bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2633: Histone deacetylase inhibitors induce CXCR4 mRNA but antagonize CXCR4 migration
Authors: Ierano Caterina , To Kin Wah , Robey Robert W. , Bates Susan E. , Scala Stefania 
Published: June 2012

Abstract
The stromal cell-derived factor-1α SDF-1α (CXCL12)/CXCR4 axis has a critical role, particularly in renal cancer where CXCR4 expression has been linked to poor prognosis. Histone deacetylase inhibitors (HDIs) exert antitumor effects by targeting both histone and nonhistone proteins affecting cell migration, apoptosis, cell proliferation and angiogenesis. Thus, the aim of the present work was to evaluate the effects of the HDIs apicidin, vorinostat, MS-275 and romidepsin on the expression and function of CXCR4 in human cancer cell lines including renal, non-small cell lung, breast, colon and glioma cell lines. After treatment with romidepsin or apicidin, CXCR4 mRNA expression increased 12-fold in UOK121 and 2.5-fold in UOK143 renal cancer cell lines; treatment with vorinostat or MS-275 yielded similar effects. CXCR4 induction was also observed in H460 non-small cell lung cancer cells, and SF-295 glioblastoma cells, but not in MCF-7 breast cancer cells or SW620 colon cancer cells. To evaluate the corresponding CXCR4 functional increase, CXCL12-induced ERK1/2, STAT-3, and c-SRC activation and cell migration were examined in UOK121, SF295 and H460 cells. In general, the HDIs increased pERK1/2, while reducing pSTAT-3 and pSRC. Following CXCL12 pERK1/2 induction was maintained but STAT3 and SRC phosphorylation was impaired. These findings resulted in reduced basal and CXCL12-mediated cell migration. In conclusion, HDIs up-regulated CXCR4 mRNA expression but impaired signalling cascades CXCL12-dependent on STAT3 and c-SRC, suggesting a role for HDI in delaying or preventing metastatic process in solid 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 2633. doi:10.1158/1538-7445.AM2011-2633
Abstract 2634: Methionine metabolites specifically protect anticancer effect of 5-FU but not for cisplatin in human lung cancer cells
Authors: Ham Myeong-Sun , Jeong Jong-Woo , Lee Ju-Kyung , Park Jin-Ah , Kim Kyeong-Ah , Kim Keun-Cheol 
Published: June 2012

Abstract
It has been known that cellular methylation is associated with stabilization of chromatin structure. S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), as metabolites of methionine metabolism, are the substrate and end product of essential cellular methyltransferase reactions, respectively. In this study, we are to explain that these metabolites specifically regulate anticancer effect of 5-FU but not for cisplatin. Using MTT assay, we have found that combination treatment of SAM or SAH with 5-FU specifically protect the anticancer effect of 5-FU in time or dose dependent manner, whereas combination treatment with cisplatin had no effect. This result was also consistent in cell cycle distribution by FACS analysis. Induction of tumor suppressor p53 by anticancer drugs was decreased in combination treatment of those metabolites with 5-FU. We hypothesized what cellular methylation related proteins involve in the protection effect. SUV39H1 and G9a, typical HMTases for H3K9, also have no change in combination treatment of those metabolites with 5-FU. However, expression of DNMT3A and DNMT3B were increased at the combination treatment of SAM and 5-FU. Interestingly, there were no change on expression of DNMT3A and DNMT3B in combination treatment of SAH with 5-FU, indicating protection effect of SAM and SAH on 5-FU differently act at the molecular level. Together, we suggest that cellular methylation can specifically modulate anticancer effect of DNA damage agent 5-FU and this can be modulated by aberrant DNA methylation.
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 2634. doi:10.1158/1538-7445.AM2011-2634
Abstract 2639: RanGAP1·SUMO1 hyperphosphorylation (RGSH) and mitotic arrest by ON 01910.Na, okadaic acid or tubulin agents
Authors: Oussenko Irina , Holland James F. , Reddy E. Premkumar , Ohnuma Takao 
Published: June 2012

Abstract
INTRODUCTION: RanGAP1·SUMO1 is phosphorylated before nuclear envelope breakdown when cells enter mitosis. Previous work from our laboratory showed that a new anticancer antimitotic agent, ON 01910.Na (abbreviated 1910), a benzyl styryl sulfone analog, induced RGSH in all four human tumor cell lines tested. RGSH was not observed in the presence of 1911, inactive analog of 1910. However, RGSH was observed in the presence of tubulin depolymerizing agent nocodazole. Tubulin polymerization assay revealed that, unlike nocodazole, neither 1910 nor 1911 had effects on tubulin polymerization in vitro. In this study, we examined whether other tubulin agents induce RGSH and whether known mitotic phosphatases are involved. METHODS and RESULTS: We used two cell lines, MOLT-3 ALL and DU145 prostate cancer cell lines. We examined RGSH in the presence of known tubulin toxins including paclitaxel, vinblastine, vincristine, colchicine and nocodazole at a concentration of 1 µM in 4 h and 24 h. Doxorubicin and camptothecin served as negative controls. Following treatment with drugs, cells were analyzed by Western blotting. Drug concentrations that inhibited cell growth by 50% (IC50) or 90% (IC90) were determined in 3-day drug exposure experiments. All tubulin agents in the study were capable of inducing RGSH after 4h and 24 h exposure in both cell lines. The drug-induced RGSH was inhibited by caffeine, an ATM and ATR kinase inhibitor, and roscovitine, a Cdk kinase inhibitor. Okadaic acid (OA), known primarily as PP1 and PP2A phosphatase inhibitor, was also found to be capable of RGSH, therefore making it plausible by analogy that 1910 is RanGAP1·SUMO1 phosphatase inhibitor. The concentrations of 1910, OA or tubulin agents sufficient to elicit RGSH in 24 h, also caused 50 to 90% growth inhibition, respectively. 1910, as well as all tubulin agents in the study, induced phosphorylation of the phosphatase Cdc25C (aka “mitotic” Cdc25C) and down-regulation of interphase form of Cdc25C. CONCLUSION: 1910 and selected tubulin agents caused RGSH at IC50 – IC90 concentrations. Similar to tubulin agents, 1910 produced Cdc25C phosphorylation and down-regulation of its interphase form. OA inhibition of PP1 phosphatase and activation of RGSH suggest that 1910 could also serve as a phosphatase inhibitor.
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 2639. doi:10.1158/1538-7445.AM2011-2639
Abstract 265: c-Myc and NFκB are reciprocal and contextual transcriptional regulators of glioma cell proliferation or invasion
Authors: Dhruv Harshil D. , McDonough Wendy S. , Tran Nhan , Armstrong Brock , Tuncali Serdar , Eschbacher Jenny , Kislin Kerri , Berens Michael E. 
Published: June 2012

Abstract
Classic histological features of glioblastoma include dense proliferative areas rich in angiogenesis as well as centripetal dissemination of neoplastic cells into adjacent brain tissue (most frequently white matter). The infiltrative dispersion patterns of malignant glioma preclude complete tumor resection; growth of satellite lesions causes significant neurological morbidity and mortality, and accounts for much of the post-treatment, recurrent (fatal) disease. Distinct transcriptomes are discernable between GBM cells at the tumor core and invasive rim, and many of the differentially-expressed genes are co-associated with migration and the collateral phenotype of cell survival; reciprocal downregulation of genes in invasive glioma cells are ontologically associated with proliferation. Our studies of glioma cells from paired core and rim human biopsy specimens reveal a higher proliferative index (Ki67 Mib-1 IHC score) at the core as compared to the rim (19 out of 35 specimens) p &lt; 0.002. Analysis of activation states of transcription factors (Luminex multiplex assay) revealed that nuclear c-myc activity is up in the tumor core while nuclear NFκB activity is up at the invasive rim of the tumor. Depletion of c-myc (siRNA oligonucleotides) resulted in an increase in the migration rate of glioma cells in vitro, whereas inhibition of NFκB by SN50 resulted in a decrease in migration rate both in vitro and ex vivo (rat brain slice). Immunohistochemical validation using a glioma tissue microarray containing paired core and rim biopsy specimens showed that phosphorylated c-myc staining was higher in the core than in the rim for 23 out of 39 biopsy specimens scored, and that phosphorylated NFκB was higher in the rim than the core for 30 out of 43 biopsy specimens scored. The Go vs Grow hypothesis suggests cell proliferation and cell migration are temporally exclusive behaviors and tumor cells postpone cell division for migration. Our findings argue that differential suppression/activation of c-myc and NFκB underlie the shift of glioma cells from growing to going.
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 265. doi:10.1158/1538-7445.AM2011-265
Abstract 2658: Phase II study of chemoradiation therapy and erlotinib for stage III non-small cell lung cancer
Authors: Komaki Ritsuko U. , Wistuba Ignacio , Tang Xi Ming , Meyn Raymond E. , Lee J. Jack , Wei Xiong , Allen Pamela K. , O'Reilly Michael S. , Welsh James , Hong Wuan Ki 
Published: June 2012

Abstract
Preclinical evidence that the epidermal growth factor receptor (EGFR) inhibitor erlotinib has radiosensitizing properties in vitro led us to test its use, in combination with standard chemoradiation therapy (ChRT), in a prospective phase II study of patients with locally advanced non-small cell lung cancer. Endpoints were radiographic response, survival rates, and toxicity. We also tested if EGFR copy number or protein expression and mutations in EGFR exons 19-21 or KRAS codons 12-13, all measured in formalin-fixed paraffin-embedded biopsy specimens, predicted response to this therapy. Patients were to receive ChRT (RT=63 Gy in 35 fractions in 7 wks; Ch=weekly paclitaxel 45 mg/m2+carboplatin AUC 2) with erlotinib 150 mg po daily (except on Ch days) followed by two cycles of consolidation Ch. Of the 48 patients enrolled (30 male, 18 female; median age 64 yr; all with good performance status), 38 were evaluable for response. At a median follow-up of 11 months, the response rate was 79% (29% complete and 50% partial); 10% had stable disease and 11% progressive disease. The overall survival rate at 1 yr was 85%; 42% were alive without evidence of disease, 34% alive with disease, and 24% dead. Severe acute toxicity (grade 3 in the NCI Common Terminology Criteria v3) was manageable and included pneumonia (n=7), skin reactions (n=4), pneumonitis (n=3), and dehydration (n=3); several hematologic toxicity included leukopenia (n=13), neutropenia (n=7), and thrombocytopenia (n=1). No patients died of treatment-related causes. Of the 34 patients with biopsy specimens, only 3 showed EGFR mutation and 1 a KRAS mutation, and none correlated with response. However, complete response was more likely among current or former smokers (n=10) than never-smokers (n=0, P=0.023). We conclude that the 1-yr overall survival rate was promising but the complete response rate was disappointing. Erlotinib may have had a radiosensitizing effect in vivo, but additional patients and longer follow-up are needed.
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 2658. doi:10.1158/1538-7445.AM2011-2658
Abstract 2668: Radiosensitization of solid tumor cell lines by an MDM2 inhibitor
Authors: Cerna David , LI Hongyun , Flaherty Siobhan , Carter Donna , Coleman C. Norman , Yoo Stephen 
Published: June 2012

Abstract
The tumor suppressor p53 is a key molecule in the prevention of cancer. More than half of all human cancers have mutation or loss of the p53 gene. A significant percentage of the other half contain overexpression of Hdm2 which serves as a ubiquitin ligase (E3) to target p53 for degradation. While it has been established that an inhibitor of Hdm2 ubiquitin E3 ligase activity HLI373 (5-(3-dimethylaminopropylamino)-3,10-dimethyl-10H-pyrimido(4,5-b)quinoline-2,4-dione, NSC373989), selectively kills tumor cells harboring wild-type p53, we investigated the effect of the Hdm2 inhibitor HLI373, in the response to ionizing radiation in solid tumor lines expressing wild-type, mutant or null p53 in vitro and in vivo. We now report HLI373 enhances radiosensitivity in a panel of human tumor cell lines in p53 deficient and competent cell lines using clonogenic assay. HCT116 cells exposed to HLI373 (5-7.5 uM) for 16 hours before and maintained in the medium after irradiation had an increase in radiosensitivity. Cell cycle distribution of treated cells after 16 hours was measured using flow cytometry. In a comparison of wildtype and null cell lines, cell cycle arrest in G1 was only detected in cells with active p53 at 5uM of HLI373. In contrast, cells with a null or mutated p53 progressed to and arrested in G2. In addition, wild type p53 cells pretreated with 5 uM HLI373 and irradiated continued to be arrested in G1 and did not progress to a G2. However, cells without p53 treated with HLI373 and radiation increased in accumulation in G2. Treatment with higher dosages of HLI373 (&gt;10uM) resulted in the accumulation of cells in G2 regardless of p53 status. These results indicate that HLI373 enhances tumor cell radiosensitivity in vitro and agents such as HLI373 may have potential for use in the clinics.
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 2668. doi:10.1158/1538-7445.AM2011-2668
Abstract 2708: Functional characterization of a fluorescent highly tumorigenic ovarian cancer line to test cellular therapy in experimental models
Authors: Ingersoll Susan Blaydes , Ahmad Sarfraz , Stoltzfus Gregory P. , Merchant Mohammed H. , Radi Michael J. , Finkler Neil J. , Edwards John R. , Holloway Robert W. 
Published: June 2012

Abstract
Introduction: Because current therapies for ovarian cancer have little impact on the long-term survival, there is a compelling need to develop innovative strategies. Our aim was to functionally characterize a fluorescent highly tumorigenic ovarian cancer line to test cellular therapy in combination with cytokines or chemotherapies in experimental models.
Methods: Two fluorescent highly tumorigenic sub-lines (SKOV3-AF1 and SKOV3-AF2) were derived from the SKOV-3 ovarian cancer cell line. Peripheral blood mononuclear cells (PBMC)-mediated cytotoxicity in combination with IL-2 and IFNα-2b of SKOV3-AF1 and -AF2 was assayed by lactate dehydrogenase release. Sensitivity of SKOV3-AF2 cells to polyethylene glycol (PEG)-IFNα-2b or IL-2 was assayed in a xenograph nude mouse model. Histopathology was performed on tumors harvested from mice to determine necrosis and tumor infiltrating lymphocytes in the solid tumors.
Results: SKOV3-AF1 and -AF2 sub-lines exhibit increased cytotoxicity mediated by PBMC, IL-2, and IFNα-2b compared to parental SKOV-3 cells. The average cytotoxicity was 59% for both SKOV3-AF1 and -AF2 compared to 28% for SKOV-3 parental cells (p&lt;0.05). SKOV3-AF1 and -AF2 cells are more tumorigenic in vivo compared to SKOV-3 cells as indicated by tumor incidence (SKOV3 66%, SKOV3-AF1 100%, SKOV3-AF2 100%), time to sacrifice, tumor weight, and ascitic fluid production. In addition, the SKOV3-AF2 cells continue to fluoresce when harvested from the mice. SKOV3-AF2 tumor growth was inhibited by PEG-IFNα-2b but not low-dose IL-2. The average tumor weight was 0.96 g in the control treatment group that did not receive PEG-IFNα-2b versus 0.23 g for PEG-IFNα-2b (12,000 U per week); p &lt; 0.05). There was no significant difference in any of the IL-2 treatment groups (0-4,000 U, thrice weekly). Both PEG-IFNα-2b and IL-2 were well tolerated by the mice as demonstrated by no significant weight loss during the treatment. Histopathology revealed that the tumors consisted of poorly differentiated surface epithelial carcinoma and there was no significant difference in the percent necrosis or TIL score in any of the treatment groups.
Conclusions: Characterization of SKOV3-AF2 cells revealed that these cells are more susceptible to PBMC-mediated cytotoxicity than SKOV-3 cells, are highly tumorigenic in a xenograph model, and continue to fluoresce when harvested from mice. Our data suggests that the SKOV3-AF2 sub-line will be a useful tool to test cellular therapy for the treatment of ovarian cancer utilizing experimental models.
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 2708. doi:10.1158/1538-7445.AM2011-2708
Abstract 272: Transcriptional regulation of REG4, a novel diagnostic marker of gastrointestinal cancer, by CDX2
Authors: Naito Yutaka , Oue Naohide , Sentani Kazuhiro , Sakamoto Naoya , Anami Katsuhiro , Hayashi Tetsutaro , Uraoka Naohiro , Oo Htoo Zarni , Wakamatsu Yuta , Yasui Wataru 
Published: June 2012

Abstract
Regenerating gene family, member 4 (REG4, encodes Reg IV), was originally identified from cDNA library of inflammatory bowel disease tissues, and is specifically expressed in gastrointestinal tract. We have identified REG4 as an overexpressed gene in gastric cancer from SAGE analysis in gastric cancer tissues and noticed as a novel serum marker of cancer. The expression of Reg IV is associated with intestinal mucin differentiation, and RegIV is expressed in CDX2-positive cells. CDX2, the intestine-specific caudal-related homeobox transcription factor, plays a key role in intestinal development and differentiation. In the present study, we investigated whether CDX2 induce RegIV expression.
Western blot analysis indicated that forced expression of CDX2 in HT29 colon cancer cell line induced Reg IV expression. In silico analysis of 2-kilobase upstream region of REG4 revealed at least four putative CDX2 consensus sequences. To assess the role of these putative CDX2 consensus sequences in regulating REG4 transcription, we performed luciferase assay into HSC39 gastric cancer cell line, in which CDX2 is highly expressed. Reporter gene constructs containing 2-kilobase of 5’-flanking region from the REG4 gene showed strong reporter activity. Significant change of reporter activity was not observed between 2.0 and 0.65-kilobase upstream region of REG4 constructs, apart from that significant lower expression level at 0.1-kilobase. These results suggest that expression of REG4 is regulated by CDX2, and upstream region of REG4 has enhancer sequences at proximal region at 0.1-kilobase upstream region. Based on the analysis of single mutation in the putative CDX2 consensus sequences in the 5’-flanking region of the REG4 gene, two putative CDX2 consensus sequences were found to activate REG4 expressions. Therefore, RegIV may be a key factor mediating CDX2 function in intestinal determination. To identify the CDX2-binding site in detail, ChIP assay and mutagenesis with multiple mutations in the putative CDX2 consensus sequences must be carried out.
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 272. doi:10.1158/1538-7445.AM2011-272
Abstract 2724: Intravesical treatment with Vesicular Stomatitis virus decreases the size of bladder tumors without adversely affecting the health and well-being of immune-competent mice
Authors: Skinner Lisa A. , Zhang Kevin , Jia William , Rennie Paul , So Alan 
Published: June 2012

Abstract
Recent studies have shown that wild-type Vesicular Stomatitis virus (VSV) and the Δ51M recombinant IFN-inducing mutant of wild-type VSV (AV3) have powerful oncolytic activity against bladder cancer cells in an immune-compromised bladder cancer model. The objective of the current study was to determine the safety and efficacy of the wild-type VSV and AV3 when intravesically administered to an immune-competent bladder cancer model. Using an established orthotopic bladder cancer model, 100 µL of 108 pfu mL−1 wild-type VSV, AV3, or UV-inactivated wild-type VSV (UVI) was instilled into the urinary bladders of female C3H mice. Half of the mice had normal, healthy bladders and were instilled with the oncolytic virus on day 0, 2, and 4. The remaining mice were given non-muscle invasive bladder tumors through the transurethral instillation of luciferase expressing MBT-2 mouse bladder carcinoma cells. On day 5 after initial tumor inoculation, tumor-bearing mice were imaged for bioluminescence and tumor size was quantified. On days 6, 8, and 10 after the initial tumor inoculation, tumor-bearing mice were randomized for treatment, and wild-type VSV, AV3, or UVI was instilled into each mouse. Levels of tumor bioluminescence (a correlate of tumor size), and body weight (a key variable of animal health and indicator of treatment toxicity) were monitored for 22 days. Following three consecutive intravesical treatments of an oncolytic virus, there were no differences in weight between the treated mice (wild-type VSV and AV3) and the control mice (UV-inactivated wild-type VSV), regardless of tumor presence. In addition, tumor bioluminescence in the AV3 treated mice was slightly decreased (30%) compared to the control mice, but not different from the wild-type VSV treated mice. These data correspond to in vitro data which show that wild-type VSV and AV3 are inhibitors of proliferation in MBT-2 mouse bladder carcinoma cells. In conclusion, our data strongly suggest that oncolytic viruses such as wild-type VSV and its attenuated form, AV3, can be used to treat superficial bladder cancer in immune-competent mice, without adversely affecting the health and well-being of the animal.
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 2724. doi:10.1158/1538-7445.AM2011-2724