bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP
Authors: Galligan Leeona , Longley Daniel B. , McEwan Miranda , Wilson Timothy R. , McLaughlin Kirsty , Johnston Patrick G.
Published: March 2006

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain–like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis. Although chemotherapy treatment did not modulate mRNA or cell surface expression of the TRAIL receptors death receptor 4, death receptor 5, decoy receptor 1, or decoy receptor 2, it was found to down-regulate expression of the caspase-8 inhibitor, c-FLIP. Stable overexpression of the long c-FLIP splice form but not the short form was found to inhibit chemotherapy/rTRAIL–induced apoptosis. Furthermore, siRNA-mediated down-regulation of c-FLIP, particularly the long form, was found to sensitize colon cancer cells to rTRAIL-induced apoptosis. In addition, treatment of a 5-FU-resistant cell line with 5-FU down-regulated c-FLIP expression and sensitized the chemotherapy-resistant cell line to rTRAIL. We conclude that TRAIL-targeted therapies may be used to enhance conventional chemotherapy regimens in colon cancer regardless of tumor p53 status. Furthermore, inhibition of c-FLIP may be a vital accessory strategy for the optimal use of TRAIL-targeted therapies. [Mol Cancer Ther 2005;4(12):2026–36]
Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery
Authors: Wang Yong , Wang He , Li Chuan-Yuan , Yuan Fan
Published: March 2006

Recent studies have shown that up to 90% of viral vectors could disseminate to normal organs following intratumoral infusion. The amount of dissemination might be dependent on the infusion conditions. Therefore, we investigated the effects of infusion rate, volume, and dose on transgene expression in liver and tumor tissues after intratumoral infusion of an adenoviral vector encoding luciferase. Luciferase expression was determined through bioluminescence intensity measurement. We observed that the luciferase expression in the liver was independent of the infusion rate but increased with the infusion dose, whereas the luciferase expression in the tumor was a bell-shaped function of the infusion rate. The latter observation was consistent with the distribution pattern of Evans blue–labeled albumin after its solution was infused into tumors at the same infusion rates. We also observed that the infusion volume could affect luciferase expression in the tumor but not in the liver. These observations implied that virus dissemination was determined mainly by the infusion dose, whereas the amount of transgene expression in the tumor depended on the distribution volume of viral vectors in the tumor as well as the infusion dose. [Mol Cancer Ther 2006;5(2):362–6]
Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein
Authors: Kotha Anupama , Sekharam Madhavi , Cilenti Lucia , Siddiquee Khandaker , Khaled Annette , Zervos Antonis S. , Carter Bradford , Turkson James , Jove Richard
Published: March 2006

Resveratrol is a naturally occurring phytoalexin with antioxidant and antiinflammatory properties. Recent studies suggest that resveratrol possesses anticancer effects, although its mechanism of action is not well understood. We now show that resveratrol inhibits Src tyrosine kinase activity and thereby blocks constitutive signal transducer and activator of transcription 3 (Stat3) protein activation in malignant cells. Analyses of resveratrol-treated malignant cells harboring constitutively-active Stat3 reveal irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human breast (MDA-MB-231), pancreatic (Panc-1), and prostate carcinoma (DU145) cell lines at the G0-G1 phase or at the S phase of human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. By contrast, cells treated with resveratrol, but lacking aberrant Stat3 activity, show reversible growth arrest and minimal loss of viability. Moreover, in malignant cells harboring constitutively-active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol treatment represses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that the antitumor cell activity of resveratrol is in part due to the blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, further defining the mechanism of antitumor cell activity of resveratrol and raising its potential application in tumors with an activated Stat3 profile. [Mol Cancer Ther 2006;5(3):621–9]
A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases
Authors: Zhou Bingsen , Shao Jimin , Su Leila , Yuan Yate-Ching , Qi Christina , Shih Jennifer , Xi Bixin , Chu Bernard , Yen Yun
Published: March 2006

Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA biosynthesis. A tyrosine residue in the small subunit of class I ribonucleotide reductase harbors a stable radical, which plays a central role in the catalysis process. We have discovered that an additional tyrosine residue, conserved in human small subunits hRRM2 and p53R2, is required for the radical formation and enzyme activity. Mutations of this newly identified tyrosine residue obliterated the stable radical and the enzymatic activity of human ribonucleotide reductases shown by electron paramagnetic resonance spectroscopy and enzyme activity assays. Three-dimensional structural analysis reveals for the first time that these two tyrosines are located at opposite sides of the diiron cluster. We conclude that both tyrosines are necessary in maintaining the diiron cluster of the enzymes, suggesting that the assembly of a dityrosyl-diiron radical cofactor center in human ribonucleotide reductases is essential for enzyme catalytic activity. These results should provide insights to design better ribonucleotide reductase inhibitors for cancer therapy. [Mol Cancer Ther 2005;4(12):1830–6]
SUMOylation plays a role in gemcitabine- and bortezomib-induced cytotoxicity in human oropharyngeal carcinoma KB gemcitabine-resistant clone
Authors: Chung Vincent , Zhou Bingsen , Liu Xiyong , Zhu Lijun , Boo Lee M. , Nguyen Ha-Van , Ann David K. , Song Jing , Chen Yuan , Yen Yun
Published: March 2006

Bortezomib, a novel dipeptide boronic acid proteasome inhibitor, has been shown in previous studies to be synergistic with gemcitabine; however, the molecular mechanisms are not fully understood. Because post-translational modification of proteins, such as ubiquitination and SUMOylation, plays a critical role in governing cellular homeostasis, we explored this further by treating human oropharyngeal carcinoma KB wild-type (KBwt) and gemcitabine-resistant (KBGem) cells with gemcitabine and bortezomib in a time-dependent and sequence-dependent manner. Treatment with bortezomib at 4 to 8 hours post-gemcitabine significantly induced cell death in KBwt cell lines. However, in KBGem cells, bortezomib alone was just as cytotoxic. Using reporter assays, nuclear factor-κB (NF-κB) activity was found to be 5-fold higher in KBGem cells than that in KBwt cells, and the combination treatment decreased NF-κB activity by 44% in KBwt cells and 28% in KBGem cells, respectively. By Western blot analyses, treatment with gemcitabine and bortezomib resulted in a cleavage of NF-κB in KBwt but not in KBGem cells. SUMOylation capacity was modulated by transducing KBwt and KBGem cells with lenti-SUMO-1 or the unconjugatable lenti-SUMO-1aa followed by drug treatment. The expression of cyclins A, D1, and E was differentially regulated by SUMOylation capacity in KBGem but not in KBwt cells. We report herein that the activation of NF-κB signaling plays a critical role in eliciting KBwt cell survival against gemcitabine, whereas the role of SUMOylation in modulating the steady-state levels of key cell cycle regulator proteins seems more significant in KBGem cells. [Mol Cancer Ther 2006;5(3):533–40]
Modulation of nuclear factor E2-related factor 2–mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin
Authors: Shen Guoxiang , Xu Changjiang , Hu Rong , Jain Mohit R. , Gopalkrishnan Avantika , Nair Sujit , Huang Mou-Tuan , Chan Jefferson Y. , Kong Ah-Ng Tony
Published: March 2006

Curcumin has been shown to prevent and inhibit carcinogen-induced tumorigenesis in different organs of rodent carcinogenesis models. Our objective is to study global gene expression profiles elicited by curcumin in mouse liver and small intestine as well as to identify curcumin-regulated nuclear factor E2-related factor 2 (Nrf2)–dependent genes. Wild-type C57BL/6J and Nrf2 knockout C57BL/6J/Nrf2(−/−) mice were given a single oral dose of curcumin at 1,000 mg/kg. Liver and small intestine were collected at 3 and 12 hours after treatments. Total RNA was extracted and analyzed using Affymetrix (Santa Clara, CA) mouse genome 430 array (45K) and GeneSpring 6.1 software (Silicon Genetics, Redwood City, CA). Genes that were induced or suppressed >2-fold by curcumin treatments compared with vehicle in wild-type mice but not in knockout mice were filtered using GeneSpring software and regarded as Nrf2-dependent genes. Among those well-defined genes, 822 (664 induced and 158 suppressed) and 222 (154 induced and 68 suppressed) were curcumin-regulated Nrf2-dependent genes identified in the liver and small intestine, respectively. Based on their biological functions, these genes can be classified into the category of ubiquitination and proteolysis, electron transport, detoxification, transport, apoptosis and cell cycle control, cell adhesion, kinase and phosphatase, and transcription factor. Many phase II detoxification/antioxidant enzyme genes, which are regulated by Nrf2, are among the identified genes. The identification of curcumin-regulated Nrf2-dependent genes not only provides potential novel insights into the biological effects of curcumin on global gene expression and chemoprevention but also points to the potential role of Nrf2 in these processes. [Mol Cancer Ther 2006;5(1):39–51]
Targeting signal transducer and activator of transcription 3 with G-quartet oligonucleotides: a potential novel therapy for head and neck cancer
Authors: Jing Naijie , Zhu Qiqing , Yuan Ping , Li Yidong , Mao Li , Tweardy David J.
Published: March 2006

Signal transducer and activator of transcription 3 (Stat3) is a critical mediator of oncogenic signaling activated frequently in many types of human cancer where it contributes to tumor cell growth and resistance to apoptosis. Stat3 has been proposed as a promising target for anticancer drug discovery. Recently, we developed a series of G-quartet oligodeoxynucleotides (GQ-ODN) as novel and potent Stat3 inhibitors, which significantly suppressed the growth of prostate and breast tumors in nude mice. In the present study, we showed that GQ-ODN specifically inhibited DNA-binding activity of Stat3 as opposed to Stat1. Computer-based docking analysis revealed that GQ-ODN predominantly interacts with the SH2 domains of Stat3 homodimers to destabilize dimer formation and disrupt DNA-binding activity. We employed five regimens in the treatment of nude mice with tumors of head and neck squamous cell carcinoma (HNSCC): placebo, paclitaxel, GQ-ODN T40214, GQ-ODN T40231, and T40214 plus paclitaxel. The mean size of HNSCC tumors over 21 days only increased by 1.7-fold in T40214-treated mice and actually decreased by 35% in T40214 plus paclitaxel–treated mice whereas the mean size of HNSCC tumors increased 9.4-fold in placebo-treated mice in the same period. These findings show that GQ-ODN has potent activity against HNSCC tumor xenografts alone and in combination with paclitaxel. [Mol Cancer Ther 2006;5(2):279–86]
Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes
Authors: Tuthill Matthew C. , Oki Carolyn E. , Lorenzo Patricia S.
Published: March 2006

The antitumor agent bryostatin 1 and the tumor-promoting phorbol esters function as structural mimetics of the second lipid messenger diacylglycerol (DAG) by binding to the C1 domain of DAG receptors. However, bryostatin 1 and the phorbol esters often differ in their cellular actions. In mouse skin, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent tumor promoter, whereas bryostatin 1 lacks this activity and antagonizes the tumor-promoting effects of TPA. Although protein kinase C mediates many of the effects of DAG on skin, the exact mechanisms responsible for the biology of bryostatin 1 and TPA in the epidermis have not been elucidated. We recently reported that the novel DAG receptor RasGRP1 is expressed in mouse keratinocytes and mediates TPA-induced Ras activation. This finding prompted us to examine the regulation of RasGRP1 by bryostatin 1. We found that whereas TPA induced translocation of RasGRP1 to both the plasma and internal membranes of the keratinocytes, bryostatin 1 recruited RasGRP1 only to internal membranes and the nuclear envelope. In addition, TPA led to a concentration-dependent down-regulation of RasGRP1, whereas bryostatin 1 failed to induce full RasGRP1 down-regulation. Interestingly, bryostatin 1 was less effective than TPA at activating Ras. The results presented here suggest the possibility that a differential modulation of RasGRP1 by bryostatin 1 compared with TPA could participate in the disparate responses of the epidermal cells to both DAG analogues. This result may have implications in the understanding of the antitumor effects of bryostatin 1 in the skin. [Mol Cancer Ther 2006;5(3):602–10]
Targeted delivery of methotrexate to epidermal growth factor receptor–positive brain tumors by means of cetuximab (IMC-C225) dendrimer bioconjugates
Authors: Wu Gong , Barth Rolf F. , Yang Weilian , Kawabata Shinji , Zhang Liwen , Green-Church Kari
Published: March 2006

We have constructed a drug delivery vehicle that targets the epidermal growth factor receptor (EGFR) and its mutant isoform EGFRvIII. The monoclonal antibody, cetuximab, previously known as C225, which binds to both EGFR and EGFRvIII, was covalently linked via its Fc region to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. As measured by mass spectrometry and UV/vis spectroscopy, the resulting bioconjugate, designated C225-G5-MTX, contained 12.6 molecules of methotrexate per unit of dendrimer. Specific binding and cytotoxicity of the bioconjugate was evaluated against the EGFR-expressing rat glioma cell line F98EGFR. Using a competitive binding assay, it was shown that the bioconjugate retained its affinity for F98EGFR cells, with a 0.8 log unit reduction in its EC50. Only cetuximab completely inhibited binding of the bioconjugate, which was unaffected by methotrexate or dendrimer. Cetuximab alone was not cytotoxic to F98EGFR cells at the concentration tested, whereas the IC50 of the bioconjugate was 220 nmol/L, which was a 2.7 log unit decrease in toxicity over that of free methotrexate. The biodistribution of C225-G5-MTX in rats bearing i.c. implants of either F98EGFR or F98WT gliomas was determined 24 hours following convection enhanced delivery of 125I-labeled bioconjugate. At this time, 62.9 ± 14.7% ID/g tumor was localized in rats bearing F98EGFR gliomas versus 11.3 ± 3.6% ID/g tumor in animals bearing F98WT gliomas, thereby showing specific molecular targeting of the tumor. The corresponding radioactivity of normal brain from the F98EGFR tumor-bearing right and non-tumor-bearing left cerebral hemisphere were 5.8 ± 3.4% and 0.8 ± 0.6% ID/g, respectively. Based on these results, therapy studies were initiated in F98EGFR glioma-bearing rats. Animals that received C225-G5-MTX, cetuximab, or free methotrexate had median survival times of 15, 17, and 19.5 days, respectively, which were not statistically different from each other or untreated control animals. Our results, which are both positive and negative, show that specific molecular targeting is but one of several requirements that must be fulfilled if an antibody-drug bioconjugate will be therapeutically useful. [Mol Cancer Ther 2006;5(1):52–9]
Tumor necrosis factor receptor deficiency exacerbated Adriamycin-induced cardiomyocytes apoptosis: an insight into the Fas connection
Authors: Lien Yu-Chin , Lin Shu-Mei , Nithipongvanitch Ramaneeya , Oberley Terry D. , Noel Teresa , Zhao Qing , Daosukho Chotiros , St. Clair Daret K.
Published: March 2006

Cardiomyopathy is a major dose-limiting factor for applications of Adriamycin, a potent chemotherapeutic agent. The present study tested the hypothesis that increased tumor necrosis factor (TNF)-α signaling via its receptors protects against Adriamycin-induced cardiac injury. We used mice in which both TNF receptor I and II have been selectively inactivated (DKO) with wild-type mice as controls. Morphometric studies of cardiac tissue following Adriamycin treatment revealed greater ultrastructural damage in cardiomyocyte mitochondria from DKO mice. Biochemical studies of cardiac tissues showed cytochrome c release and the increase in proapoptotic protein levels, suggesting that lack of TNF-α receptor I and II exacerbates Adriamycin-induced cardiac injury. The protective role of TNF receptor I and II was directly confirmed in isolated primary cardiomyocytes. Interestingly, following Adriamycin treatment, the levels of Fas decreased in the wild-type mice. In contrast, DKO mice had an increase in Fas levels and its downstream target, mitochondrial truncated Bid. These results suggested that TNF-α receptors play a critical role in cardioprotection by suppression of the mitochondrial-mediated associated cell death pathway. [Mol Cancer Ther 2006;5(2):261–9]
Angiostatic activity of DNA methyltransferase inhibitors
Authors: Hellebrekers Debby M.E.I. , Jair Kam-Wing , Viré Emmanuelle , Eguchi Sayaka , Hoebers Nicole T.H. , Fraga Mario F. , Esteller Manel , Fuks François , Baylin Stephen B. , van Engeland Manon , Griffioen Arjan W.
Published: March 2006

Inhibitors of DNA methyltransferases (DNMT) and histone deacetylases can reactivate epigenetically silenced tumor suppressor genes and thereby decrease tumor cell growth. Little, however, is known on the effects of these compounds in endothelial cell biology and tumor angiogenesis. Here, we show that the DNMT inhibitors 5-aza-2′-deoxycytidine and zebularine markedly decrease vessel formation in different tumor models. We show that DNMT inhibitors are antiproliferative for tumor-conditioned endothelial cells, without affecting endothelial cell apoptosis and migration. Furthermore, these compounds inhibit angiogenesis in vitro and in vivo as shown by inhibition of endothelial cells sprouting in a three-dimensional gel and inhibition of microvessel formation in the chorioallantoic membrane, respectively. 5-Aza-2′-deoxycytidine, as well as the histone deacetylase inhibitor trichostatin A, reactivates the growth-inhibiting genes TSP1, JUNB, and IGFBP3, which are suppressed in tumor-conditioned endothelial cells. Despite enhanced DNMT activity and increased overall genomic methylation levels in tumor-conditioned endothelial cells, silencing of these genes seemed not to be regulated by direct promoter hypermethylation. For IGFBP3, gene expression in endothelial cells correlated with histone H3 acetylation patterns. In conclusion, our data show that DNMT inhibitors have angiostatic activity in addition to their inhibitory effects on tumor cells. This dual action of these compounds makes them promising anticancer therapeutics. [Mol Cancer Ther 2006;5(2)467–75]
Sphingolipid targets in cancer therapy
Authors: Modrak David E. , Gold David V. , Goldenberg David M.
Published: March 2006

Considerable progress has been made recently in our understanding of the role of ceramide in the induction of apoptotic cell death. Ceramide is produced by cancer cells in response to exposure to radiation and most chemotherapeutics and is an intracellular second messenger that activates enzymes, leading to apoptosis. Because of its central role in apoptosis, pharmacologic manipulation of intracellular ceramide levels should result in attenuation or enhancement of drug resistance. This may be achieved through direct application of sphingolipids or by the inhibition/activation of the enzymes that either produce or use ceramide. In addition, attention should be given to the subcellular location of ceramide generation, because this has been shown to affect the biological activity of sphingolipids. This review summarizes the sphingolipid biosynthetic pathway, as it relates to the identification of important targets for drug discovery, and the development of novel agents capable of enhancing chemotherapy. [Mol Cancer Ther 2006;5(2):200–8]
Survivinand Granzyme B–induced apoptosis, a novel anticancer therapy
Authors: Caldas Hugo , Jaynes Florinda O. , Boyer Michael W. , Hammond Sue , Altura Rachel A.
Published: March 2006

Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural killer cells and CTLs following noxious stimuli, including foreign invaders. Here, we took advantage of the properties of these two functionally divergent molecules to create a molecular agent that specifically activates Granzyme B within tumor cells. We designed Survivin and Granzyme B–induced apoptosis (SAGA), which consists of a fusion of the Survivin gene promoter to the coding sequence of active Granzyme B. In cultured human tumor cells transfected with SAGA DNA, Granzyme B is rapidly expressed and results in significant tumor cell death. In vivo, mice harboring human ovarian tumors had statistically significant clinical responses to SAGA treatment that were magnified following combination therapy with SAGA and paclitaxel. At the completion of a 3-week therapeutic trial, 3 of 15 animals were free of disease in the SAGA-treated group, and an additional eight animals had tumors that were nonpalpable and only detected on surgical resection. In contrast, 15 of 15 animals in the control and paclitaxel-only–treated groups had tumors at end of therapy. Treatment with SAGA with or without paclitaxel also prevented disease dissemination in 19 of 20 animals. These results strongly suggest that SAGA has the potential to be a potent agent for the treatment of primary and recurrent human ovarian carcinoma. Moreover, we predict that SAGA will be useful therapeutically in any human cancer that expresses Survivin. [Mol Cancer Ther 2006;5(3):693–703]
Targeted therapy by disablingcrossroadsignaling networks: the survivin paradigm
Authors: Altieri Dario C.
Published: March 2006

Embedded in the concept of targeted cancer therapy is the expectation that disabling a single oncogenic pathway will eliminate the tumor cells and leave the normal tissues unscathed. Although validated by clinical responses in certain malignancies, challenges exist to generalize this approach to most tumors, as multiple genetic lesions, chromosomal instability, insensitivity of the cancer stem cell compartment, and emergence of drug resistance complicate the identification and therapeutic exploitation of a single, driving oncogenic pathway. Instead, broader therapeutic prospects may be offered by targeting crossroad signaling networks that are selectively exploited in cancer and oversee multiple aspects of tumor cell maintenance. One such pathway is centered on survivin, a cancer gene that intersects cell proliferation, cell survival, and the cellular stress response. Several clinical trials targeting survivin with a collection of approaches from immunotherapy to small-molecule antagonists are currently under way. By simultaneously disabling multiple signaling circuitries, targeting survivin may provide a novel perspective in rational cancer therapy selective for specific cancer mechanisms but broadly applicable to disparate tumors regardless of their genetic makeup. [Mol Cancer Ther 2006;5(3):478–82]
Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis
Authors: Sanderson Sharon , Valenti Melanie , Gowan Sharon , Patterson Lisa , Ahmad Zahida , Workman Paul , Eccles Suzanne A.
Published: March 2006

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in maintaining the correct conformation and stability of its client proteins. This study investigated the effects of Hsp90 inhibitors on client protein expression and key cellular functions required for tumor angiogenesis. The benzoquinone ansamycin Hsp90 inhibitors geldanamycin and/or its derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin inhibited production of vascular endothelial growth factor (VEGF)-A by tumor cells and blocked proliferative responses of human endothelial cells at nanomolar concentrations. 17-AAG also significantly reduced endothelial cell migration, tubular differentiation, invasion through Matrigel, and secretion of urokinase-type plasminogen activator at concentrations at or below those that inhibited proliferation. 17-AAG significantly reduced expression of VEGF receptor (VEGFR)-2 and established Hsp90 client proteins in human endothelial cells in vitro as well as in mouse vena cava, mesenteric vessels, and blood vessels within human tumor xenografts in vivo; this was associated with decreased tumor microvessel density. Finally, we showed for the first time that Hsp90 inhibitors also reduce expression of VEGFR-1 on human vascular endothelial cells, VEGFR-3 on lymphatic endothelial cells in vitro, and all three VEGFRs on mouse vasculature in vivo. Thus, we identify Hsp90 inhibitors as important regulators of many aspects of tumor angiogenesis (and potentially lymphangiogenesis) and suggest that they may provide therapeutic benefit not only via direct effects on tumor cells but also indirectly by inhibiting the production of angiogenic cytokines and responses of activated endothelial cells that contribute to tumor progression and metastasis.[Mol Cancer Ther 2006;5(3):522–32]
Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells
Authors: Mantena Sudheer K. , Sharma Som D. , Katiyar Santosh K.
Published: March 2006

Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and antitumor properties in some in vitro systems. Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10–100 μmol/L) and time-dependent (24–72 hours) manner. Treatment of nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under identical conditions did not significantly affect their viability. The berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP cells was associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk. Berberine also significantly (P < 0.05–0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pretreatment with the pan-caspase inhibitor z-VAD-fmk partially, but significantly, blocked the berberine-induced apoptosis, as also confirmed by the comet assay analysis of DNA fragmentation, suggesting that berberine-induced apoptosis of human prostate cancer cells is mediated primarily through the caspase-dependent pathway. The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy. [Mol Cancer Ther 2006;5(2):296–308]
A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex
Authors: Marchand Christophe , Antony Smitha , Kohn Kurt W. , Cushman Mark , Ioanoviciu Alexandra , Staker Bart L. , Burgin Alex B. , Stewart Lance , Pommier Yves
Published: March 2006

We show that five topoisomerase I inhibitors (two indenoisoquinolines, two camptothecins, and one indolocarbazole) each intercalate between the base pairs flanking the cleavage site generated during the topoisomerase I catalytic cycle and are further stabilized by a network of hydrogen bonds with topoisomerase I. The interfacial inhibition paradigm described for topoisomerase I inhibitors can be generalized to a variety of natural products that trap macromolecular complexes as they undergo catalytic conformational changes that create hotspots for drug binding. Stabilization of such conformational states results in uncompetitive inhibition and exemplifies the relevance of screening for ligands and drugs that stabilize (“trap”) these macromolecular complexes. [Mol Cancer Ther 2006;5(2):287–95]
PDMP sensitizes neuroblastoma to paclitaxel by inducing aberrant cell cycle progression leading to hyperploidy
Authors: Dijkhuis Anne-Jan , Klappe Karin , Jacobs Susan , Kroesen Bart-Jan , Kamps Willem , Sietsma Hannie , Kok Jan Willem
Published: March 2006

The sphingolipid ceramide has been recognized as an important mediator in the apoptotic machinery, and its efficient conversion to glucosylceramide has been associated with multidrug resistance. Therefore, inhibitors of glucosylceramide synthase are explored as tools for treatment of cancer. In this study, we used d,l-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol to sensitize Neuro-2a murine neuroblastoma cells to the microtubule-stabilizing agent paclitaxel. This treatment resulted in a synergistic inhibition of viable cell number increase, which was based on a novel mechanism: (a) After a transient mitotic arrest, cells proceeded through an aberrant cell cycle resulting in hyperploidy. Apoptosis also occurred but to a very limited extent. (b) Hyperploidy was not abrogated by blocking de novo sphingolipid biosynthesis using ISP-1, ruling out involvement of ceramide as a mediator. (c) Cyclin-dependent kinase 1 and 2 activities were synergistically decreased on treatment. In conclusion, instead of inducing apoptosis through ceramide accumulation, d,l-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol by itself affects cell cycle–related proteins in paclitaxel-arrested Neuro-2a cells resulting in aberrant cell cycle progression leading to hyperploidy. [Mol Cancer Ther 2006;5(3):593–601]
Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase
Authors: Powis Garth , Wipf Peter , Lynch Stephen M. , Birmingham Anne , Kirkpatrick D. Lynn
Published: March 2006

The cytosolic thioredoxin redox system composed of thioredoxin-1 and the NADPH-dependent thioredoxin reductase-1 reductase is an important regulator of cell growth and survival. Thioredoxin-1 is overexpressed in many human tumors where it is associated with increased cell proliferation, decreased apoptosis, and decreased patient survival. We hypothesized that thioredoxin reductase-1 provides a target to inhibit the activity of overexpressed thioredoxin-1 for the development of novel anticancer agents. We found that the naphthoquinone spiroketal fungal metabolite palmarumycin CP1 is a potent inhibitor of thioredoxin reductase-1, but attempts to exploit the activity of palmarumycin CP1 analogues as antitumor agents in vivo were hampered by their insolubility. We have therefore developed PX-916, a water-soluble prodrug of a palmarumycin CP1 analogue. PX-916 rapidly releases the parent compound at physiologic pH and in plasma but is stable at acid pH, allowing its i.v. administration. PX-916 is a potent inhibitor of purified human thioredoxin reductase-1 and of thioredoxin reductase-1 activity in cells and tumor xenografts when given to mice and inhibits the downstream targets of thioredoxin-1 signaling, hypoxia-inducible factor-1α, and vascular endothelial growth factor in tumors. PX-916 showed excellent antitumor activity against several animal tumor models with some cures. Thus, the study shows that water-soluble inhibitors of thioredoxin reductase-1, such as PX-916, can block thioredoxin-1 signaling in tumors producing marked inhibition of tumor growth. [Mol Cancer Ther 2006;5(3):630–6]
Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2
Authors: Dalal Darshan , Molin Lorraine H. , Piccini Jonathan , Tichnell Crystal , James Cynthia , Bomma Chandra , Prakasa Kalpana , Towbin Jeffrey A. , Marcus Frank I. , Spevak Philip J. , Bluemke David A. , Abraham Theodore , Russell Stuart D. , Calkins Hugh , Judge Daniel P.
Published: March 2006

Background—

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in
PKP2
, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of
PKP2
mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with
PKP2
mutations.

Methods and Results—

DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in
PKP2
. Clinical features of ARVD/C were compared between 2 groups of patients: those with a
PKP2
mutation and those with no detectable
PKP2
mutation. Thirteen different
PKP2
mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a
PKP2
mutation (28±11 years) than in those without (36±16 years) (
P
<0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a
PKP2
mutation than among those without a
PKP2
mutation (
P
<0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a
PKP2
mutation (
P
<0.05).

Conclusions—

Our study highlights the clinical relevance of
PKP2
mutations in ARVD/C. Presence of a
PKP2
mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a
PKP2
mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.
Relationship Between Homocysteine and Mortality in Chronic Kidney Disease
Authors: Menon Vandana , Sarnak Mark J. , Greene Tom , Wang Xuelei , Pereira Arema A. , Beck Gerald J. , Kusek John W. , Selhub Jacob , Collins Allan J. , Levey Andrew S. , Shlipak Michael G.
Published: March 2006

Background—

The relationship between total homocysteine (tHcy) and outcomes has not been investigated in patients with chronic kidney disease stages 3 to 4.

Methods and Results—

The Modification of Diet in Renal Disease Study was a randomized, controlled trial of 840 patients. Serum tHcy was measured in frozen samples collected at baseline (n=804). Survival status and cause of death were obtained from the National Death Index. To evaluate its association with all-cause and cardiovascular disease (CVD) mortality, tHcy was evaluated both as tertiles (<14.7, 14.7 to 19.5, ≥19.6 μmol/L) and as a continuous variable (per 10/μmol/L). Participants had a mean age of 52±12 years and glomerular filtration rate (GFR) of 33±12 mL/min per 1.73 m
2
; 60% were male, and 85% were white. During a median follow-up of 10 years, 195 (24%) died from any cause, and 118 (15%) from CVD. The level of GFR was lower and proteinuria higher in the highest tHcy tertile. There was no association between the highest tertile of tHcy and all-cause (hazard ratio [HR]; 95% confidence interval [CI[, 1.32, 0.94 to 1.85) or CVD (HR; 95% CI, 1.50, 0.96 to 2.34) mortality in univariate analyses; this association was further attenuated by adjustment for GFR (HR; 95% CI all-cause, 1.04, 0.72 to 1.51; CVD, 1.20, 0.73 to 1.95). There was no association between tHcy as a continuous variable and all-cause (0.98, 0.83 to 1.16) or CVD (1.04, 0.85 to 1.27) mortality.

Conclusions—

Hyperhomocystinemia does not appear to be a risk factor for all-cause or CVD mortality in the Modification of Diet in Renal Disease Study. Prior studies demonstrating an association between tHcy and CVD risk may have inadequately adjusted for the confounding effects of kidney function.
An Administrative Claims Model Suitable for Profiling Hospital Performance Based on 30-Day Mortality Rates Among Patients With an Acute Myocardial Infarction
Authors: Krumholz Harlan M. , Wang Yun , Mattera Jennifer A. , Wang Yongfei , Han Lein Fang , Ingber Melvin J. , Roman Sheila , Normand Sharon-Lise T.
Published: March 2006

Background—

A model using administrative claims data that is suitable for profiling hospital performance for acute myocardial infarction would be useful in quality assessment and improvement efforts. We sought to develop a hierarchical regression model using Medicare claims data that produces hospital risk-standardized 30-day mortality rates and to validate the hospital estimates against those derived from a medical record model.

Methods and Results—

For hospital estimates derived from claims data, we developed a derivation model using 140 120 cases discharged from 4664 hospitals in 1998. For the comparison of models from claims data and medical record data, we used the Cooperative Cardiovascular Project database. To determine the stability of the model over time, we used annual Medicare cohorts discharged in 1995, 1997, and 1999–2001. The final model included 27 variables and had an area under the receiver operating characteristic curve of 0.71. In a comparison of the risk-standardized hospital mortality rates from the claims model with those of the medical record model, the correlation coefficient was 0.90 (SE=0.003). The slope of the weighted regression line was 0.95 (SE=0.007), and the intercept was 0.008 (SE=0.001), both indicating strong agreement of the hospital estimates between the 2 data sources. The median difference between the claims-based hospital risk-standardized mortality rates and the chart-based rates was <0.001 (25th and 75th percentiles, −0.003 and 0.003). The performance of the model was stable over time.

Conclusions—

This administrative claims-based model for profiling hospitals performs consistently over several years and produces estimates of risk-standardized mortality that are good surrogates for estimates from a medical record model.
Ancient Mystēria and Modern Mystery Cults
Authors: Wellman Tennyson Jacob
Published: March 2006

The modern study of the ancient Hellenic and Hellenistic cults called mystēria has struggled over taxonomic issues related to typicality and modelling for several decades. By refocusing on the artiﬁciality and rhetorical deployment of both the ancient word mystēria and the modern phrase mystery cults, it is possible to step back from issues of reiﬁcation and focus on ancient social contexts for another view. Doing so allows one to note the numerous points of overlap (in ritual action, goals, symbols and narratives) between mystery cults and the broader cultural ﬁelds of ancient Hellenic communities. For instance, when one does not assume that mystery cults are the major origin for eschatological thinking in Greece, other (at times competing) vectors come into view and present a much more diverse ﬁeld of data on the topic. Using Eleusis as an example, it is possible to see that many of the other allegedly typical features of mystery cults are at best problematic viewed against their social backgrounds and not placed in decontextualised juxtaposition with another mystery cult. This suggests that modern theories of culture-as-repertoire and of popular religious cultures are appropriate for making sense of ancient mystēria and thereby rectifying the scholarly construct of mystery cults.
Making Mysteries. From the Untergang der Mysterien to Imperial Mysteries – Social Discourse in Religion and the Study of Religion
Authors: van den Heever Gerhard
Published: March 2006

This article considers the ‘fate’ of Graeco-Roman mysteries in late Antiquity in the context of the gradual Christianising of the Roman Empire. It is argued that the mysteries of the imperial era were themselves contributing to and demonstrative of the social ideology underlying the making of the Roman Empire. The mysteries were embedded in the imperial performance of Saturnalian good times. In order to see this one should change the perspective to study them ﬁrst and foremost as imperial performances. Concomitantly, one should also study the constructions of mysteries in scholarship in order to understand the birth of our conventional understanding of the mysteries in the context of the social ideologies of the 19th century. In this way the Graeco-Roman mysteries serve as a useful case study of the constructedness of religion as social discourse as well as scholarship on religion as equally a social discourse.
Rethinking the Study of Gnosticism
Authors: Desjardins Michel
Published: March 2006

Pointing to parallels in the study of Jesus traditions and Pauline literature, but focusing explicitly on Gnosticism, it is argued that the Gestalt of ancient religions are often the result of ideological projections into the texts and the assumed religious traditions standing behind them by modern scholars. Dealing more appropriately with such a problematic phenomenon as Gnosticism, would entail reconsidering the conceptual categories employed in the description and interpretation of the phenomenon, as well as an object lesson in scholarly humility to avoid the hybris of colonising ancient texts and the communities who produced and valued them.
‘Witless in your own Cause’: Divine Plots and Fractured Characters in the Life of Aesop and the Gospel of Mark
Authors: Elliott Scott S.
Published: March 2006

Juxtaposing the Life of Aesop and the Gospel of Mark, this article explores how ancient ﬁction destabilizes characters, which function as complex and shifting products of storied intersections. Characters are conscripted by discursive plots reﬂecting both the mysteries of divine ‘providence’ and the interpellative power of ‘discourse’ itself. Plots are neither propelled by pre-existent ‘characters,’ nor connotative of the essence of ‘characters;’ rather, ‘subjects’ are continually constructed and deconstructed in the fractured and ambiguous play of events and context. Ancient novels (reﬂecting the eﬀects of empire, cultural displacement, and dialogism) represent human subjects as neither purely active nor purely passive. The article implicitly critiques biblical narrative criticism while reading the Gospel of Mark vis-à-vis ancient novels to model a diﬀerent approach to ancient narrative that problematizes both notions of literary characters as autonomous agents or subjects, and treatments of literary characters as historical referents.
Redescribing Graeco-Roman Antiquity: on Religion and History of Religion
Authors: van den Heever Gerhard
Published: March 2006

In introducing the theme ‘Redescribing Graeco-Roman Antiquity’ this article shows how conventional claims to uniqueness of early Judaism and early Christianity misconstrue religious history. In fact, the conventional portrayal of early Judaism, early Christianity, and Graeco-Roman religions (especially, in this case, the mystery religions) is in itself a social discourse. This is set in the context of the Graeco-Roman constructions of deity, which is demonstrated to be in themselves, too, social discourses, more speciﬁcally, an imperialising discourse. Attention is paid to the discursivity of the phenomena under consideration and it is argued that history of religion is both a study of the construction of the historical ‘object’ as well as the construction of the construction of the historical ‘object’.
Dealing with Psychological Tensions
Authors: Rogers Carl R.
Published: March 2006

The behavioral sciences have made modest but real progress in learning to deal with psychological tensions within the individual; with tensions between individuals; with tensions between small groups. We have practical skills which permit us to create deep and harmonious relationships in a group of diverse individuals. We have even made a small beginning in dealing with international tensions on a simulated basis.

What is needed is a concerted effort-an interdisciplinary task force-to push out the boundaries of such knowledge and to apply these growing skills to existing tensions-interracial, international, and other.
The Union-Management Intergroup Laboratory: Strategy for Resolving Intergroup Conflict
Authors: Blake Robert R. , Mouton Jane Srygley , Sloma Richard L.
Published: March 2006

Behavioral science concepts and theories are rapidly finding increased application in business, government, and other organizations and institutions.

The following article is a description of a recent step in applying behavioral science theories and research findings to a concrete organization situation. Described is a systematic approach for confronting the intense intergroup hostility between a management and an international union and moving the relationship toward a sound problem-solving one.

Following a brief description of the setting in which this intergroup situation is embedded, a "blow-by-blow" accounting of the events that occurred during a Union-Management Inter-group Laboratory is presented. The attitudes, assumptions, values, misunderstandings, and goals of each group are brought into bold relief as they jointly examine their present relationship. Through a series of systematic steps, the two groups, working independently and jointly, examine their relationship in depth. Specific or concrete issues are set aside to focus underlying barriers that are causing eruption of conflict at the surface level.

The Intergroup Laboratory permits groups in conflict to come together to work through tensions and frictions that have builtup over an extended period of time. Confrontation at this level permits group representatives to get beneath the issues separating them. Once areas of misunderstanding and sources of tension have been identified and resolved, it is possible for the two groups to more effectively deal with the day-to-day operational problems shared by them.