bluuebunny/crossref_metadata_2025_split huggingface dataset:
AZ703, an Imidazo[1,2-a]Pyridine Inhibitor of Cyclin-Dependent Kinases 1 and 2, Induces E2F-1-Dependent Apoptosis Enhanced by Depletion of Cyclin-Dependent Kinase 9
Authors: Cai Dongpo , Byth Kate F. , Shapiro Geoffrey I. 
Published: January 2006

Abstract
Preclinical studies were performed of a novel selective imidazopyridine cyclin-dependent kinase (cdk) inhibitor, AZ703. In vitro kinase assays showed that IC50 values for AZ703 against purified cyclin E/cdk2 and cyclin B/cdk1 were 34 and 29 nmol/L, respectively. In contrast, the IC50 against cdk4 was &gt;10 μmol/L. AZ703 also inhibited cdk7 and cdk9 with IC50 values of 2.1 μmol/L and 521 nmol/L, respectively. Treatment of U2OS, NCI-H1299, and A549 cells for 24 hours resulted in growth arrest involving multiple cell cycle phases. At low drug concentrations (&lt;2 μmol/L), G2 arrest predominated, whereas at higher concentrations (≥2 μmol/L), S-G2 arrest was observed. When cells were synchronized in G1 by starvation and released into AZ703, a block in G1 occurred that was not evident in exponentially growing cells. Cell cycle arrest was associated with reduced phosphorylation of the retinoblastoma protein and p27Kip1 at cdk2 phospho-sites. Following longer exposures, apoptosis was evident. Cells were further sensitized to AZ703 following recruitment to S phase by synchronization. Consistent with the inhibition of cdks during S and G2 that modulate the activity and stability of E2F-1, AZ703 treatment induced E2F-1 expression. In U2OS and NCI-H1299 cells engineered to inducibly express the dominant-negative mutant E2F-1 (1-374), expression of the mutant decreased AZ703-mediated apoptosis, indicating dependence on E2F-1 transcriptional targets. AZ703-induced apoptosis in NCI-H1299 cells was enhanced by small interfering RNA–mediated depletion of cdk9, which caused reduced levels of Mcl-1 and XIAP, suggesting that cdk2, cdk1, and cdk9 represent a rational subset of family members for drug targeting. (Cancer Res 2006; 66(1): 435-44)
Black Raspberry Extracts Inhibit Benzo(a)Pyrene Diol-Epoxide–Induced Activator Protein 1 Activation and VEGF Transcription by Targeting the Phosphotidylinositol 3-Kinase/Akt Pathway
Authors: Huang Chuanshu , Li Jingxia , Song Lun , Zhang Dongyun , Tong Qiangsong , Ding Min , Bowman Linda , Aziz Robeena , Stoner Gary D. 
Published: January 2006

Abstract
Previous studies have shown that freeze-dried black raspberry extract fractions inhibit benzo(a)pyrene [B(a)P]–induced transformation of Syrian hamster embryo cells and benzo(a)pyrene diol-epoxide [B(a)PDE]–induced activator protein-1 (AP-1) activity in mouse epidermal Cl 41 cells. The phosphotidylinositol 3-kinase (PI-3K)/Akt pathway is critical for B(a)PDE-induced AP-1 activation in mouse epidermal Cl 41 cells. In the present study, we determined the potential involvement of PI-3K and its downstream kinases on the inhibition of AP-1 activation by black raspberry fractions, RO-FOO3, RO-FOO4, RO-ME, and RO-DM. In addition, we investigated the effects of these fractions on the expression of the AP-1 target genes, vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Pretreatment of Cl 41 cells with fractions RO-F003 and RO-ME reduced activation of AP-1 and the expression of VEGF, but not iNOS. In contrast, fractions RO-F004 and RO-DM had no effect on AP-1 activation or the expression of either VEGF or iNOS. Consistent with inhibition of AP-1 activation, the RO-ME fraction markedly inhibited activation of PI-3K, Akt, and p70 S6 kinase (p70S6k). In addition, overexpression of the dominant negative PI-3K mutant Δp85 reduced the induction of VEGF by B(a)PDE. It is likely that the inhibitory effects of fractions RO-FOO3 and RO-ME on B(a)PDE-induced AP-1 activation and VEGF expression are mediated by inhibition of the PI-3K/Akt pathway. In view of the important roles of AP-1 and VEGF in tumor development, one mechanism for the chemopreventive activity of black raspberries may be inhibition of the PI-3K/Akt/AP-1/VEGF pathway. (Cancer Res 2006; 66(1): 581-7)
Dasatinib (BMS-354825), a Dual SRC/ABL Kinase Inhibitor, Inhibits the Kinase Activity of Wild-Type, Juxtamembrane, and Activation Loop Mutant KIT Isoforms Associated with Human Malignancies
Authors: Schittenhelm Marcus M. , Shiraga Sharon , Schroeder Arin , Corbin Amie S. , Griffith Diana , Lee Francis Y. , Bokemeyer Carsten , Deininger Michael W.N. , Druker Brian J. , Heinrich Michael C. 
Published: January 2006

Abstract
Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 &gt; 5-10 μmol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y ≫ D816F &gt; D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations. (Cancer Res 2006; 66(1): 473–81)
Fibronectin Stimulates Non–Small Cell Lung Carcinoma Cell Growth through Activation of Akt/Mammalian Target of Rapamycin/S6 Kinase and Inactivation of LKB1/AMP-Activated Protein Kinase Signal Pathways
Authors: Han ShouWei , Khuri Fadlo R. , Roman Jesse 
Published: January 2006

Abstract
The Akt/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathway is considered a central regulator of protein synthesis and of cell proliferation, differentiation, and survival. However, the role of the Akt/mTOR/p70S6K pathway in lung carcinoma remains unknown. We previously showed that fibronectin, a matrix glycoprotein highly expressed in tobacco-related lung disease, stimulates non–small cell lung carcinoma (NSCLC) cell growth and survival. Herein, we explore the role of the Akt/mTOR/p70S6K pathway in fibronectin-induced NSCLC cell growth. We found that fibronectin stimulated the phosphorylation of Akt, an upstream inducer of mTOR, and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E–binding protein 1 (4E-BP1), two downstream targets of mTOR in NSCLC cells (H1792 and H1838), whereas it inhibited the phosphatase and tensin homologue deleted on chromosome 10, a tumor suppressor protein that antagonizes the phosphatidylinositol 3-kinase/Akt signal. In addition, treatment with fibronectin inhibited the mRNA and protein expression of LKB1 as well as the phosphorylation of AMP-activated protein kinase (AMPKα), both known to down-regulate mTOR. Rapamycin, an inhibitor of mTOR, blocked the fibronectin-induced phosphorylation of p70S6K and 4E-BP1. Akt small interfering RNA (siRNA) and an antibody against the fibronectin-binding integrin α5β1 also blocked the p70S6K phosphorylation in response to fibronectin. In contrast, an inhibitor of extracellular signal-regulated kinase 1/2 (PD98095) had no effect on fibronectin-induced phosphorylation of p70S6K. Moreover, the combination of rapamycin and siRNA for Akt blocked fibronectin-induced cell proliferation. Taken together, these observations suggest that fibronectin-induced stimulation of NSCLC cell proliferation requires activation of the Akt/mTOR/p70S6K pathway and is associated with inhibition of LKB1/AMPK signaling. (Cancer Res 2006; 66(1): 315-23)
The Role of 17β-Hydroxysteroid Dehydrogenases in Modulating the Activity of 2-Methoxyestradiol in Breast Cancer Cells
Authors: Newman Simon P. , Ireson Christopher R. , Tutill Helena J. , Day Joanna M. , Parsons Michael F.C. , Leese Mathew P. , Potter Barry V.L. , Reed Michael J. , Purohit Atul 
Published: January 2006

AbstractThe bis-sulfamoylated derivative of 2-methoxyestradiol (2-MeOE2), 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE), has shown potent antiproliferative and antiangiogenic activity in vitro and inhibits tumor growth in vivo. 2-MeOE2bisMATE is bioavailable, in contrast to 2-MeOE2 that has poor bioavailability. In this study, we have examined the role of 17β-hydroxysteroid dehydrogenase (17β-HSD) type 2 in the metabolism of 2-MeOE2. In MDA-MB-231 cells, which express high levels of 17β-HSD type 2, and in MCF-7 cells transfected with 17β-HSD type 2, high-performance liquid chromatography analysis showed that a significant proportion of 2-MeOE2 was metabolized to inactive 2-methoxyestrone. Furthermore, MCF-7 cells transfected with 17β-HSD type 2 were protected from the cytotoxic effects of 2-MeOE2. In contrast, no significant metabolism of 2-MeOE2bisMATE was detected in transfected cells and 17β-HSD type 2 transfection did not offer protection against 2-MeOE2bisMATE cytotoxicity. This study may go some way to explaining the poor bioavailability of 2-MeOE2, as the gastrointestinal mucosa expresses high levels of 17β-HSD type 2. In addition, this study shows the value of synthesizing sulfamoylated derivatives of 2-MeOE2 with C17-position modifications as these compounds have improved bioavailability and potency both in vitro and in vivo. (Cancer Res 2006; 66(1): 324-30)
Activation of Vav/Rho GTPase Signaling by CXCL12 Controls Membrane-Type Matrix Metalloproteinase–Dependent Melanoma Cell Invasion
Authors: Bartolomé Rubén A. , Molina-Ortiz Isabel , Samaniego Rafael , Sánchez-Mateos Paloma , Bustelo Xosé R. , Teixidó Joaquin 
Published: January 2006

Abstract
Melanoma cells express the chemokine receptor CXCR4, which confers invasive signals on binding to its ligand CXCL12. We show here that knocking down membrane-type matrix metalloproteinase (MT1-MMP) expression translates into a blockade of invasion across reconstituted basement membranes and type I collagen gels in response to CXCL12, which is the result of lack of MMP-2 activation. Interference with MMP-2 expression further confirms its important role during this invasion. Vav proteins are guanine-nucleotide exchange factors for Rho GTPases that regulate actin dynamics and gene expression. We show that melanoma cells express Vav1 and Vav2, which are activated by CXCL12 involving Jak activity. Blocking Vav expression by RNA interference results in impaired activation of Rac and Rho by CXCL12 and in a remarkable inhibition of CXCL12-promoted invasion. Importantly, up-regulation of MT1-MMP expression by CXCL12, a mechanism contributing to melanoma cell invasion, is blocked by knocking down Vav expression or by inhibiting Jak. Together, these data indicate that activation of Jak/Vav/Rho GTPase pathway by CXCL12 is a key signaling event for MT1-MMP/MMP-2–dependent melanoma cell invasion. (Cancer Res 2006; 66(1): 248-58)
Blockade of EGFR and ErbB2 by the Novel Dual EGFR and ErbB2 Tyrosine Kinase Inhibitor GW572016 Sensitizes Human Colon Carcinoma GEO Cells to Apoptosis
Authors: Zhou Yunfei , Li Song , Hu Yi P. , Wang Jing , Hauser Jennie , Conway Alexis N. , Vinci Michelle A. , Humphrey Lisa , Zborowska Elizabeth , Willson James K.V. , Brattain Michael G. 
Published: January 2006

Abstract
Coexpression of the epidermal growth factor receptor (EGFR) family receptors is found in a subset of colon cancers, which may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. Recently, efforts have been made to develop novel 4-anilinoquinazoline and pyridopyrimidine derivatives to inhibit EGFR and ErbB2 kinases simultaneously. In this study, we tested the efficacy of a novel reversible dual inhibitor GW572016 compared with the selective EGFR and ErbB2 tyrosine kinase inhibitors (TKI) AG1478 and AG879 and their combination, using the human colon adenocarcinoma GEO mode. GEO cells depend on multiple ErbB receptors for aberrant growth. A synergistic effect on inhibition of cell proliferation associated with induction of apoptosis was observed from the combination of AG1478 and AG879. Compared with AG1478 or AG879, the single TKI compound GW572016 was a more potent inhibitor of GEO cell proliferation and was able to induce apoptosis at lower concentrations. Western blot analysis revealed that AG1478 and AG879 were unable to suppress both EGFR and ErbB2 activation as well as the downstream mitogen-activated protein kinase (MAPK) and AKT pathways as single agents. In contrast, GW572016 suppressed the activation of EGFR, ErbB2, MAPK, and AKT in a concentration-dependent manner. Finally, in vivo studies showed that GW572016 treatment efficiently blocked GEO xenograft growth at a dose range of 30 to 200 mg/kg with a twice-daily schedule. In summary, our study indicates that targeting both EGFR and ErbB2 simultaneously could enhance therapy over that of single agents directed at EGFR or ErbB2 in cancers that can be identified as being primarily heterodimer-dependent. (Cancer Res 2006; 66(1): 404-11)
β1 Integrins Modulate Cell Adhesion by Regulating Insulin-Like Growth Factor-II Levels in the Microenvironment
Authors: Goel Hira Lal , Moro Loredana , King Michael , Teider Natalia , Centrella Michael , McCarthy Thomas L. , Holgado-Madruga Marina , Wong Albert J. , Marra Ersilia , Languino Lucia R. 
Published: January 2006

Abstract
The interactions between cancer cells and the extracellular matrix (ECM) regulate cancer progression. The β1C and β1A integrins, two cytoplasmic variants of the β1 integrin subfamily, are differentially expressed in prostate cancer. Using gene expression analysis, we show here that the β1C variant, an inhibitor of cell proliferation, which is down-regulated in prostate cancer, up-regulates insulin-like growth factor-II (IGF-II) mRNA and protein levels. In contrast, β1A does not affect IGF-II levels. We provide evidence that β1C-mediated up-regulation of IGF-II levels increases adhesion to Laminin-1, a basement membrane protein down-regulated in prostate cancer, and that the β1C cytoplasmic domain contains the structural motif sufficient to increase cell adhesion to Laminin-1. This autocrine mechanism that locally supports cell adhesion to Laminin-1 via IGF-II is selectively regulated by the β1 cytoplasmic domain via activation of the growth factor receptor binding protein 2–associated binder-1/SH2-containing protein-tyrosine phosphatase 2/phosphatidylinositol 3-kinase pathway. Thus, the concurrent local loss of β1C integrin, of its ligand Laminin-1, and of IGF-II in the tumor microenvironment may promote prostate cancer cell invasion and metastasis by reducing cancer cell adhesive properties. It is, therefore, conceivable that reexpression of β1C will be sufficient to revert a neoplastic phenotype to a nonproliferative and highly adherent normal phenotype. (Cancer Res 2006; 66(1): 331-42)
Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer
Authors: Kong-Beltran Monica , Seshagiri Somasekar , Zha Jiping , Zhu Wenjing , Bhawe Kaumudi , Mendoza Nerissa , Holcomb Thomas , Pujara Kanan , Stinson Jeremy , Fu Ling , Severin Christophe , Rangell Linda , Schwall Ralph , Amler Lukas , Wickramasinghe Dineli , Yauch Robert 
Published: January 2006

Abstract
Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation–driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer. (Cancer Res 2006; 66(1): 283-9)
Inhibition of Bladder Tumor Growth by 1,1-Bis(3′-Indolyl)-1-(p-Substitutedphenyl)Methanes: A New Class of Peroxisome Proliferator-Activated Receptor γ Agonists
Authors: Kassouf Wassim , Chintharlapalli Sudhakar , Abdelrahim Maen , Nelkin Gina , Safe Stephen , Kamat Ashish M. 
Published: January 2006

Abstract
1,1-Bis(3′-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC6H5) substituents have been identified as a new class of peroxisome proliferator-activated receptor γ (PPARγ) agonists that exhibit antitumorigenic activity. The PPARγ-active C-DIMs have not previously been studied against bladder cancer. We investigated the effects of the PPARγ-active C-DIMs on bladder cancer cells in vitro and bladder tumors in vivo. In this study, the PPARγ-active compounds inhibited the proliferation of KU7 and 253J-BV bladder cancer cells, and the corresponding IC50 values were 5 to 10 and 1 to 5 μmol/L, respectively. In the less responsive KU7 cells, the PPARγ agonists induced caveolin-1 and p21 expression but no changes in cyclin D1 or p27; in 253J-BV cells, the PPARγ agonists did not affect caveolin-1, cyclin D1, or p27 expression but induced p21 protein. In KU7 cells, induction of caveolin-1 by each of the PPARγ agonists was significantly down-regulated after cotreatment with the PPARγ antagonist GW9662. DIM-C-pPhCF3 (60 mg/kg thrice a week for 4 weeks) inhibited the growth of implanted KU7 orthotopic and s.c. tumors by 32% and 60%, respectively, and produced a corresponding decrease in proliferation index. Treatment of KU7 cells with DIM-C-pPhCF3 also elevated caveolin-1 expression by 25% to 30%, suggesting a role for this protein in mediating the antitumorigenic activity of DIM-C-pPhCF3 in bladder cancer. (Cancer Res 2006; 66(1): 412-8)
Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte as Tumorigenic Precursor andDMRT1as Candidate Chromosome 9 Gene
Authors: Looijenga Leendert H.J. , Hersmus Remko , Gillis Ad J.M. , Pfundt Rolph , Stoop Hans J. , van Gurp Ruud J.H.L.M. , Veltman Joris , Beverloo H. Berna , van Drunen Ellen , Geurts van Kessel Ad , Reijo Pera Renee , Schneider Dominik T. , Summersgill Brenda , Shipley Janet , McIntyre Alan , van der Spek Peter , Schoenmakers Eric , Oosterhuis J. Wolter 
Published: January 2006

AbstractSpermatocytic seminomas are solid tumors found solely in the testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and numerical chromosomal changes through conventional karyotyping, spectral karyotyping, and array comparative genomic hybridization using a 32 K genomic tiling-path resolution BAC platform (confirmed by in situ hybridization). Our panel of five spermatocytic seminomas showed a specific pattern of chromosomal imbalances, mainly numerical in nature (range, 3-24 per tumor). Gain of chromosome 9 was the only consistent anomaly, which in one case also involved amplification of the 9p21.3-pter region. Parallel chromosome level expression profiling as well as microarray expression analyses (Affymetrix U133 plus 2.0) was also done. Unsupervised cluster analysis showed that a profile containing transcriptional data on 373 genes (difference of ≥3.0-fold) is suitable for distinguishing these tumors from seminomas/dysgerminomas. The diagnostic markers SSX2-4 and POU5F1 (OCT3/OCT4), previously identified by us, were among the top discriminatory genes, thereby validating the experimental set-up. In addition, novel discriminatory markers suitable for diagnostic purposes were identified, including Deleted in Azospermia (DAZ). Although the seminomas/dysgerminomas were characterized by expression of stem cell–specific genes (e.g., POU5F1, PROM1/CD133, and ZFP42), spermatocytic seminomas expressed multiple cancer testis antigens, including TSP50 and CTCFL (BORIS), as well as genes known to be expressed specifically during prophase meiosis I (TCFL5, CLGN, and LDHc). This is consistent with different cells of origin, the primordial germ cell and primary spermatocyte, respectively. Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas. (Cancer Res 2006; 66(1): 290-302)
Mouse Models of Human Cancers Consortium Workshop on Nervous System Tumors
Authors: Gutmann David H. , Maher Elizabeth A. , Van Dyke Terry 
Published: January 2006

Abstract
Nervous system tumors are clinically challenging neoplasms that form within the central and peripheral nervous system. Although there have been many clinical trials using novel agents for the treatment of primary brain tumors, there have been few advances that positively affect overall patient survival. Over the past several years, there has been significant progress in the development of accurate small-animal spontaneous brain tumor models, small-animal neuroimaging, and tools for the bioinformatic analysis of complex molecular data sets, all of which have contributed to an improved understanding of the pathogenesis of human brain tumors. Whereas these models will continue to be of great value in basic science investigations, they can also be used to identify and validate potential therapies for brain tumors and to evaluate these drugs in preclinical trials. The National Cancer Institute recently convened a workshop to review the current state of small-animal brain tumor modeling and to make recommendations about the use of these models to improve the clinical outcome for patients with brain tumors. In this meeting report, we outline the current state of small-animal models for brain tumors, the potential applications of these models, and the recommendations made by the workshop participants for the use of mouse models in the preclinical evaluation of potential brain tumor therapies. (Cancer Res 2006; 66(1): 10-3)