bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4087: Metabolic changes associated with acquired cisplatin resistance
Authors: Sullivan Elizabeth J. , Kurtoglu Metin , Wangpaichitr Medhi , Savaraj Niramol , Lampidis Theodore 
Published: July 2012

Abstract
Although cisplatin is the drug of choice in treating lung cancer patients, acquired resistance appears to be a common and serious drawback to its effectiveness in the clinic. Using two pairs of cisplatin sensitive and resistant lung cancer cell lines developed in vitro, we have found significantly lowered hexokinase II (HKII) levels in both resistant cell lines. As a consequence of lowered HKII, these cell lines, when grown under anaerobic conditions, are markedly more sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2DG) than their parental cell lines from which they were derived. This was our first indication that lowered HKII levels in these cisplatin resistant cells has metabolic consequences in different environmental conditions. Thus, it appears that a fundamental difference in glucose metabolism is associated with resistance to cisplatin in these cell lines. It is the aim of this study to explore whether reduced HKII is a common occurrence in cisplatin resistant cells and whether these differences uncover metabolic targets that can be exploited for therapeutic gain.
Much like the Atkins diet, when carbohydrates are lowered or glycolysis is inhibited, other sources of energy such as fatty acids and amino acids can be used to maintain cell viability. A trypan blue cytotoxicity assay was used to determine the sensitivity of our cisplatin resistant cell lines to a pharmacological inhibitor, etomoxir, toward fatty acid oxidation. Thus, we tested and found that one of these cisplatin resistant cell lines is sensitive to interference with fatty acid oxidation. Next, we placed our cell lines in glutamine free medium, and found that the second cisplatin resistant cell line is sensitive to glutamine deprivation. Moreover, when lactate production was measured in anaerobic conditions, cisplatin resistant cell lines produced less lactate when challenged with the glycolytic inhibitor, 2DG, than their cisplatin sensitive parental cell lines.
Overall, our results indicate that lowered HKII levels in two cisplatin resistant cell lines appear to be associated with a decreased reliance on glucose metabolism, with a shift to either fatty acid oxidation or glutaminolysis. Moreover, these cisplatin resistant cells are sensitive to glycolytic inhibition when placed in oxygen-deprived conditions. Thus, these new metabolic targets may be exploited for therapeutic gain in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4087. doi:10.1158/1538-7445.AM2011-4087
Abstract 4090: The role of caspase-2 in apoptotic signaling in AML cells
Authors: Haag Petra , Lindberg Marita Lagergren , Kanter Lena , Stenke Leif , Lewensohn Rolf , Viktorsson Kristina 
Published: July 2012

Abstract
We are investigating signaling molecules involved in apoptotic cell death in acute myeloid leukemia (AML) cells after treatment with the targeted drug gemtuzumab ozogamicin (GO) and the conventional drug daunorubicin, with focus on caspase-2.
New effective therapeutic drugs are highly desirable in the treatment of AML. Although a majority of treated patients initially respond to conventional treatment, most patients will relapse within 1-2 years. Also, the treatment is associated with severe off-target effects. GO is a novel therapeutic approach, consisting of a monoclonal CD33 antibody coupled to calicheamicin, which cause DNA double strand breaks (DSB). We demonstrated that activation of Bak and Bax is critical for GO- and daunorubicin- induced apoptotic signaling in AML cells. The activation was followed by mitochondrial depolarization, caspase-3 activation and nuclear fragmentation.
We continued to examine potential proapoptotic signaling events upstream of mitochondria in HL60 AML cells in vitro. We identified caspase-2 and the pro-apoptotic BH3-only protein Bid as two candidates. By analyzing caspase-2 by western blotting after GO treatment we found that GO caused cleavage of caspase-2 after 24h, which was prior to mitochondria-mediated signaling. Also, full-length Bid was cleaved to its truncated, active form tBid. The importance of caspase-2 activation in the signaling cascade after GO treatment was demonstrated using z-VDVAD-fmk, a caspase-2 inhibitor. Preincubation with this inhibitor reduced caspase-3 activation with around 50%, suggesting that caspase-2 is an important molecule, located upstream of caspase-3, in the signaling between DNA double stranded breaks and apoptosis signaling in AML cells.
In conclusion, we demonstrate that GO and daunorubicin, at clinically applicable concentrations, induce pro-apoptotic signaling which involve activation of caspase-2, and activation of the BH3-only protein Bid. Blocking caspase-2 activity reduced caspase-3 activation with 50%. This suggests multiple signaling pathways capable of activating caspase-3. The caspase-2 pathway appears central for downstream caspase-3 activity, after GO treatment in AML. Our findings may highlight possible resistance mechanisms in AML, which might have profound therapeutic implications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4090. doi:10.1158/1538-7445.AM2011-4090
Abstract 4107: p38-HSP27 as modulators from survival to apoptosis: Combined treatment with TRAIL and curcumin to prostate cancer cells
Authors: Yoon Hyo R. , Sun Bo K. , Nguyen Hoan N. , Kim So Y. , Oh Seeun , Choi Hye J. , Kim Joo-Hang , Song Jae J. 
Published: July 2012

Abstract
The effect of combination of TRAIL and curcumin enhanced apoptotic cell death in many other studies. However, the exact molecular mechanism of enhanced apoptotic cell death by TRAIL plus curcumin was not yet completely understood. In this study, we clearly observed the depression of phosphorylated Akt and increase of phosphorylated p38 during combined treatment with TRAIL and curcumin. Previously, we observed that TRAIL induced the catalytic activation of Akt in TRAIL-sensitive cells and here, the catalytic activation of Akt was reversely decreased by curcumin pretreatment followed by TRAIL. We also found that significant increase of p38 phosphorylation was deeply linked to the decrease of Akt catalytic activity by regulation of the level of phosphorylated HSP27, which leads to the change of interaction between TRAF6 and Src, and subsequent Src-Akt inactivation. For the examination of relationship of p38-HSP27 with Akt activity, in vitro Akt kinase assay, and siRNA technique were used to confirm the biological effect of p38-HSP27 as modulators from survival to apoptosis by combined treatment with TRAIL and curcumin to prostate cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4107. doi:10.1158/1538-7445.AM2011-4107
Abstract 4108: BH3 only Bcl-2 family member BNIP3 repressed expression of death receptor 5 (DR5) in glioblastoma cells: Implications for regulation of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) cell death pathway
Authors: Henson Elizabeth S. , Burton Teralee R. , Azad Meghan B. , Eisenstat David D. , Gibson Spencer B. 
Published: July 2012

Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer. The median survival for patients with GBM is less than 15 months, even with treatment such as surgery, radiation and chemotherapy with temozolomide. Resistance to the standard treatment regimes represents a serious clinical challenge. GBM tumors contain extensive regions of necrosis, indicative of hypoxia. BNIP-3 (Bcl-2 nineteen kilodalton interacting protein) is a BH-3 only, pro-cell death member of the Bcl-2 family. BNIP-3 is up-regulated in hypoxia and leads to a non-classical programmed cell death through the mitochondria. In the majority of glioblastoma multiforme tumors, BNIP3 is localized to the nucleus and does not induce cell death. Our group has shown that when located in the nucleus, BNIP3 binds to DNA including the promoters of cell death genes such as AIF (apoptosis inducing factor). Herein, we found that BNIP3 bound to the promoter region of death receptor 5 (DR5). DR5 binds to the tumor necrosis factor related apoptosis inducing ligand (TRAIL) leading to induction of apoptosis. TRAIL is currently in phase 2 clinical trials for a wide variety of tumor types but glioblastoma tumors are resistant to TRAIL induced apoptosis. Our data showed that binding of BNIP3 to the promoter of DR5 prevented its expression and led to resistance to TRAIL induced cell death in glioma cells. Furthermore, when a BNIP3 construct was transiently over-expressed in the nucleus, DR5 mRNA and protein levels were reduced; also when BNip3 was knocked down using shRNA, DR5 message and protein levels increased. In BNIP3 knockout mice, we demonstrated that increased DR5 levels were increased in primary astrocytes compared to wild type controls as detected by western blot and immunofluorescence. We also showed similar results in brain sections from BNIP3 knockout mice. In paraffin embedded GBM tumors, we found that tumors that had BNIP3 in the nucleus had decreased levels of DR5, whereas tumors without BNIP3 in the nucleus had higher levels of DR5. Taken together, this represents a novel mechanism for regulation of DR5 expression, contributing to TRAIL resistance in GBM tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4108. doi:10.1158/1538-7445.AM2011-4108
Abstract 4200: EXO1 is required for normal SN1 methylator-induced DNA damage response
Authors: Izumchenko Eugene 
Published: July 2012

Abstract
The mismatch repair (MMR) system plays an important role in mutation avoidance and its inactivation, which is commonly seen in both hereditary and sporadic cancers, results in genomic instability and increased cancer risk.
SN1 DNA methylating agents are potent chemotherapeutics that can methylate the O6 position of guanine. This O6meG adduct subsequently mispairs with thymine during DNA replication, MMR recognizes these O6meG/T mispairs, and consequently activates DNA damage response (DDR). While the exact mechanism by which MMR activates DDR signaling remains unresolved, the DNA repair activity of MMR has been implicated as important in this process.
Exonuclease I (EXO1) plays a crucial role in eukaryotic MMR by removing the strand containing the mismatched base. Several studies describe direct association between EXO1 and several MMR proteins (ie, MSH2, MLH1) and that EXO1 is activated during MMR processing of O6meG lesions. However, whether EXO1 is required to activate MMR-dependent response to O6meG remains unknown.
Here we show that Lentiviral shRNA-mediated EXO1 knockdown in mouse embryonic fibroblasts (MEFs) results in decreased G2/M arrest in response to treatment with the SN1 methylator MNNG. Accordingly, we observed reduced phosphorylation of the checkpoint proteins Cdc2 and Chk1, consistent with reduced MMR-dependent signaling in response to MNNG. We also found that EXO1 knockdown resulted in a limited effect on cell proliferation and loss of viability while MEFs transduced with control virus displayed clear growth arrest and a heightened cytotoxic response following MNNG exposure. Taken together, these data support our interpretation that reduced EXO1 activity results in an alkylation-tolerant phenotype similar to documented defects stemming from loss of MMR. Moreover, these findings seemingly strengthen the hypothesis that MMR-associated DNA repair activity is required for response to O6meG lesions. However, several lines of evidence suggest that EXO1 may function in both a catalytic and a structural manner during MMR-mediated mutation avoidance. Therefore, we are currently testing if EXO1 is required for MMR complex assembly at sites of mismatches within duplex DNA, and if exonuclease activity is required for normal response to SN1 methylators.
Our long-term goal is to better understand the mechanisms that guide response to SN1 alkylators since deducing MMR-mediated DNA damage response will yield essential insights for designing drugs targeting these pathways, and predicting drug response in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4200. doi:10.1158/1538-7445.AM2011-4200
Abstract 4273: Circulating human prostate cancer cells from an orthotopic mouse model rapidly captured by immunomagnetic beads and imaged by GFP expression
Authors: Kolostova Katarina , Pinterova Daniela , Hoffman Robert M. , Bobek Vladimir 
Published: July 2012

Abstract
Circulating tumor cells (CTC) are potential precursors of metastasis. They are also of use in diagnosing malignancy and for prognostic purposes. Our laboratory has previously isolated CTC from orthotopic nude mouse models of human prostate cancer cells where the PC-3 cancer cells express green fluorescent protein (GFP). It was found that only orthotopic tumors produced CTC and not subcutaneous tumors, which may explain why orthotopic tumors metastasize and subcutaneous tumors do not. However, in this previous study, CTC were observed only after culture. In the present study, using the GFP-expressing PC-3 orthotopic model and immunomagnetic beads coated with anti-EpCAM and anti-PSMA, GFP-expressing CTC were isolated within 15 minutes and were readily visualized by GFP fluorescence. The immunomagnetic-bead-captured GFP-expressing PC-3 CTC could be immediately placed in 3-dimensional sponge cell culture where they proliferated. The combination of GFP-expression and immunomagnetic beads is very powerful method to obtain CTC for either immediate analysis or for biological characterization in vivo or 3-dimensional culture.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2011-4273
Abstract 429: The value of Tenascin-C expression in neoadjuvant breast cancer therapy
Authors: Bastelberger Stephan , Swierczynski Stefan , Pradel Leon , Beil Jane , Hinterseer Elisabeth , Rendl Gundula , Hauser-Kronberger Cornelia , Dietze Otto 
Published: July 2012

Abstract
Introduction: The extra cellular matrix molecule Tenascin-C (TNC) in its many isoforms is highly expressed during tissue repair and pathological conditions such as cancer and stress. Utilising the selective pressure of neoadjuvant chemotherapy on carcinoma cells we screened for a subgroup of breast cancer patients with elevated TNC expression and a bad therapy response. TNC expression was correlated with biomarkers, histopathological (stage) and clinical data. Breast cancer cell lines were tested on TNC levels and their expression behaviour under competitive conditions.
Methods: Paraffin sections from 68 preoperatively treated breast cancer patients were used for automated immunohistochemistry (IHC) with antibodies targeting TNC, AE1/AE3, Ki67, CD3 and p53. In addition F-18 FDG PET-CT was performed to evaluate therapy response. Protein- and gene expression experiments performed onto six breast cancer cell lines (MCF-7, MDA-MB231, MDA-MB453, SK-BR3, SUM-159, T47-D) showed TNC-expression in MDA-MB453 breast cancer cell line. Gene expression of TNC in hedgehog positive cells (MCF-7) was evaluated after co-cultivation with TNC positive cells (MDA-MB453) by qRT-PCR. The qRT-PCR results confirmed the protein expression results on in vitro stained cell-slides after cell-cell interactions and different growth times. Growth and migration behaviour was studied in 3D-matrigels.
Results: We demonstrate that TNC expression in breast cancer is immensely reduced after neoadjuvant chemotherapy (43% of patients lost TNC expression) and that expression profiles after treatment correlate with tumor grade, lymph node status and estrogen receptor status, indicating prognostic value, probably for endocrine treatment. Post-therapeutical correlation and co-localisation of the proliferation marker Ki67 in cancer cells and TNC in the surrounding tumor-stroma of patients having a less beneficial response to chemotherapy. The evaluation of expression levels revealed a linear correlation of TNC and Ki67. Submitting cell lines to selective environmental pressure on cell chamber slides, we observed differentiated staining patterns and cellular localization for TNC. After co-cultivation with MDA-MB453, the hedgehog positive cell line MCF-7 expressed highly elevated levels of TNC.
Conclusions: These findings concur with the role of TNC in tissue reorganisation, wound healing and it's growth promoting properties in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 429. doi:10.1158/1538-7445.AM2011-429
Abstract 4307: Establishment of a patient-derived diffuse infiltrative pontine glioma primary cell line and animal model: Implications for future investigations and treatment
Authors: Hashizume Rintaro , Aoki Yasuyuki , Liu Sharon , Smirnov Ivan , Phillips Joanna J. , McKnight Tracy , James Charles D. , Gupta Nalin 
Published: July 2012

Abstract
Diffuse infiltrating brainstem glioma arises almost exclusively in children and despite advances in imaging, neurosurgery and radiotherapy, the majority of patients die within 2 years after initial diagnosis. Because of the infiltrative nature and anatomic location in an eloquent area of the brain, most brainstem gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and biochemical abnormalities associated with these tumors, and is a substantial obstacle for the development of animal model designed specifically for the preclinical testing of specific molecular target of brainstem gliomas. We established a brainstem glioma cells originated from human biopsy sample of a low grade brainstem glioma. The brainstem glioma cells were subsequently modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase) to immortalize the cells and analyzed genetic and biochemical abnomalities of the cells. The established human brainstem glioma cells were tumorgenic in athymic rodents and the developed brainstem tumor was recapitulated the infiltrative growth of diffuse infiltrating brainstem glioma in patients, and can be monitored for tumor growth noninvasively by bioluminescence imaging (BLI).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4307. doi:10.1158/1538-7445.AM2011-4307
Abstract 4314: A mouse model of cerebral cavernous malformations
Authors: Yang Guili , Wei Huijie , Han Zhenying , Zhang Zhisong , Duan Biyan , Zhang Jianning , Li Lu-yuan 
Published: July 2012

Abstract
Cerebral cavernous malformations (CCM) are prevalent cerebral vascular lesions involving aberrant angiogenesis that can lead to hemorrhage, epilepsy, and other neurological manifestations. CCM consists of brittle, proliferating caverns filled with blood and lined with endothelial cells. However, the underlying mechanism of CCM development is poorly understood. The cytokine vascular endothelial cell growth inhibitor (VEGI; TNFSF15; TL1A) is an endogenous negative regulator of angiogenesis produced largely by endothelial cells and exerts a specific inhibitory activity on the proliferation of endothelial cells. We found that the production of VEGI by the endothelium is nearly completely diminished in the CCM tissues. In sharp contrast, the expression of VEGI is readily detectable on the vasculature in nearby brain tissues. On the other hand, angiogenic factors such as vascular endothelial cell growth factor (VEGF) is known to be highly expressed in CCM lesions. We show here that an imbalance of angiogenesis promoters and inhibitors, namely, the down-regulation of VEGI and up-regulation of VEGF, are attributable to the development of CCM. We have constructed a mouse CCM model by implanting mouse endothelial cell line bEnd3 cells in the brain of a female BALB/C mouse. The cavernous blood vessels formed in the model closely resemble those observed in CCM and thus may be used to study the pathology and treatment options of CCM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4314. doi:10.1158/1538-7445.AM2011-4314