bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

AbstractThe 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

AbstractWe 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

AbstractCardiomyopathy 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

AbstractInhibitors 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

Abstract
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

AbstractSurvivin 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

AbstractEmbedded 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

Abstract
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

Abstract
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 &lt; 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

Abstract
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

Abstract
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

Abstract
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]
Ancient Mystēria and Modern Mystery Cults
Authors: Wellman Tennyson Jacob 
Published: March 2006

AbstractThe 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.