bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4523: Design and synthesis of sorafenib analogues as SHP-1 activators for hepatocellular carcinoma cells
Authors: Huang Jui-Wen , Chen Kuen-Feng , Tai Wei-Tien , Chen Wei-Lin , Chen Pei-Jer , Cheng Ann-Lii , Shiau Chung-Wai 
Published: June 2012

Abstract
Sorafenib, a small molecule kinase inhibitor, has been approved for renal carcinoma (RCC) and hepatocellular carcinoma (HCC) by FDA. Our data shows that sorafenib inhibits signal transducers and activators of transcription 3 activity and induces apoptosis in HCC cells. The major target is that Sorafenib enhances Src homology-2-containing protein tyrosine phosphatase-1 (SHP-1) activity, reduces the phosphorylation of STAT3 and subsequently reduces the STAT3-regulating protein, Mcl-1, survivin and cyclinD1. Therefore, we design and synthesize a series of sorafenib analogues which show the higher potency in inducing apoptosis and inhibiting phosphorylation of STAT3 than sorafenib. In addition, these agents have no inhibition of Raf and VEGFR in HCC cells. Therefore, the new agents provide a new concept that increasing SHP-1 activity along and synergizing with other therapeutic agents will be applicable in HCC 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 4523. doi:10.1158/1538-7445.AM2011-4523
Abstract 4528: Genotoxic and estrogenic properties of new antiestrogens
Authors: Shibutani Shinya , Santosh Laxmi Y. R. , Suzuki Naomi , Okamoto Yoshinori 
Published: June 2012

Abstract
Long-term administration of tamoxifen (TAM) to breast cancer patients and women at high risk of developing this disease gives serious side effects, including endometrial cancer. These side-effects are due to the DNA damaging and/or estrogenic action of the drug. Several antiestrogens have been developed in last three decades, but were dropped out from the clinical trials due to their undesirable effects on the uterus. To avoid this serious side-effect, we have synthesized a new triphenylethylene antiestrogen, E-3-{4-[(E)-4-chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]-phenyl} acrylic acid (SS1020) and a new benzopyran antiestrogen, 2E-3-{4-[(7-hydroxy-2-oxo-3-phenyl-2H-chromen-4-yl)-methyl]-phenyl}-acrylic acid (SS5020). SS1020 and SS5020 had antitumor potential much higher than that of TAM or other antiestrogens at the human equivalent doses (TAM 0.3-1.0 mg/kg/day), against 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats or human MCF-7 breast cancer xenograft implanted into athymic nude mice. To evaluate their genotoxic activity, the capability of forming hepatic DNA adducts in rats was determined. When rats were treated orally at a dose molar equivalent to TAM (20 mg/kg/day), a high level (∼1 adduct/105 nucleotides) of DNA adducts was detected in TAM-treated rats whereas no DNA adducts were observed in rats treated with SS1020 or SS5020. To evaluate the estrogenic potential, the uterotrophic activity of our compounds was determined in ovariectomized (OVX) rats at a dose molar equivalent to TAM (10 mg/kg/day), which is 30 times higher than the human equivalent dose of TAM. TAM had high uterotrophic activity while SS1020 and SS5020 did not present significant uterotrophic activity. Therefore, SS1020 and SS5020, lacking estrogenic and genotoxic actions, are expected not to induce reproductive cancers. Interestingly, the antitumor activities of several antiestrogens examined were, rather, increased significantly to the lowering uterotrophic activity evaluated with OVX-rats, but not to their antiproliferative activities against cultured estrogen receptor positive human MCF-7 breast cancer cells. The use of uterotrophic assay, not antiproliferative assay, may be a suitable screening system to exploit antiestrogen alternatives. Non-genotoxic and non-estrogenic SS1020 and SS5020, having strong antitumor potency superior to that of TAM, could be safer alternatives for breast cancer therapy and prevention.
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 4528. doi:10.1158/1538-7445.AM2011-4528
Abstract 453: Myeloid regulatory cells in cancer patients
Authors: Pirruccello Samuel J. , Samson Holly , Dafferner Alicia , Maas Sarah , Julius Howard , Weisenburger Dennis , Warkentin Phyllis , Talmadge James E. 
Published: June 2012

Abstract
Adaptive immunotherapy can augment host immunity, although the outcomes to date in cancer patients have been limited, due in part, to increased numbers of myeloid derived suppressor cells (MDSCs) in the peripheral blood. MDSCs are key cellular regulators that can limit T-cell and dendritic cell (DC) number and function. They are believed to be myeloid precursors that are increased as part of the hematopoietic response to myelosuppression, stress, chemotherapy, and tumor growth. Recently, we found that mononuclear cell apheresis of some cancer patients (melanoma, leukemia and lymphoma), but not normal donors were enriched for hypodense myeloid cells as confirmed by elutriation and Ficoll-Hypaque gradients. These cells are also found in the peripheral blood, although their frequency is enriched by mononuclear cell apheresis. Despite their low density, cytologically they appear as granulocytes containing &lt; 1% bands or metamyelocytes. Phenotypic analysis by flow cytometry revealed that &gt;98% of the granulocytes (FSxSS), were MDSCs, defined as linage−(CD3, CD19 and CD56)DR−CD14dullCD13dull CD11b+CD33+. Consistent with an immature granulocyte phenotype &gt; 50% of the granulocytes were CD16dull/− as compared to &lt;3% of the granulocytes in the PB or apheresis products of normal donors. The frequency of these cells in an apheresis product or the peripheral blood from cancer patients can be as high as 60% of total nucleated cells and following mononuclear cell elutriation &gt;95% of nucleated cells. It is emphasized that this is not observed in all patients and in our limited experience occurs in 20% or less of patients with advanced disease. Enrichment of hypodense MDSCs by Miltenyi magnetic bead selection of CD11b+ cells following subtractive depletion of DR+ cells provided a 60-85% pure population of MDSCs that can suppress an allogeneic T-cell response and by quantitative TaqMan analysis have significantly increased levels of NOS2, IL10, LTB4R1, MPO, MMP9 and VEGFα. We conclude that the majority of MDSCs in cancer patients are immature granulocytes; rather than myeloid precursors, as evidenced by their CD16dull phenotype, a lack of CD34 expression and segmented granulocyte morphology. Further, the presence of hypodense MDSCs has a significant impact on monocyte enrichment (apheresis, elutriation and Ficoll Hypaque separation) for maturation of monocytes into dendritic cells and use as a vaccine.
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 453. doi:10.1158/1538-7445.AM2011-453
Abstract 4531: Molecular determinants of sensitivity to pralatrexate in a panel of human cancer cell lines
Authors: Serova Maria , Pronk Gijsbertus J. , Bieche Ivan , Vidaud Michel , Cvitkovic Esteban , Faivre Sandrine , Raymond Eric 
Published: June 2012

Abstract
Background: Pralatrexate (FOLOTYN®), an antifolate inhibiting dihydrofolate reductase (DHFR), is a high affinity substrate for cellular uptake via reduced folate carrier-1 (RFC-1) and polyglutamation by folyl-polyglutamyl synthetase (FPGS). This study evaluated the sensitivity of human cancer cell lines to pralatrexate and methotrexate, and investigated molecular determinants of primary sensitivity and acquired resistance.
Materials and Methods: Anti-proliferative activity was evaluated in a panel (N=15) of human cancer cell lines using the MTT assay. mRNA expression was analyzed by qRT-PCR and protein expression by Western blot.
Results: Two groups of cell lines with at least 100-fold difference in sensitivity to pralatrexate were identified. Pralatrexate was 3- to 19-fold (mean: 9-fold) more potent than methotrexate in the sensitive lines (N=9). Sensitivity to pralatrexate correlated with higher FPGS mRNA expression. Two pralatrexate-resistant cell lines (DU-PDX & HEP-PDX) and two methotrexate-resistant cell lines (DU-MTX & HEP-MTX) were established from DU-145 (prostate) and HEP2 (head & neck) cell lines. DU-PDX and HEP-PDX cells were cross-resistant to methotrexate. DU-MTX and HEP-MTX cells showed partial cross-resistance to pralatrexate but remained more sensitive to pralatrexate compared to methotrexate (7.5- and 11-fold, resp.). Acquired resistance to pralatrexate was associated with decreased RFC-1 expression in both DU-PDX and HEP-PDX cell lines, suggesting that reduced pralatrexate uptake may be an important mechanism of acquired resistance. No change in DHFR mRNA expression was found in the pralatrexate-resistant cells. In contrast, significant increases in DHFR mRNA and protein expression were seen in the methotrexate-resistant HEP-MTX cells, suggesting different mechanisms of resistance for these two antifolates.
Conclusions: Consistent with prior findings, pralatrexate was more potent than methotrexate against a panel of human cancer cell lines. Primary sensitivity to pralatrexate was associated with higher FPGS expression whereas acquired resistance was associated with decreased RFC-1 expression. Increased DHFR expression correlated with resistance to methotrexate, but not pralatrexate. The marked differences in potency and molecular determinants of tumor response observed in these preclinical models provide rationale for development of pralatrexate in methotrexate-sensitive cancers as well as in settings of acquired methotrexate resistance.
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 4531. doi:10.1158/1538-7445.AM2011-4531
Abstract 4533: Interaction between androgen receptor and its corepressor SLIRP is regulated by Ack1 tyrosine kinase
Authors: Zhang Zhentao , De Silva Dinuka , Liu Yuanbo , Earp H. Shelton , Whang Young E. 
Published: June 2012

Abstract
Reactivation of androgen receptor (AR) is critical to castration resistant progression of prostate cancer. We previously demonstrated that Ack1 (activated cdc42-associated kinase) promotes growth of prostate xenograft tumors in castrated animals by activation of AR through phosphorylation of the Tyr-267 site. However, the molecular mechanisms underlying activation of AR by Ack1 need to be fully elucidated. Using the proteomics-based approach of Differential In-Gel Electrophoresis, we searched for proteins whose interaction with AR was regulated by Ack1 by characterizing proteins coimmunoprecipitating with AR in transfected 293T cells in the absence or in the presence of activated Ack1 kinase. SLIRP (SRA stem-loop interacting RNA binding protein) was identified as a candidate protein. We confirmed that the interaction between AR and SLIRP is abrogated by Ack1 expression and dihydrotestosterone (DHT) in 293T cells and in LNCaP prostate cancer cells. Additionally, treatment with heregulin, a ligand activating HER-2/HER-3 and Ack1 downstream, also led to dissociation of AR and SLIRP in LNCaP cells. Tyrosine kinase activity of Ack1 was shown to be required for its ability to dissociate AR and SLIRP through the use of a kinase-dead mutant in 293T cells and the use of an Ack1 inhibitor dasatinib in LNCaP cells treated with heregulin. However, disruption of interaction between AR and SLIRP by Ack1 cannot be attributed to any known AR tyrosine phosphorylation sites since Ack1 expression led to disruption of binding between SLIRP and AR Y267F, Y363F, and Y534F mutants. Since SLIRP does not contain tyrosine residues, the substrate of Ack1 involved in AR-SLIRP dissociation is not known yet. We showed that SLIRP functions as a physiologically relevant corepressor of AR in prostate cancer cells. Chromatin immunoprecipitation analysis demonstrated that SLIRP was bound to the androgen regulated enhancers of AR target genes in the absence of androgen and that androgen or heregulin treatment led to loss of SLIRP binding at the androgen regulated enhancers. AR-dependent reporter activity was inhibited by overexpression of SLIRP and was increased by SLIRP knockdown. SLIRP knockdown also increased the expression of endogenous AR target mRNA levels of PSA and hK2. In summary, our data suggest that Ack1 kinase inhibits the interaction between AR and the SLIRP corepressor and causes dissociation of SLIRP from the AR target gene enhancers and thereby enhance AR transcriptional activity.
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 4533. doi:10.1158/1538-7445.AM2011-4533
Abstract 4534: Lung cancer epidermal growth factor receptors are transactivated by neurotensin
Authors: Moody Terry W. , Osefo Nauramy , Sancho Veronica , DiFlorio Alessia , Mantey Samuel , Jensen Robert T. 
Published: June 2012

Abstract
Neurotensin (NT) is an autocrine growth factor for some lung cancer cells (Moody et al., Life Sci 36:1727(1985)). The NTS1 receptor (R), which causes phosphatidylinositol turnover, elevates cytosolic Ca2+ and increases proliferation of lung cancer cells, is blocked by SR48692 (Moody et al., Peptides 22:109 (2001)). Previously we found that NT caused tyrosine phosphorylation of focal adhesion kinase in non-small cell lung cancer (NSCLC) cells (Leyton et al., Eur. J. Pharm. 442:179 (2002)). Here the ability of NT to cause tyrosine phosphorylation of the epidermal growth factor (EGF)R in lung cancer cells was investigated. NT and NT8-13 but not NT1-8 caused tyrosine phosphorylation of the EGFR using NCI-H1299 or H345 cells. The transactivation of the EGFR caused by NT addition to lung cancer cells was inhibited by SR48692 (NTS1R antagonist) or gefitinib (EGFR tyrosine kinase inhibitor). NT significantly increased EGFR tyrosine phosphorylation (4-fold) after 0.5 min in a dose-dependent manner. The ability of NT to increase EGFR or ERK tyrosine phosphorylation was inhibited by PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), or antibody to transforming growth factor (TGF) α. By ELISA, NT stimulated significantly the release of TGFα from NCI-H838 cells. NT stimulation of EGFR tyrosine phosphorylation was inhibited by addition of N-acetylcysteine (anti-oxidant), tiron (superoxide scavenger), DPI (NADPH oxidase inhibitor). These results indicate that NT causes transactivation of lung cancer EGFR in an oxygen-dependent, Src-dependent manner resulting in activation of matrix metalloprotease and release of TGFα.
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 4534. doi:10.1158/1538-7445.AM2011-4534
Abstract 4538: Small ubiquitin-related modifier-1 (SUMO-1) modification of retinoic acid receptor α (RARα) regulates its nuclear localization and metabolic stability
Authors: Fang Yanfen , Zhang Lei , Yan Yan , Yang Bo , He Qiaojun 
Published: June 2012

Abstract
Retinoic acid receptor α (RARα) has been demonstrated to be one of the most important retinoic acid receptors through which all-trans retinoic acid (ATRA) exerts its biologic effects on differentiation of leukemic cells. Previous studies have demonstrated that RARα is subject to several post-translational modifications that regulate its functions, including phosphorylation and ubiquitination. Here we are the first to show a small ubiquitin-related modifier-1 (SUMO-1) modification of RARα, and this modification might play an essential role in ATRA-induced differentiation of acute myeloid leukemia cells (HL60 and NB4) and osteosarcoma cells (U2OS). We found that SUMO-1 covalently modified RARα both in vivo and in vitro, and lysine 399 is the modification site as mutation of lysine 399 to arginine in RARα completely abolished the conjugation of SUMO-1 to RARα. We then observed that covalent modification by SUMO-1 led to the nuclear localization of RARα after ATRA treatment. Either mutation of RARα at lysine 399 or silencing of SUMO-1 could significantly block ATRA-induced RARα nuclear localization. We further found that SUMO-1 also regulated the functions of RARα by controlling RARα metabolic stability. The conjugation of ubiquitin to RARα was markedly enhanced when the lysine 399 site of RARα was mutated into arginine. Moreover, the half-life of the wild type RARα was much longer (approximate 3-fold) than the lysine 399 mutant form. These two lines of evidence indicated that SUMO-1 modification protected RARα from ubiquitin-dependent degradation. Furthermore, we observed that RARα with the deficient of SUMO-1 modification could not exert its function to regulate ATRA-induced differentiation of leukemia cells and osteosarcoma cells, which was evidenced by the decreased expression of the differentiation markers. Taken together, our data presented for the first time that sumoylation of RARα proteins at lysine 399 by SUMO-1 contributed to the nuclear localization and stability of the nuclear receptor, which might facilitate the ATRA signal transduction. Our study reveals a novel molecular mechanism for the regulation of RARα in ATRA-induced differentiation of tumor 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 4538. doi:10.1158/1538-7445.AM2011-4538
Abstract 454: Targeting macrophages in a preclinical model of malignant mesothelioma
Authors: Blakely Collin M. , Kolhatkar Nikita , Johansson Magnus , Beltran Adam , Barbone Dario , Bueno Raphael , Sugarbaker David , Jahan Thierry , Jablons David , Broaddus V. Courtney , Coussens Lisa M. 
Published: June 2012

Abstract
Malignant pleural mesothelioma (MPM) is a debilitating, incurable cancer that exhibits a high degree of resistance to standard chemotherapy; thus, we sought to identify novel therapeutic targets for treatment. In the vast majority of cases, MPM is associated with exposure to asbestos fibers, which result in a chronic pro-inflammatory state. As such, we hypothesized that MPMs were infiltrated by leukocytes possessing tumor-potentiating activities. To address this, we evaluated MPMs, resected from 26 patients, by flow cytometry and found that tumors were highly infiltrated with macrophages (31 ± 4.6% of total CD45+), a percentage that is significantly higher that that observed in other thoracic malignancies (NSCLC cancer, 9%; esophageal, 4%). Since recent experimental data has revealed that tumor-associated macrophages (TAMs) secrete proangiogenic, prosurvival, and proinvasive factors that foster tumor progression, we evaluated macrophage-depletion in MPM as a novel therapeutic strategy. Using a syngeneic murine transplantation model and liposomal-encapsulated clodronate that efficiently deplete phagocytic macrophages, as monotherapy, and in combination with chemotherapy, we revealed a significant decrease in tumor growth and a decrease in tumor-burden in tumor-bearing mice depleted of macrophages. Furthermore, when macrophage-depletion was combined with the cytotoxic agents gemcitabine and TRAIL, an even greater reduction in tumor burden was observed as compared to mice treated with either agent alone. These studies indicate that: 1) mesothelioma-associated macrophages provide a protumor function, and 2) depletion of mesothelioma-associated macrophages may improve efficacy of cytotoxic chemotherapy. Ongoing studies to reveal the effect of macrophage-depletion plus chemotherapy in limiting MPM development in NF2ko/+ mice exposed to asbestos are underway.
This work was supported by an NIH T32 training grant to Dr. Blakely, and by a DoD Mesothelioma Program grant (PR080717) to Drs. Broaddus and Coussens.
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 454. doi:10.1158/1538-7445.AM2011-454
Abstract 4543: Nuclear receptor estrogen-related receptor alpha promotes hypoxic growth prostate cancer cells
Authors: Zou Chang , Yu Shan , Yew David T. , Chan Franky L. 
Published: June 2012

Abstract
Estrogen-related receptors (ERRα,β,γ) which share significant homology with estrogen receptors, are orphan nuclear receptors and constitutively transactivated without estrogen-binding. Among the three subtypes, ERRα has been characterized to play a pivotal role in diverse aspects of energy homeostasis, including oxidative phosphorylation and mitochondrial biogenesis, via its transcriptional regulation of target genes. Expression studies in clinical tumor tissues show that ERRα expression is positively associated with a few hormone-dependent cancers, including breast, ovarian and endometrial cancers, and has been proposed to be useful as a prognostic marker for these cancers. We have previously reported that ERRα displays a ubiquitous expression pattern in various prostatic cell lines and an apparent elevated expression in high grade prostate cancer. However, its exact functional roles and prognostic value in prostate cancer still remains unclear. In this study, we analyzed the functional significance of ERRα in prostate cancer cell growth regulation by its stable expression in a hormone-sensitive prostate cancer cell line LNCaP. Our results showed that stable expression of ERRα in LNCaP cells could enhance their in vitro cell proliferation, adhesion to fibronectin, invasion and colony formation capacities of LNCaP cells under both normoxia and hypoxia condition (1% O2), while such in vitro growth phenotypes could be suppressed by an ERRα specific antagonist XCT790, suggesting that ERRα-induced growth phenotypes were ERRα specific. Moreover, under hypoxia condition, stable ERRα over-expression could stabilize HIF1α protein, up-regulate VEGF expression with an ERRα dose dependent pattern.
Taken together, our results showed that ERRα over expression promotes hypoxic growth of prostate cancer cells.
(This study is supported by a RGC General Research Fund CUHK461009)
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 4543. doi:10.1158/1538-7445.AM2011-4543