concentration of MK-2206 required for 50% reduction in viable cells after 72 hour treatment (IC50). CI values represent the level of synergy resulting from concurrent MK-2206 plus Dasatinib treatment. +/− symbols indicate calculated CI range (+++, synergism; ++++, strong synergism).Cell lineSarcoma typeIC50 (M)Combination Index (CI)meanSEMnmeanSEMnSynergyU2-OSosteo12.5E-6809.5E-9120.400.103+++MNNG HOSosteo9.3E-61.2E-6110.210.202++++A-673Ewing9.6E-6963.4E-9120.440.173+++RD-ESEwing8.5E-61.0E-6100.180.032++++SK-ES-1Ewing3.0E-6371.3E-9120.230.084++++SK-LMS-1leiomyo8.2E-6936.4E-9110.320.033+++SK-UT-1leiomyo6.6E-6889.7E-9110.260.153++++SW-872lipo9.0E-61.1E-6120.480.205+++HT-1080fibro11.7E-6694.9E-9110.540.203+++
In Caspase 3/7 activation assays, MK-2206 induced apoptosis in most cell lines at low µM concentrations. Concurrent MK-2206 plus Dasatinib treatment synergistically enhanced apoptosis during the first 24 hrs of treatment in 4 of 9 cell lines. Ongoing experiments are underway to identify the effects of drug sequencing on cell viability and find mechanisms that can account for the synergistic interactions. However, results of current experiments indicate that a MK-2206, Dasatinib combination may be an effective treatment regimen for sarcoma patients. MK-2206 was provided by Merck & Co. Inc. Funded by the Pediatric Cancer Foundation.
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 5403.
Abstract 5404: Inhibition of AKT sensitizes HeLa-S3 cells to arsenite-induced mitotic cell apoptosis
Authors: Yih Ling-Huei , Hsu Nai-Chi , Wu Yi-Chen , Yen Wen-Yen , Tang Yu-Hsuan 
Published: February 2011

Abstract
Arsenic trioxide (ATO) was proved effective in the treatment of promyelocytic leukemia by inducing apoptosis. However, the use of ATO as a single agent in clinical trials against solid tumors was found to be mostly not effective or too toxic. Induction of mitotic arrest was recently shown to be one of the major mechanisms for arsenite-induced apoptosis in cancer cells. Reagents that could effectively enhance ATO-induced mitotic arrest might help improve the therapeutic potential ATO. Cotreatement of HeLa-S3 cells with ATO and LY294002 or a specific AKT inhibitor significantly enhanced mitotic cell accumulation and suppressed the viability of cells at concentrations at which ATO alone was relatively ineffective. The suppression of cell viability was associated with enhanced induction of ATO-induced mitotic abnormalities and was due to induction of mitotic cell apoptosis. Ectopic expression of the constitutively active AKT1 had no effect on ATO-induced mitotic abnormalities, but accelerated mitosis exit, prevented mitotic cell apoptosis, and enhanced the formation of micro- or multi-nuclei after cell division. In addition, AKT1 activation upregulated the expression of aurora kinase B (AURKB) and survivin, and depletion of AURKB and survivin reversed the resistance of AKT1-activated cells to arsenite-induced apoptosis. These results indicate that AKT1 activation suppresses arsenite-induced mitotic cell apoptosis, despite the presence of numerous spindle abnormalities, by upregulation of AURKB and survivin and that inhibition of AKT effectively sensitizes cancer cells to ATO by enhancing mitotic cell apoptosis.
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 5404.
Abstract 541: TGF-β signaling in the tumor microenvironment promotes tumor formation and tumor progression
Authors: Moore Lakisha D. , Isayeva Tatyana , Gurley Jessica , Ponnazhagan Selvarangan 
Published: February 2011

Abstract
Recent studies indicated that the tumor microenvironment plays an important role in tumor growth. Both tumor cells and stromal cells produce TGF-β1, which contributes to autocrine and paracrine functions in the tumor microenvironment. During cell transformation, TGF-β induces angiogenesis, produces reactive stroma, and tumor invasiveness suggesting that crosstalk between the tumor and the stroma is very important in the progression of metastatic disease. The present study examined the effects of TGF-β1 crosstalk in the tumor microenvironment and its role in mediating tumor formation and tumor development by targeted abrogation of TGF-β expression in the tumor cells in situ. Athymic female mice were injected subcutaneously with either normal or tumor derived fibroblast, unmodified MDA-MB 435 breast cancer cells, MDA-MB 435 clones containing TGF-β siRNA either alone or in combination with fibroblasts. Implantation of the cells subcutaneously showed significant difference in tumor formation between the groups. Control animals injected with fibroblast only developed no tumors. In animals injected with TGF-β-silenced MDA-MB 435 clones there was 12.5% tumor incidence. When these same cells were injected in combination with fibroblast the tumor incidence increased to 57%. Unmodified MDA-MB 435 cells showed a tumor incidence of 85% when injected alone and 100% in the presence of fibroblasts. This data suggests that when TGF-β is inhibited in the tumor cells the surrounding stroma can provide growth factors that continue to support tumor formation. In addition to measuring the tumor incidence, tumor growth was assessed every two days over the course of 6 weeks or until tumor was removed due to necrosis. Control animals injected with fibroblasts alone showed no tumor growth. The tumors formed from TGF-β-silenced MDA-MB 435 clones display an average tumor volume of 11.2 mm3. When these cells were co-injected with fibroblasts, the average tumor volume increased to 76 mm3. Unmodified MDA-MB 435 cells produced an average tumor volume of 164.3 mm3 but when injected with fibroblast the volume increased to 229.1 mm3. This data suggests that signaling from the tumor microenvironment can promote tumor progression through TGF-β signaling pathway. Thus, understanding the role of TGF-β1 expression in the tumor microenvironment will help to develop targeted therapies for 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 541.