bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2465: Microenvironmental sugars regulate pancreatic cancer stem cell transcription to promote an invasive phenotype
Authors: Liu Haibo , Wang Charles , Du Li , Heaney Anthony 
Published: June 2012

Abstract
Pancreatic cancer is a lethal disease and there are few effective therapies. Increased refined carbohydrate and specifically fructose consumption have been associated with increased pancreatic cancer risk in some studies. We recently demonstrated that fructose-treated pancreatic cancer cells grow in vitro at equivalent rates to glucose and observed that cancer cell metabolism of glucose and fructose are quite different whereby fructose increased nucleic acid synthesis, a feature of a highly aggressive cancer phenotype.
A subset of cells within a tumor, termed cancer stem cells (CSC) that highly tumorigenic and resistant to chemotherapy. We recently demonstrated that the metabolism of fructose and glucose in pancreatic cancer is very different with fructose preferentially providing carbons for nucleic acid synthesis. To gain insight into how nutrients such as fructose might differentially regulate cancer cell metabolic pathways to promote an aggressive phenotype, we performed mRNA expression profiling followed by QT-PCR in fructose-treated pancreatic CSCs and compared gene expression to pancreatic CSCs maintained in normal medium. Following fructose-treatment (0.55-5.5mM), we demonstrated increased chemokine receptor4 (CXCR4), epidermal growth factor receptor (EGFR) and glutathione peroxidase (GPX1) mRNA expression in comparison to glucose- (0.55-5.5mM) or normal medium (22mM glucose) -treated pancreatic CSCs and in comparison to fructose- or glucose-treated pancreatic cancer non stem cells (NSC), whole Panc-1 cells and normal pancreatic ductal HPDE6 cells.
In additional studies we observed that the nutrient sugar fructose selectively activates distinct tumorigenic signaling cascades in pancreatic CSCs including phosphorylated Akt and GSK-3α/β to increase CXCR4 to potentially promote growth, survival and metastases of pancreatic cancer stem cells. We also observed that fructose potently induced pancreatic CSC mRNA expression of the selective fructose transporter GLUT5, providing further insight into fructose-mediated actions in pancreatic CSCs. In summary, we demonstrate that sugars mediate effects beyond that of a simple substrate and that environmental dietary nutrients can alter gene expression to potentially modify the cancer phenotype.
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 2465. doi:10.1158/1538-7445.AM2011-2465
Abstract 2471: The tumor suppressor gene Rb1 controls telomeric length and genomic instability that predisposes to osteosarcoma development in irradiated mice
Authors: Gonzalez-Vasconcellos Iria , Sanli-Bonazzi Bahar , Anastasov Natasa , Atkinson Michael J. , Rosemann Michael 
Published: June 2012

Abstract
Osteosarcomas are capable of exhibiting both alternative lengthening of telomeres (ALT) and genomic instability, and are commonly associated with inactivation of the Rb1 gene implicated in both, cell cycle checkpoint regulation and telomere maintainance. We demonstrate a functional relationship between the loss of Rb1, genomic instability and the shortening of telomeres in radiation-induced osteosarcoma. Conditional somatic deletion of a floxed-Rb1 allele in the osteoblastic lineage produces an increased sensitivity to the osteosarcomagenic effects of radiation (Gonzalez-Vasconcellos et al, 2010).
In Rb1 +/- osteoblast cell lines established from non-irradiated Rb1fl/+ Col1a1-Cre mice we show that after irradiation there was the expected impaired cell cycle arrest accompanied by an increase in genomic instability and reduced radiation induced senescence. The DNAmicronucleus assay showed an increase of 1.53 fold in Rb +/- primary cells as compared to Rb+/+ after 2 Gy irradiation (p=0.0032).
We could prove that the reduced Rb1 gene expression in primary osteoblasts leads to a reduction in telomeric length of up to 50% that increases in a passage dependent manner and was shown to be independent of radiation exposure. These mutant cells showed an inclination towards tetraploidy and radiation induced anaphase bridges formation was increased in 2.6 fold in the mutant cells after 2 Gy irradiation (p = 0.001).
These studies suggest the tumor suppressor gene Rb1 functioning not only as a gatekeeper if not also as a caretaker of the genome controlling the telomere dynamics and genomic stability. This maintenance of the genome by Rb1 was proven to be driven by epigenetic changes on the Rb+/- primary osteoblasts involving histone methylation. Lower levels of 3metLys20-H4 fluorescence intensity (p = 0.0079) were detected in Rb1 mutant osteoblasts as compared to wt.
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 2471. doi:10.1158/1538-7445.AM2011-2471
Abstract 2492: Protein phosphatase PP6 regulates the sensitivity of glioblastoma cells to radiation
Authors: Shen Ying , Fei Xin , Wang Yongbin , Kong Xianming , Qiu Yongming , Mi Jun 
Published: June 2012

Abstract
Glioblastoma is one of most aggressive primary tumors. The average survival time of GBM patients is 12 months; moreover, GBM is highly resistant to radiotherapy and chemotherapy, so, how to increase the sensitivity of GBM cells to radiotherapy is still a challenging to all oncologists. Our study demonstrate serine/threonine protein phosphatase PP6 is associated with the radioresistance of glioblastoma (GBM) cells, and the expression level of PP6c (PP6 catalytic subunit) is highly correlated with the survival time of GBM patients (R2 = -0.7). Lentiviruses-mediated PP6c knocking down increases the radiosensitivity of glioblastoma in xenografted mouse model, and prolong the survival time of tumor-bearing mouse; while the overexpression of PP6c decreases the radiosensitivity of glioblastoma and shortens the survival time of tumor-bearing mouse. Our data also show the PP6 is complexed with DNA-PK by the co-immunoprecipitation assay, the siRNA knock-down of PP6c inhibits DNA damage-induced DNA-PK activation and DNA-repair capacity, and sensitized the U251, T98G, U87 three cell lines to radiation in vitro. These results strongly suggest PP6 is a therapeutic target for radiosensitization.
Key Words: DNA-PK, PP6, ubiquitination, radiosensitivity, GBM
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 2492. doi:10.1158/1538-7445.AM2011-2492
Abstract 2503: Distinct radiosensitivities of human FancG-/- and FancD2-/- cell lines
Authors: Bernard Mark E. , Epperly Michael W. , Franicola Darcy , Zhang Xichen , Shields Donna , Houghton Frank , Bakkenist Christopher J. , Guinan Eva C. , Kannan Neeta , Greenberger Joel S. 
Published: June 2012

Abstract
Background: Fanconi Anemia is an autosomal recessive disorder marked by a dysfunction of DNA repair, an increased sensitivity to DNA crosslinking agents, and some patients poorly tolerating ionizing irradiation. We determined the radiosensitivity of two Fanconi patient cell lines and we determined if the nitroxide radioprotector Tempo or a novel mitochondrial targeted nitroxide JP4-039 could alter their radiosensitivity.
Materials and Methods: Fanconi patient derived fibroblastic cell lines, PD326 and PD20F, and their respective transgene restored cell lines FancG and FancD2 were irradiated to doses ranging from 0 to 8 Gy in the presence or absence of Tempo or JP4-039 (10 µm), plated, and colonies greater than 50 cells were counted eight days later.
Results: The PD20F cell line was more radiosensitive compared to the restored FancD2 cell line (n = 1.6 + 0.2 and 10.7 + 3.1, respectively, p = 0.0423). In contrast the PD326 cell line was more radioresistant than its restored FancG cell line as seen by an increased shoulder on the survival curve (n = 8.1 + 1.4 and 2.2 + 0.3, respectively, p = 0.0174). JP4-039 but not Tempo increased radioresistance in the PD326 (n = 15.7 + 2.5, p = 0.0373), and FancG cell lines (10.2 + 2.1, p = 0.0151).
Conclusions: The human Fanconi Anemia cell line PD326 is radioresistant when compared to its transgene restored FancG cell line, and this radioresistance is increased by treatment with the mitochondrial targeted nitroxide JP4-039. In contrast, PD20F is more radiosensitive when compared to its transgene restored FancD2 cell line. Testing the efficacy of JP4-039 and Tempo on mitigating the effects of mitomycin C treatment is being evaluated.
Supported by 2U19A1068021-06
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 2503. doi:10.1158/1538-7445.AM2011-2503
Abstract 2537: Novel 2′-deoxycytidine analogs as DNA demethylation agents
Authors: Thottassery Jaideep V. , Tiwari Kamal , Westbrook Louise , Secrist John A. , Parker William B. 
Published: June 2012

Abstract
Epigenetic therapies using cytidine/deoxycytidine analogs are proving to be effective as indicated by the recent approvals of 5-azacytidine (5-azaCyd) and 5-aza-2’-deoxycytidine (5-azadCyd) in myelodysplastic syndromes (MDS) and certain leukemias. Studies suggest that the inhibition of DNA cytosine-5 methylation and the re-expression of silenced tumor suppressors contribute to the beneficial effects of these drugs. However inhibition of DNA synthesis and other toxicities of these compounds represent major drawbacks in the clinic. Recently another analog previously examined in our anticancer discovery program, 4’-thio-2’-deoxycytidine (T-dCyd), had been shown to be an inhibitor of methyl transfer by the M. HhaI DNA cytosine-5 methyltransferase. In the current studies we demonstrate that T-dCyd and its 5-aza analogue 4’-thio-5-aza-2’-deoxycytidine (5-aza-T-dCyd), can deplete human DNMT1 protein in NCI-H23 lung carcinoma and the myeloid leukemia lines THP-1 and KG1a. Consistent with this we also found that T-dCyd and 5-aza-T-dCyd were also effective in decreasing DNMT activities in cancer cells. Methylation-specific PCR (MSP) analysis also demonstrated that both T-dCyd and 5-aza-T-dCyd induced CpG demethylation and re-expression of the tumor suppressor p15 in KG1a cells. We have also found that T-dCyd is inserted into replicating DNA at nanomolar doses as readily if not better than the natural 2’-deoxycytidine (dCyd) and exhibited very little toxicity at these doses. T-dCyd is therefore readily activated to its triphosphate T-dCTP, which is a good substrate for DNA polymerase mediated incorporation, and DNA polymerases also readily extend the chain after incorporation. Furthermore we also observed that T-dCyd and 5-aza-T-dCyd are efficacious in in vivo tumor models. Collectively our data suggest that these compounds or their analogs could be developed as novel DNA methylation inhibitors with better properties for cancer therapy.
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 2537. doi:10.1158/1538-7445.AM2011-2537
Abstract 256: Downregulation of Pim-3 kinase inhibits cell growth and chemosensitizes pancreatic cancer cells to gemcitabine
Authors: Xu Dapeng , Gavilano Lily , Witherspoon Sam M. , Bednarski Brian , Kim Hongjin , Baldwin Albert S. , Baines Antonio T. 
Published: June 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer of the pancreas, comprising over 85% of all cases. PDAC has a relative 1-year survival rate of 24% and a 5-year survival rate of 5%. Recent clinical studies indicate that patients with advanced pancreatic cancer show a 12% tumor response rate after treatment with the chemotherapeutic drug gemcitabine. Even in combination with other chemotherapeutic agents such as erlotinib, survival rates are only increased by a few weeks. Past studies have shown that members of the oncogenic Pim kinase family are aberrantly expressed in a variety of solid tumors, including prostate and pancreatic cancers. Most recently, Pim kinase has been correlated with chemoresistance in prostate cancer cells. Our study aimed to investigate the role of Pim-3 kinase in the chemoresistance of PDAC cancer cells to gemcitabine. We hypothesize that inhibition of Pim-3 will decrease cell growth and sensitize PDAC cells to gemcitabine treatment. Initially, we confirmed by immunohistochemistry and western blot analysis that Pim-3 is aberrantly expressed in PDAC tissues and cell lines, respectively. We found that inhibition of Pim-3 expression by shRNA decreased PDAC cell growth and resulted in an accumulation of cells in G1 or S phase of the cell cycle. Additionally, we demonstrated that PDAC cells expressing Pim-3 shRNA had increased apoptosis after gemcitabine treatment compared to controls. To determine a possible mechanism for this resensitization of PDAC cells to gemcitabine, we measured multidrug resistance (MDR)1 activity in the Pim-3 shRNA cells. We found that inhibition of Pim-3 protein expression in PDAC cells promoted gemcitabine sensitivity, in part, by lowering MDR1 activity. Our results suggest that downregulation of Pim-3 potentiates the efficacy of gemcitabine in combating pancreatic cancer. These findings support the idea that inhibiting Pim kinases, in combination with chemotherapeutic agents, could play an important role in pancreatic cancer treatment by targeting the clinical problem of chemoresistance.
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 256. doi:10.1158/1538-7445.AM2011-256
Abstract 2561: Inhibiting the mTOR pathway synergistically enhances etoposide-induced cytotoxicity by upregulating c-Jun in ovarian cancer cells
Authors: Itamochi Hiroaki , Nonaka Michiko , Sato Seiya , Uegaki Kazunori , Naniwa Jun , Sato Shinya , Shimada Muneaki , Tetsuro Oishi , Terakawa Naoki , Kigawa Junzo , Harada Tasuku 
Published: June 2012

Abstract
Objective: The mammalian target of rapamycin (mTOR) pathway is considered to be a central regulator of proliferation and survival of cells. Rapamycin and its analogs are undergoing clinical trials in patients with epithelial ovarian cancer. Rapamycin has been reported to enhance the effectiveness of several chemotherapeutic agents. The present study aimed to assess the potential of combination effects of rapamycin and anticancer drugs used as first- or second-line chemotherapy to treat ovarian cancer.
Methods: Six cell lines of ovarian serous adenocarcinoma (KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS-3, TU-OS-4) were used in this study. We treated the cells with rapamycin combined with anticancer agents, then assessed cell viability, apoptosis, and the expression of proteins in apoptotic pathways and molecules downstream of the mTOR signaling pathways. We also investigated the effect of combined treatment on survival in xenograft models with nude mice.
Results: The protein expression levels of PTEN, phosphorylated (p) Akt, pmTOR, p4E-BP1, and pS6K1 were confirmed in all cell lines. Synergistic effects with rapamycin were observed in combination with etoposide in five cell lines, with doxorubicin in four lines, and with SN38, which is an active metabolite of camptothecin-11, in two lines. However, we observed antagonistic effects when rapamycin was combined with gemcitabine, cisplatin, or paclitaxel on more than two cell lines. Rapamycin dramatically enhanced apoptosis induced by etoposide and the expression of cleaved caspase 9. This effect was associated with up-regulation of phosphorylated c-Jun and down-regulation of Bcl-xL. The synergistic interaction of rapamycin and etoposide was lower when the c-Jun pathway was suppressed by a c-Jun N-terminal kinase inhibitor (SP600125). Finally, treating nude mice with rapamycin and etoposide significantly prolonged survival in model mice with ovarian cancer xenografts (P&lt;0.001).
Conclusion: Combination chemotherapy consisting of rapamycin and etoposide showed synergistic effect against epithelial ovarian cancer. This treatment modality is worth exploring further for patients with ovarian 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 2561. doi:10.1158/1538-7445.AM2011-2561
Abstract 2566: Beneficial impact of valproate on the response of small cell lung cancer to cisplatin – etoposide therapy
Authors: Vandermeers Fabian , Hubaux Roland , Crisanti Maria Cecilia , Kapoor Veena , Albelda Steven M. , Willems Luc 
Published: June 2012

Abstract
Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years. We hypothesized that SCLC chemotherapy could be improved by using histone deacetylase (HDAC) inhibitors based on their ability to interfere with lysine acetylation and to alter gene expression. The goal of this study was to evaluate the anticancer efficacy of a HDAC inhibitor (valproate: VPA) on SCLC cells in combination with the standard chemotherapeutic first-line regimen (cisplatin + etoposide). We show that VPA induces apoptosis of small cell lung cancer cell lines and improves efficacy of cisplatin combined with etoposide. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. As expected for an HDAC inhibitor, VPA hyperacetylates histone H3. The mechanism of VPA pro-apoptotic activity involves induction of p21, inhibition of Bcl-XL, cleavage of Bid and phosphorylation of Erk and H2AX. In the presence of VPA, Bax is translocated from the cytoplasm to the mitochondria and cleaved in an 18 kDa isoform. Cytochrome c is released from the mitochondria into the cytosol. Transcriptomic analyses by microarray show that VPA modulates transcription of genes (Na+/ K+ ATPase, Bcl-XL) involved in chemoresistance to cisplatin and etoposide. Finally, the efficacy of VPA combined with cisplatin and etoposide is supported by preclinical models of SCLC cells engrafted into SCID mice. Together, these data demonstrate that VPA augments anticancer activity of cisplatin and etoposide, two components of the standard first-line chemotherapy of small cell lung 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 2566. doi:10.1158/1538-7445.AM2011-2566
Abstract 2588: Targeting overexpressed PLK1 and Aurora kinases in childhood medulloblastoma
Authors: Holst Martin I. , Westerhout Ellen , Kool Marcel , Caron Huib , Versteeg Rogier , Clifford Steve , Rutkowski Stefan , Pietsch Torsten 
Published: June 2012

Abstract
The European research project Kids Cancer Kinome (KCK) is focusing on the investigation of aggressive childhood cancers. The competence of nine research centers is combined to explore the human protein kinase family in different highly malignant pediatric tumors (medulloblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, ALL) to validate novel drug targets and develop novel therapeutic options. Medulloblastomas belong to the most frequent malignant brain tumors in children and represent about 20% of all pediatric CNS cancers. Analyzing mRNA expression profiles (Affymetrix microarrays) we discovered a series of kinases considerably overexpressed in primary medulloblastoma tumors samples and medulloblastoma cell lines compared to non-neoplastic tissues.
We found a significant mRNA overexpression of PLk1 and Aurora kinases A and B in medulloblastoma tumor samples and cell lines. For further investigation we selected these kinases which are all involved in cell cycle control. Defects in the process of cell division are believed to be associated with tumorigenesis.
Using the small molecules inhibitors ZM447439 and VX680 for Aurora kinases and BI2536 and GW843682 for PLK1 inhibition we evaluated the effects on medulloblastoma cell proliferation and apoptosis. Incubation of medulloblastoma cells with the inhibitors for 72h resulted in a concentration dependent decrease of the proliferative activity as measured by MTS proliferation assays and an increased apoptosis determined by Caspase-Glo 3/7 assay.
In a second approach, we transduced cell lines with lentiviral particles carrying shRNA targeting PLK1 or Aurora kinases A and B. The specific downregulation of the kinases mediated by the lentiviral shRNA was confirmed by Western blotting and had a negative effect on the viability of the medulloblastoma cells. We observed that the effect of PLK1 inhibition on the proliferation of the medulloblastoma cell lines was more effective compared to the aurora kinases.
In conclusion, these data suggest that the inhibition of PLK1 or Aurora kinases may represent a promising approach for novel targeted strategies in the treatment of medulloblastoma.
http://www.kidscancerkinome.org
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 2588. doi:10.1158/1538-7445.AM2011-2588