bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3493: Expression of VEGFR and FRGFR on endothelial cells isolated from hepatocellular carcinoma and adjacent liver tissue
Authors: Hui-Chuan Sun , Kong Ling-Qun , Zhu Xiao-Dong , Chai Zong-Tao , Wang Wen-Quan , Wu Wei-Zhong 
Published: June 2012

Abstract
Background Heterogenity in gene expression profiles in tumor endothelial cells (TEC) has been reported reported. Our previous studies showed TEC is also different from endothelial cells isolated from adjacent normal liver tissue (NEC) in term of response to chemotherapeutics and anti-angiogenesis drugs.
Methods TEC and NEC were isolated by CD31 and CD105 antibody conjuaged magnetic beads from tumor and adjacent nontumor liver tissues from 5 patients who were diagnosed as hepatocellular carcinoma with a positive alpha fetoprotein (&gt; 20ng/ml). The purity of ECs was proved by LDL internalization assay, tube formation, immunostaining and RT-PCR to exclude tumor cell contamination. VEGFR1, VEGFR2, FGFR-2, CD31 and CD105 expression on the isolated ECs were assayed by flow cytometry within 3-5 passages. Response of different types of ECs to sorafenib treatment was observed, including cell proliferation, VEGFRs and FGFR expression.
Results The isolated ECs were proved by tumor formation and LDL internalization. More than 97% cells are LDL positive. AFP was not detectable on the isolated ECs in both flow cytometry assay and immunostaining assay. VEGFRs and FGFR expression were different on CD105+TEC and CD31+TEC among different patients, ranging from 18% to 67% for VEGFR1, 1% to 8% for VEGFR2, and 18% to 25% for FGFR-2 on CD105+TEC, and 18% to 90% for VEGFR1, 10% to 40% for VEGFR2, and 18% to 30% for FGFR-2 on CD31+TEC. Expression of VEGFRs and FGFR is higher on CD105+ECs than those on CD31+ECs. While between TEC and NEC, the expression of VEGFRs and FGFR is also heterogeneous. Sorafenib at 5 mM inhibted proliferation of TEC and NEC in a dose-dependent manner, while NEC is more sensitive to sorafenib treatment.
Conclusions VEGFRs and FGFR expression were different among different patients; CD105+EC and CD31+EC are probably two types of ECs with different biological features.
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 3493. doi:10.1158/1538-7445.AM2011-3493
Abstract 3501: Flavopiridol decreases Mcl-1 and XIAP in acute myeloid leukemia cell resulting in augmentation of sorafenib-induced apoptosis
Authors: Xia Lijuan , Gabrilove Janice , Jing Yongkui 
Published: June 2012

Abstract
The PI3K/AKT/mTOR and Raf/MEK/ERK pathways, resulting in increased levels of Mcl-1, XIAP and survivin, have been found to be activated in acute myeloid leukemia cells (AML) due to the mutant receptor tyrosine kinases. FMS-like tyrosine kinase (FLT3) mutations including FLT3-internal tandem duplication (FLT3-ITD) are found in about 30% of cases of acute myeloid leukemia and confer an increased relapse rate and reduced overall survival. Sorafenib, inhibiting Raf-1 of the MAPK pathway resulting in diminished MEK and ERK phosphorylation, is being tested in AML patients with FLT3-ITD and modest responses have been observed: similarly flavopiridol, a CDK and mRNA transcription inhibitor, has been tested in AML patients with some evidence of activity. We hypothesize that sorafenib plus flavopiridol will have enhanced therapeutic effects. The combined apoptotic effects of sorafenib plus flavopiridol were investigated in HL-60, MV4;11 FLT3-ITD+ cells, as well as in primary leukemic cells isolated from AML patients. Sorafenib and flavopiridol indepedently induced apoptosis at 10 μM and 200 nM, respectively, in HL-60 cells which was correlated with the down-regulation of Mcl-1, XIAP and/or survivin. The combination of sorafenib (5 μM) plus flavopiridol (100 nM) produced augmented apoptosis associated with enhanced diminution in levels of Mcl-1. MV4;11 cells were more sensitive than HL-60 cells to sorafenib-induced apoptosis, but not to flavopiridol, with the down-regulation of Mcl-1 and survivin. Addition of flavopiridol to MV4;11 cells enhanced sorafenib-induced apoptosis with augmented down-regulation of XIAP. Primary cells isolated from two AML patients with FLT3-ITD+ cells exhibited augmented apoptosis induction with the combination treatment of sorafenib plus flavopiridol. Our data suggest that the augmented apoptosis induction in AML cells by sorafenib plus flavopiridol is mediated by decreasing levels of complimentary anti-apoptotic proteins. This novel combination therapy is worthy of a clinical trial in FLT3-ITD+ AML patients.
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 3501. doi:10.1158/1538-7445.AM2011-3501
Abstract 3513: MK-2206 combined with ridaforolimus or topoisomerase inhibitors synergistically impede the growth of sarcoma cells
Authors: Cubitt Christopher L. , Menth Jillaina L. , Dawson Jana L. , Reed Damon R. , Sullivan Daniel M. 
Published: June 2012

Abstract
The number of effective drugs available for the treatment of soft tissue and bone sarcomas is limited to a small group of antineoplastic agents. The goal of this study was to determine the effectiveness of MK-2206 (Akt inhibitor) when used in combination with Ridaforolimus (mTor inhibitor), Cisplatin, Topotecan or Etoposide in a panel of ten cell lines. Six different types of sarcomas are represented in the panel, including rhabdo-, osteo-, Ewing, leiomyo-, lipo- and fibrosarcomas.
Cell Titer-Blue cell viability experiments were performed to test dilutions of MK-2206 alone and in combination at various molar ratios over a 72 hour time period. The observed IC50s for MK-2206 or Ridaforolimus alone ranged from 4.2 to 12.9 µM or 23.7 to 62.3 µM, respectively. The observed IC50 range for Etoposide was 0.5 to 7.5 µM. To determine the relative potentiation of drug combinations, Excess over Highest Single Agent (HSA) analysis was performed (Table). The average Excess HSA score for MK-2206 combinations with Ridaforolimus or Etoposide were 0.17 and 0.15 respectively with levels of significance (p value) &lt; 0.032. This was in contrast to MK-2206 combinations containing Cisplatin or Topotecan with average HSA scores of 0.084 and 0.085, respectively, indicating less potentiation.

Using Chou and Talalay combination index (CI) analyses (effective dose levels of 0.7, 0.9 and 0.95), a synergistic to strongly synergistic reduction in cell viability was observed in 5 cell lines for MK-2206 plus Ridaforolimus and MK-2206 plus Etoposide combinations. Ongoing experiments are underway to identify the effects of MK-2206 combinations on apoptosis and the effect of drug sequencing on growth inhibition. The results of this study indicate that a MK-2206 plus Ridaforolimus or a MK-2206 plus Etoposide combination may be an effective treatment regimen for sarcoma patients. This work was funded by the Pediatric Cancer Foundation.
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 3513. doi:10.1158/1538-7445.AM2011-3513
Abstract 3526: Coadministration of nicotinic acid with the Nampt inhibitor MPC-9528 enhances antitumor activity in Naprt deficient cancer cells in culture and in xenografts
Authors: Fleischer Tracey C. , Baichwal Vijay R. , Boniface J Jay , Cimbora Daniel M. , DeMie Lynn , Douce Thomas B. , Gassman Andrew D. , Papac Damon I. , Peterson Ashley , Robinson Rosann , Terry-Lorenzo Ryan T. , Carlson Robert O. 
Published: June 2012

Abstract
Background: The tumoricidal small molecule MPC-9528 is a picomolar inhibitor of nicotinamide phosphoribosyltransferase (Nampt). Nampt catalyzes the first and rate-limiting step in NAD synthesis from nicotinamide. Nicotinic acid phosphoribosyltransferase (Naprt) catalyzes the first and rate-limiting step in an alternate pathway of NAD synthesis from nicotinic acid (NA). Cancer cells are particularly dependent on NAD and many cancer cell lines, but not most normal tissues, are deficient in Naprt activity. Therefore administration of NA could prevent MPC-9528-induced NAD depletion in normal tissues, but not in Naprt-deficient tumors, resulting in greater therapeutic index and efficacy.
Methods: Cell viability was determined based on ATP levels. Naprt protein expresson was quantified by western blot and qRT-PCR. NAD was acid-extracted from cells and quantified by a coupled reaction based on fluorescent resorufin. Xenograft studies were performed in nu/nu mice.
Results: In 44 out of 153 cancer cell lines surveyed, NA did not prevent MPC-9528-induced cell death, which correlated with low to undetectable levels of Naprt. MPC-9528-induced NAD depletion and cell death in HCT116 colon carcinoma cells were prevented by the addition of NA, consistent with high Naprt expression. A single dose of MPC-9528 at the maximum-tolerated dose (MTD) of 75 mg/kg caused tumor regression in HCT116 xenografts and NA coadministration completely blocked this effect. NA also completely blocked mortality in mice induced by 300 mg/kg MPC-9528, consistent with the finding that most mouse tissues have high Naprt expression. In Naprt-deficient MIA PaCa-2 xenografts, NA coadministration allowed tolerance of 200 mg/kg MPC-9528 with a substantially increased anti-tumor response relative to the MTD of 75 mg/kg MPC-9528 alone.
Conclusions: Low Naprt expression correlates with the lack of effect of NA on MPC-9528 tumoricidal activity. Because Naprt deficiency is prevalent in cancer cell lines and in primary tumor specimens, but not in normal tissues, NA coadministration with MPC-9528 should increase the tolerability and efficacy of MPC-9528 in patients with Naprt-deficient tumors. A companion diagnostic designed to measure Naprt expression or activity in tumors could be used to identify tumors that would most likely benefit from such combination 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 3526. doi:10.1158/1538-7445.AM2011-3526
Abstract 3539: Targeting levels and oligomerization of mutant nucleophosmin induces differentiation and loss of survival of human AML cells with mutant NPM1
Authors: Balusu Ramesh , Fiskus Warren , Rao Rekha M. , Venkannagari Sreedhar , Nalabothula Narasimha , Williams Casey , Abhyankar Sunil , McGuirk Joseph , Bhalla Kapil N. 
Published: June 2012

Abstract
NPM1 is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 plays multiple roles in cell growth and proliferation by participating in diverse biological processes, including ribosome biogenesis and transport, centrosome duplication, DNA repair, transcriptional regulation and histone chaperoning. NPM1 has an N-terminal conserved, hydrophobic, oligomerization domain (residues, 1-110), which is common to all isoforms of NPM1 and critical for its chaperone activity. Recently, NSC348884 was identified as a small molecule inhibitor that disrupts NPM1 dimer/oligomer formation, inducing apoptosis of cancer cells. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal (NES), which causes NPM1c+ to be aberrantly localized in the cytoplasm. Here, we determined the effects of targeting NPM1 in cultured and primary AML cells. Treatment with siRNA to NPM1, which depleted both NPM1c+ and un-mutated NPM1, significantly induced p21, decreased the % of cells in S-phase of the cell cycle, as well as induced differentiation of the AML OCI-AML3 cells that express both NPMc+ and un-mutated NPM1. This was associated with up-regulation of C/EBPα but attenuation of the levels of HOXA9 and MEIS1. Notably, treatment with NPM1 siRNA sensitized OCI-AML3 more than HL-60 cells (expressing only wild-type NPM1) to all-trans retinoic acid (ATRA) and cytarabine. Moreover, inhibition of NPM1 oligomerization by NSC348884-induced apoptosis and sensitized OCI-AML3 and primary AML cells expressing NPM1c+, but not AML or normal CD34+ progenitor cells expressing wild-type NPM1, to ATRA and cytarbine. NSC348884 was also able to sensitize primary AML cells that expressed NPM1c+ as well as FLT3-ITD to ATRA and cytarbine. Addtionally, co-treatment with NSC384884 sensitized these primary AML cells to the lethal effects of the FLT3 kinase inhibitor PKC412 (Novartis Pharma). These results show that attenuating levels or oligomerization of NPM1 selectively induces apoptosis and sensitizes AML cells expressing NPM1c+ alone or with FLT3-ITD to treatment with ATRA, cytarabine and FLT3 kinase 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 3539. doi:10.1158/1538-7445.AM2011-3539
Abstract 3547: In vitro and ex vivo anti-leukemia activity of AR-67, a novel lipophilic camptothecin
Authors: Tsakalozou Eleftheria , Howard Dianna , Leggas Markos 
Published: June 2012

Abstract
BACKGROUND: The overall survival and disease-free rates for Acute Myelogenous Leukemia (AML) patients treated with the gold-standard therapy comprised of Cytarabine (Ara-C) and Daunorubicin (DNR) remain significantly low. Camptothecins are potent anticancer drugs that confer their cytotoxic effect by interfering with Topoisomerase-I (Top1). Semi-synthetic camptothecin analogues have been used in the past to treat AML patients with relatively low response rates. Here, we examined the anti-leukemia activity of AR-67, a novel camptothecin analogue, alone or in combination with standard agents for the treatment of AML.
METHODS: The anti-leukemia activity of AR-67, TPT, Ara-C and DNR was studied in HL60, KG1 and K562 cells and in primary leukemia cell cultures after exposure to increasing drug concentrations for 48 hours. Cell proliferation was determined using a colorimetric assay (MTT) assay and IC50s were obtained using nonlinear-regression analysis. Drug combination treatments were assessed for synergy. The expression of Top1, phosphohistone (γ-H2AX), Bcl-2 and c-PARP were evaluated using biochemical assays.
RESULTS: The potency of AR-67 was in the nM range in the leukemic cell lines. Consistent with the lower proliferation rates of primary cells grown in culture, their IC50 values were variable and in the µM range. IC50s estimated for TPT were higher than the respective ones for AR-67. The IC50 values for Ara-C and DNR were in the μM range for the HL60, K562 and primary cells, and higher than the ones for AR-67. However, the KG-1 cell line appeared to be more sensitive to the AML gold standard therapy, but not as sensitive as to AR-67. AR-67 treatment decreased Top1 expression, increased γ-H2AX expression in a concentration-dependent manner suggesting removal of DNA-Top1 complexes and formation of double strand DNA breaks. Induction of apoptosis was manifested by decreased Bcl-2 and increased c-PARP expression suggesting a caspace-3 mediated effect. AR-67 combination treatments that included DNR and Ara-C showed synergy in HL60 cells. Additionally, pretreatment with Ara-C revealed synergy between AR-67 and DNR in both the KG1 and K562 cells, accompanied by increased γ-H2AX and c-PARP expression.
CONCLUSIONS: Our results indicate AR-67 as a potent anticancer agent that induces DNA damage and apoptosis. Using in vitro leukemia models we have shown that AR-67 is a potentially efficacious agent when combined with standard agents for the treatment of AML and may benefit AML patients resistant to Ara-C.
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 3547. doi:10.1158/1538-7445.AM2011-3547
Abstract 3552: JAK/Stat3 signaling pathway modulates human megakaryocytic differentiation
Authors: Hui-Fen Liao , Peng Hsuan-Yu , Chen Yu-Jen 
Published: June 2012

Abstract
Megakaryocytes (MKs) are differentiated from pluripotent hematopoietic stem cells toward a lineage capable of terminal differentiation to mature platelets. Various hematopoietic growth factors such as thrombopoietin, the ligand of c-mpl-encoded protein, have been identified as important regulators of MK development. Induction of MK differentiation may benefit disorders related to platelet dysfunction or thrombocytopenia. However, both effective inducer and clear mechanism of MK differentiation remain lacking. To clarify the regulatory mechanisms of MK differentiation, distinct inducers staurosporine (STS) and 12-O-Tetradecanoylphorbol-13-acetate (TPA) were used to assess the expression of Janus kinase (JAK) and Signal transducers and activators of transcription 3 (Stat3) signaling molecules in both human chronic myeloid leukemia K562 and erythroleukemia HEL cells. Our results demonstrated that STS and TPA effectively induced cell differentiation toward MK lineage in terms of development of polyploidy population, expression of MK-specific markers CD41 and CD61, and secretion of platelet factor 4. Intriguingly, enhancement in phosphorylation of Stat3 (p-Stat3), nuclear translocation and DNA-binding activity was evident in both STS- and TPA-treated cells. Blockade of Stat3 by Stat3 inhibitor VI and its upstream molecule JAK by JAK inhibitor I obviously declined MK differentiation. Furthermore, knockdown of Stat3 by RNA interference attenuated the expression of p-Stat3 and MK differentiation, indicating a crucial role of Stat3 in MK differentiation. In conclusion, JAK/Stat3 signaling pathway may involve MK differentiation and might be a target for development of therapeutic modulators for platelet disorders.
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 3552. doi:10.1158/1538-7445.AM2011-3552
Abstract 3555: Anti-tumor activity of CAL-101, a potent selective inhibitor of the p110Δ isoform of PI3K, in models of human glioblastoma
Authors: Kashishian Adam , Meadows Sarah , Steiner Bart , Lannutti Brian 
Published: June 2012

Abstract
Phosphatidylinositol 3-kinase (PI3K) activation and Akt phosphorylation play a pivotal role in cell proliferation and survival, transducing signals from several cell surface receptors through PI3K isoforms (designated p110α, β, Δ, and γ). Our previous research has elucidated a significant role of the PI3K p110Δ (PI3KΔ) isoform in hematologic malignancies. Aberrant upregulation of the PI3K/Akt pathway is a frequently observed defect in human malignancies, including glioblastoma, but the role of the PI3KΔ isoform, has not been systematically evaluated. Selective inhibition of PI3KΔ with the orally bioavailable investigational drug, CAL-101, offers the potential for targeting PI3KΔ as a therapeutic approach to glioblastoma while avoiding undesirable side effects associated with pan-inhibitors that broadly block PI3K isoforms in multiple cell types. CAL-101 potently inhibits PI3KΔ (with an EC50 of 65 nM in a whole-blood assay) and shows &gt;200-fold selectivity over other Class I PI3K isoforms and no activity against Class II and III PI3K family members or other PI3K-related proteins, including mTOR and DNA-PK. We examined expression levels of PI3KΔ and constitutive pathway activation in a panel of glioma cell lines (LN18, LN229, SF-539, U87MG, U138MG, and U251). PI3KΔ was consistently expressed and was functionally active, inducing high basal levels of phosphorylated-Akt (pAkt) in all tested cell lines. Treatment with CAL-101 decreased p-Akt levels in all cell lines and also reduced phosphorylation of the downstream pathway target, S6. Furthermore, PI3KΔ inhibition with CAL-101 resulted in an accumulation of cells in G1 and a decrease in the S phase population. Consistent with the effects of CAL-101 on G1 cell-cycle arrest, immunoblotting showed a decrease in cyclin D1 levels. In mice bearing U87MG xenografts, in vivo PI3KΔ inhibition resulted in significant anti-tumor effects, delaying time to tumor progression (tumor volume of &gt;1000 mm3) by 30 days (p&lt;0.001). Taken together, these data suggest that PI3KΔ overexpression and heightened functional activity contribute to glioblastoma proliferation, and that selective targeting of PI3KΔ may offer a novel therapeutic approach for patients with central nervous system 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 3555. doi:10.1158/1538-7445.AM2011-3555
Abstract 3576: Lapatinib in combination with doxorubicin is highly damaging to cardiac myocytes
Authors: Hasinoff Brian B. , Patel Daywin , Wu Xing 
Published: June 2012

Abstract
Lapatinib (Tykerb) is dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways. It is used to treat ER+/EGFR+/HER2+ breast cancer patients and patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents. Lapatinib, which was initially rated as having no cardiotoxicity, has recently been shown in a clinical trial to produce low levels of cardiotoxicity that is reversible. Using a neonatal rat cardiac myocyte model we have investigated the ability of lapatinib alone and in combination with doxorubicin to damage myocytes. Lapatinib alone at pharmacological concentrations did not significantly cause myocyte damage. However, doxorubicin-induced myocyte damage was greatly increased by the addition of low nanomolar lapatinib concentrations. Previous clinical studies have shown that the combination of trastuzumab (Herceptin) and doxorubicin was highly cardiotoxic. Because trastuzumab also targets HER2 receptors, the lapatinib/doxorubicin combination provides a good model to probe the mechanism of this cardiotoxicity using a rat myocyte model. Lapatinib treatment alone had little or no effect on myocyte mitochondrial membrane potential, on oxidation of intracellular DCF (dichlorofluorescein), on intracellular ATP levels or on caspase 3/7 induction. The doxorubicin cardioprotective agent dexrazoxane was able to greatly reduce doxorubicin-induced myocyte damage. However, dexrazoxane was not able to reduce the increase in myocyte damage produced by adding lapatinib to the doxorubicin treatment. The effect of lapatinib on the change in phosphorylation of ACC (acetyl-coenzyme A carboxylase), which is a measure of a change in cellular energy status, was also determined. Doxorubicin-induced growth inhibitory effects on K562 cells, which contain very low levels of ERBB1/2 protein, were not affected by the addition of lapatinib. This result suggests that inhibition of ERBB1/2 is required for the synergistic toxic effects seen with doxorubicin in myocytes. In conclusion these results suggest that combination therapy employing doxorubicin and lapatinib may produce increased cardiotoxicity. Support: CIHR and a Canada Research Chair in Drug Development to BBH.
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 3576. doi:10.1158/1538-7445.AM2011-3576