bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4389: Potential role of superoxide dismutase 3 in prevention of estrogen-induced breast cancer
Authors: Bhat Hari K. , Singh Bhupendra 
Published: February 2011

Abstract
Estrogens have been implicated in the development of human breast cancers. Literature and our studies strongly support the role of oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated for the first time that antioxidants vitamin C or butylated hydroxyanisole (BHA) attenuate 17β-estradiol (E2)-induced oxidative stress; increase the latency of tumor development; and, severely inhibit E2-induced breast tumor development in female ACI rats. The female ACI rat is an established animal model to study the mechanisms of E2-induced breast cancer. The objective of the present study was to identify genes that may provide an insight into the mechanism of inhibition of E2-induced breast carcinogenesis by vitamin C or BHA. Microarray analyses were performed on total RNA isolated from breast and breast tumor tissues of rats treated with E2 (3 mg, s.c.); vitamin C (1% in drinking water); BHA (0.7% in diet); vitamin C + E2 and BHA + E2 for 8 months. A number of genes were shown to be differentially expressed in breast tissue and tumor tissue of rats treated with E2 vs. other treatments. One gene of interest identified was extracellular superoxide dismutase (SOD3) that was 18-fold suppressed in mammary tumors vs. normal mammary tissue and more than 6-fold decreased in mammary tissue of E2 treated animals vs. normal age-matched controls. Protein expression data confirmed the suppression of SOD3 in mammary tissue of E2-treated rats and in mammary tumors. This suppression was overcome by co-treatment of rats with E2 and vitamin C or BHA. SOD3 was induced 2.9- and 2.1-fold respectively by treatments of rats with vitamin C or BHA compared to sham-treated controls. SOD3 expression was not regulated by vitamin C or BHA in the liver tissue suggesting that its expression may be target-organ specific. SOD3 is an extracellular antioxidant enzyme implicated in the prevention of oxidative stress-mediated tissue damage. Thus, SOD3 may play an important role in the prevention of breast cancer and this gene may have a great potential in the development of therapeutic strategies for the prevention of estrogen-induced neoplasia.
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 4389.
Abstract 4390: The p16INK4A tumor suppressor regulates cellular oxidative stress
Authors: Jenkins Noah , Liu Tong , Goodson Agnessa , Samadashwily George , Grossman Douglas 
Published: February 2011

Abstract
Melanoma, a malignant tumor of melanocytes, is a potentially lethal form of skin cancer linked to both environmental and genetic factors. Mutations or deletions in the cyclin-dependent kinase inhibitor p16INK4A are associated with multiple cancer types, but more commonly found in melanoma tumors and specifically associated with familial melanoma predisposition. Although p16 is thought to function as a tumor suppressor by negatively regulating the cell cycle, it remains unclear why genetic compromise of p16 predisposes to melanoma rather than other cancers. Here we describe a novel role for p16 in regulating oxidative stress in several cell types, including melanocytes. Compared to keratinocytes and fibroblasts, we also found increased ROS levels basally and following treatment with H2O2. Expression of p16 was rapidly upregulated following UV-irradiation in melanocytes, and in response to H2O2-induced oxidative stress in a p38 stress-activated protein kinase-dependent manner. Knockdown of p16 using siRNA increased intracellular ROS and oxidative (8-oxoguanine) DNA damage which was further enhanced by H2O2 treatment. Elevated ROS were also observed in p16-depleted human keratinocytes, and in whole skin and dermal fibroblasts from p16-deficient mice. ROS in p16-deficient fibroblasts were normalized by expression of exogenous p16. Finally, p16-mediated suppression of ROS could not be attributed to upregulation of antioxidant enzymes or the role of p16 in cell cycle regulation. These findings suggest a potential alternate tumor-suppressor function of p16 as an endogenous regulator of carcinogenic intracellular oxidative stress. The increased susceptibility of melanocytes to oxidative stress may explain why compromise of p16 predisposes to melanoma over other cancers.
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 4390.
Abstract 4399: EphA2-targeting antibody-gelonin conjugate specifically binds and kills target-expressing tumor cells, including multi-drug resistant (MDR) lines
Authors: Marks John W. , Gooya John , Pore Nabendu , Mao Shenlan , Jackson Dowdy , Rosenblum Michael G. 
Published: February 2011

Abstract
The EphA2 receptor is over-expressed on the surface of many different human tumors, and has been shown to internalize upon ligand or antibody binding. The fully human monoclonal antibody anti-EphA2 antibody was developed by phage display methods and specifically binds both human and rodent EphA2 receptors. The type II ribosome-inactivating protein gelonin was genetically engineered with an extra cysteine residue to facilitate chemical cross-linking with targeting proteins. The fully human anti-EphA2 antibody, anti-EphA2 antibody, was conjugated to the recombinant gelonin (rGel) using the heterobifunctional cross-linker SPDP and partially reduced rGel. The conjugated antibody (anti-EphA2 antibody/rGel) was separated from free antibody and rGel by gel-permeation and affinity chromatography. The final material was composed of antibody+1 rGel (predominant) and antibody+2 rGel (minor) and was essentially free of contaminating rGel or unreacted anti-EphA2 antibody. The anti-EphA2 antibody/rGel conjugate was assessed for cell-free protein synthesis inhibitory activity and found to be similar to free rGel. The conjugate proved specifically cytotoxic to the EphA2 expressing PC-3, MDA-MB-231 and CT-26 cell lines, with IC50 values of 3.8, 6.1 and 11 ng/ml, respectively. The Targeting Index for the anti-EphA2 antibody/rGel conjugate (vs. rGel) was high, with values of 1909, 306 and 75 for PC-3, PC-3-MDR and MDA-MB-231, respectively. Confocal microscopy showed that the anti-EphA2 antibody/rGel conjugate was specifically and rapidly internalized. The maximal intracellular concentration was achieved 4 hours after exposure. Minimal contact time studies showed specific cytotoxicity with only 1 hour exposure while optimal cytotoxicity was achieved with an exposure time of 24 hours. Of special interest, the anti-EphA2 antibody/rGel conjugate demonstrated no significant loss in specific cytotoxicity against Dox-resistant (MDR expressing) cell lines derived from either MDA-MB-231 or PC-3 cells compared to their parental cell lines. These data suggest that the development of MDR-resistant phenotypes may not impair the successful utilization of rGel-based targeted therapeutics. These results support the continued evaluation of the rGel antibody conjugate technology. Research conducted, in part, by the Clayton Foundation for Research.
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 4399.
Abstract 4422: 2-AAPA: A novel anticancer agent that induces microtubule depolymerization and apoptosis
Authors: Chen Wei , Seefeldt Teresa , Young Alan , Zhang Xiaoying , Ruffolo John , Kaushik Radhey , Guan Xiangming 
Published: February 2011

Abstract
This study was aimed to investigate the anticancer activities and the mechanism of the anticancer activities of a novel anticancer agent - 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA). 2-AAPA was found to inhibit various human cancer cell lines with a narrow range of IC50 values (28-75 μM). These cell lines include lung (NCI-H226), prostate (PC-3), breast (MCF-7), skin (A431), melanoma (UACC-62 and SK-MEL-2), and renal (UO-31) cancers, as well as human ovarian cancers (OVCAR-3 and NCI/ADR-RES) which are resistant toward doxorubicin. Flow cytometric studies revealed that 2-AAPA induced cell cycle arrest at G2/M phase and produced significant cell apoptosis in UACC-62 cells. Through immunofluorescence studies, 2-AAPA was found to depolymerize microtubules and cause cell morphological change. An HPLC (high performance liquid chromatography) assay demonstrated that proteins were glutathionylated in both OVCAR-3 and UACC-62 cells when treated with 2-AAPA. A Western blot analysis also showed that a band corresponding to the molecular weight of tubulins was significantly glutathionylated in cell lysate obtained from UACC-62 cells treated with 2-AAPA. Considering the rich thiol content of tubulin proteins and the nature of protein glutathionylation, it is likely that microtubule function might be affected through microtubule glutathionylation resulting in cell cycle arrest at G2/M phase. Immunoprecipitation is being employed to confirm that tubulins are glutathionylated in cells treated with 2-AAPA. Together, our findings could lead to an antimitotic agent with a novel mechanism which is different than those of current antimitotic drugs.
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 4422.
Abstract 4424: Molecular mechanism study of a novel microtubule-binding agent-induced mitotic cell death of human hepatocellular carcinoma
Authors: Liu Jun Jen , Ho Chun Te , Yang Li Xi , Chang Yu Jia , Liu Tsan Zon , Wei Po- Li 
Published: February 2011

Abstract
Polymerization and de-polymerization of microtubule are responsible for separation of chromosomes during cell division which has been considered to be one of major targets in cancer chemotherapy. In order to develop a newer generation of chemotherapeutic agents with higher efficacy and lower toxicity, a novel microtubule-binding agent (AD1), an analog of thiocolchicine, has been successfully synthesized. We here demonstrated AD1 could effectively kill a panel of seven human hepatocellular carcinoma (HCC) cell lines with varying degrees of differentiation. The IC50 values for all these HCC cell lines, using NCI standard protocol (sulforhodamine B, SRB), ranged from 2 to 50 nM. Cell cycle analysis study by flowcytometer unveiled that AD1 could evoke a dose-dependent cell cycle arrest in the G2/M phase. Further immunoflurorescence studies revealed that AD1 could also disrupt tubulin polymerization which would be responsible for the G2/M arrest. These prominent events provoked the disruption of cellular microtubule networks and prevented the proper formation of spindle apparatus and consequently resulted in the mitotic cell death. Interestingly, we also observed that AD1 could induce transcription factor ATF6 cleavage and subsequent reduction of the level of ER stress chaperone protein Grp78, and phosphorylated Akt expression. In vivo toxicity studies demonstrated that AD1, with maximum tolerance dose (MTD) of 150 mg/kg, was remarkably less toxic to normal C3H/HeN mice than colchicine (MTD of 1.6 mg/kg). The in vivo efficacy study of AD1 on HCC xenografts are now being investigated in nude mouse model in our laboratories.
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 4424.
Abstract 444: Hypoxia modulates EWS-FLI1 transcriptional signature and enhances invasiveness and anchorage-independent growth of Ewing's sarcoma cells in-vitro
Authors: Aryee Dave N. T , Niedan Stephan , Kauer Maximilian , Muehlbacher Karin , Walker Robert L. , Meltzer Paul , Poremba Christopher , Kofler Reinhard , Kovar Heinrich 
Published: February 2011

Abstract
Hypoxia is an important factor in the tumor cell microenvironment and approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia. Hypoxia-inducible factor-1 (HIF-1) is the major mediator of transcriptional activation under hypoxia. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. By immunohistochemistry, HIF-1α expression was readily detectable in 18/28 primary Ewing′s sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, hence we studied the effect of hypoxia on ESFT cell lines in-vitro. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is transiently up-regulated by hypoxia in a HIF-1α-dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis related genes, hypoxia stimulated the invasiveness and soft-agar colony formation of ESFT cells in-vitro. Our data represents the first transcriptome analysis of hypoxic ESFT cells and identifies hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity that may impact the malignant properties of ESFT.
This study was funded by: “European Embryonal Tumor Pipeline” 6th framework program of the European Commission (STREP “E.E.T. Pipeline” contract LSHC-CT-2006-037260) and grant 12675 from the Austrian National Bank Jubilaeumsfonds.
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 444.
Abstract 445: Significance of carbonic anhydrase-9 in gastric carcinoma
Authors: Yukihiro Kato , Yashiro Masakazu , Kashiwagi Shinichiro , Fuyuhiro Yuhiko , Noda Satoru , Doi Yosuke , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Inoue Toru , Maeda Kiyoshi , Sawada Tetsuji , Ohira Masaichi , Hirakawa Kosei 
Published: February 2011

Abstract
[purpose] Gastric carcinoma is one of the most frequent causes of cancer death. Various kinds of solid tumor including gastric cancer have heterogeneously a hypoxic environment. In gastric cancers, the hypoxia reported to develop their malignant potential. Cancer cell under hypoxic condition show resistance against various types of therapies. The poor outcome is, however, not only due to the resistance to treatment but also to the more aggressive behavior of cancer cells. Hypoxia selects tumor cells with a reduced apoptotic potential and angiogenic phenotype, which invade the surrounding tissue and easily metastasize due to the activation of matrix metalloproteinases. CA-9 (originally named MN) is a member of the α-family of carbonic anhydrases of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to carbonic acid. The purpose of our study was to clarify significance of the hypoxia in gastric carcinoma using of CA-9.
[materials and methods] A total of 265 patients who had undergone a resection of the primary tumor and were confirmed histologically to have sporadic gastric cancer, were enrolled in this study. Tumor specimens were fixed in 10% formaldehyde solution and embedded in paraffin. The expression of CA-9 was immunohistochemically determined using the antibodies against CA-9 proteins. CA-9 immunostaining was scored as 0 for 0%, 1+ for 1-20%, 2+ for 21-50%, and 3+ for &gt;50%, taking into account the percentage of cells showing membrane in all pieces of specimen from each patient mounted in one slide. Correlation of CA-9 expression and clinic-pathologic features was statistically analyzed using the Chi-square test or Fisher's exact test.
[results] The CA-9 expression was positive in 88 (33%) of 265 gastric carcinomas. The CA-9 expression level was significantly high in type 4 tumors (60%, p&lt;0.001) and diffuse type carcinoma (41%, p&lt;0.001) and significantly correlated with invasion depth (p&lt;0.001), lymph node metastasis (p&lt;0.001) and lymphatic invasion (p=0.002). In addition, the CA-9 positive example was poor prognosis in comparison with a negative example significantly, (P &lt;0.001) while multivariate analysis did not show significant difference.
[conclusion] Hypoxia might be associated with aggressive tumor phenotypes of gastric carcinomas. The hypoxic marker, CA-9, may be a useful prognostic indicator.
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 445.
Abstract 4452: Induction of cell and autophagy by the anticancer redox agent mitoquinone is regulated by Nrf2
Authors: Rao V. Ashutosh , Klein Sarah , Mizuno Naoko , Zielonka Jacek , Kalyanaraman Balarama , Shacter Emily 
Published: February 2011

Abstract
Mitoquinone (MitoQ) is a synthetically-modified, redox-active ubiquinone compound that accumulates predominantly in mitochondria. We evaluated the potential use of MitoQ as an anti-cancer agent and found that it is 30-fold more cytotoxic to breast cancer cells than to healthy mammary cells. MitoQ caused irreversible inhibition of the clonogenic growth of breast cancer cells by a combination of autophagic and apoptotic cell death mechanisms, with autophagy playing the major role. None of the cytotoxic effects of MitoQ were seen with the parent ubiquinone coenzyme Q10. Growth inhibition from MitoQ was associated with G1/S cell cycle arrest and phosphorylation of the checkpoint kinases Chk1 and Chk2. A possible role for oxidative stress in MitoQ activity is supported by observed increases in products of hydroethidine oxidation (2-hydroxyethidium, ethidium and diethidium) at cytotoxic concentrations of MitoQ. We will present data showing that Nrf2 and Keap1 regulate the response to the oxidative perturbations caused by MitoQ.
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 4452.
Abstract 4457: Omega-3 polyunsaturated fatty acids induce apoptosis cell death and inhibit LPS-induced invasion in PC3 cells
Authors: Song Kyoung-Sub , Shin Soyeon , Jing Kaipeng , Kim Nayeong , Jeong Soyeon , Kim Jong-Seok , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Kwon Hyun-Joo , Kang Jing X. , Park Jong-Il , Park Seung-kiel , Kweon Gi-Ryang , Yoon Wan-Hee , Hwang Byung-Doo , Lim Kyu 
Published: February 2011

Abstract
Dietary fat as a potential risk factor for cancer has been the focus of many epidemiologic and basic researchers, but the findings have been inconclusive. Toll-like receptor 4 (TLR4)-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. In this study, we have investigated anticancer action of ω3-PUFAs and effect of ω3-PUFAs on LPS-mediated TLR4 signaling in prostate cancer. DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) treatment resulted in a dose-dependent reduction of cell viability with apoptosis of PC3 cells as confirmed by TUNEL assay. In contrast, AA (arachidonic acid), a ω6-PUFA, exhibited no significant effect. Moreover, invasiveness of PC3 cells was inhibited in a dose-dependent manner by treatment of DHA, while AA showed no significant effect. In zymography, MMP-2 activity was inhibited by DHA treatment and MMP-9 and MMP-2 promoter activities were also inhibited. DHA inhibited Cox-2 and VEGF promoter activities and NF-kB reporter activity was also decreased. The expression of TLR4 was confirmed by RT-PCR in PC3 cells and DHA dramatically inhibited the LPS-induced invasion of PC3 cells. In in vivo experiments, when mouse prostate cancer cells (RM1) were injected into the tail vein of Fat1 mice (Fat1 transgenic mice express a Caenorhabditis elegans ω3-desaturase converting ω6- to ω3-PUFAs endogenously.) and WT (wild type mice), lung metastasis was significantly inhibited in Fat1 transgenic mice compared to WT mice. In conclusion, the present study suggests that ω3-PUFAs may inhibit prostate cancer cell growth, and invasion through decrease of MMPs, Cox-2, VEGF and NF-kB reporter activities. Moreover LPS-mediated invasiveness was inhibited by DHA. These findings provide important preclinical evidence and molecular insight for utilization of ω-3 PUFAs for the chemoprevention and treatment of human prostate cancer. [This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Infection Signaling Network Research Center (R13-2007-020-01000-0) at Chungnam National University].
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 4457.
Abstract 4460: Mechanism of action of small molecule CXCR4 antagonists in human B-lymphoma cell lines
Authors: Hu Yanping , Nguyen Tri-Hung , Swistak Mark , Gale Matt , Lonning Scott , Kaplan Johanne , Siders William 
Published: February 2011

Abstract
CXCR4 is a chemokine receptor frequently over-expressed on hematological cancers and solid tumors. CXCR4 and its ligand SDF1α (stromal derived factor-1α or CXCL12) play an important role in cancer metastasis, regulation of stem cell trafficking and neovascularization. We have observed previously that treatment with the small molecule CXCR4 antagonists Plerixafor (AMD3100, Mozobil) and AMD3465 in combination with Campath or Rituxan had a synergistic effect resulting in a prolongation of survival greater than that obtained with either agent alone in disseminated human B-lymphoma tumor models. We next explored the mechanism of action of CXCR4 antagonists in vitro using the human B-lymphoma cell lines Ramos, Raji, B104, BL31, IM9 or Wien133 which display similarly strong levels of cell surface CXCR4 expression. All cell lines responded to SDF1α but, in spite of comparable levels of CXCR4 expression, showed varying degrees of calcium influx and cell migration when stimulated. There was a good correlation between calcium influx and migratory responses for a given cell line. Addition of the CXCR4 antagonists Plerixafor or AMD3465 inhibited both responses. The compounds did not show any direct cytotoxicity and failed to inhibit spontaneous proliferation of Ramos, Raji and B104 human B-lymphoma cell lines. However, they did inhibit SDF1α-induced proliferation of these cell lines in agreement with their ability to block CXCR4. Moreover, CXCR4 antagonists inhibited SDF1α-induced phosphorylation of multiple proteins involved in cell migration, proliferation and survival signal pathways as well as some transcription factors, including Akt, ERK1/2, JNK, p70S6, p90RSK, GSK-3a/b, Tyk2, p38, MEK1, c-Jun, STAT3 and CREB.
These results suggest that the CXCR4/SDF1α axis plays an important role in the migration, proliferation and survival of human B-lymphoma cells and that disruption of these functions with CXCR4 antagonists may contribute to their observed ability to enhance the anti-tumor activity of Campath and Rituxan in human B-lymphoma models.
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 4460.