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Pharmaceuticals, Volume 6, Issue 8 (August 2013), Pages 915-1081

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Research

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Open AccessArticle The Inhibition of Stat5 by a Peptide Aptamer Ligand Specific for the DNA Binding Domain Prevents Target Gene Transactivation and the Growth of Breast and Prostate Tumor Cells
Pharmaceuticals 2013, 6(8), 960-987; doi:10.3390/ph6080960
Received: 8 July 2013 / Revised: 14 August 2013 / Accepted: 16 August 2013 / Published: 20 August 2013
Cited by 11 | PDF Full-text (1590 KB) | HTML Full-text | XML Full-text
Abstract
The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but
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The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)

Review

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Open AccessReview Targeting Platelet Thrombin Receptor Signaling to Prevent Thrombosis
Pharmaceuticals 2013, 6(8), 915-928; doi:10.3390/ph6080915
Received: 6 May 2013 / Revised: 18 July 2013 / Accepted: 26 July 2013 / Published: 2 August 2013
Cited by 3 | PDF Full-text (249 KB) | HTML Full-text | XML Full-text
Abstract
Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more
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Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer
Pharmaceuticals 2013, 6(8), 929-959; doi:10.3390/ph6080929
Received: 9 May 2013 / Revised: 3 July 2013 / Accepted: 29 July 2013 / Published: 6 August 2013
Cited by 43 | PDF Full-text (611 KB) | HTML Full-text | XML Full-text
Abstract
It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through
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It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations. Full article
(This article belongs to the Special Issue Chemokines)
Open AccessReview Personalizing Colon Cancer Therapeutics: Targeting Old and New Mechanisms of Action
Pharmaceuticals 2013, 6(8), 988-1038; doi:10.3390/ph6080988
Received: 4 June 2013 / Revised: 30 July 2013 / Accepted: 16 August 2013 / Published: 21 August 2013
Cited by 7 | PDF Full-text (1743 KB) | HTML Full-text | XML Full-text
Abstract
The use of pharmaceuticals for colon cancer treatment has been increasingly personalized, in part due to the development of new molecular tools. In this review, we discuss the old and new colon cancer chemotherapeutics, and the parameters that have been shown to be
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The use of pharmaceuticals for colon cancer treatment has been increasingly personalized, in part due to the development of new molecular tools. In this review, we discuss the old and new colon cancer chemotherapeutics, and the parameters that have been shown to be predictive of efficacy and safety of these chemotherapeutics. In addition, we discuss how alternate pharmaceuticals have been developed in light of a potential lack of response or resistance to a particular chemotherapeutic. Full article
(This article belongs to the Special Issue Chemotherapeutic Agents)
Figures

Open AccessReview Current Evidence of Chinese Herbal Constituents with Effects on NMDA Receptor Blockade
Pharmaceuticals 2013, 6(8), 1039-1054; doi:10.3390/ph6081039
Received: 29 May 2013 / Revised: 6 August 2013 / Accepted: 19 August 2013 / Published: 21 August 2013
Cited by 1 | PDF Full-text (138 KB) | HTML Full-text | XML Full-text
Abstract
NMDA receptor (NMDA-R) is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer’s Disease) is attributed to NMDA-mediated neurotoxicity. With
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NMDA receptor (NMDA-R) is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer’s Disease) is attributed to NMDA-mediated neurotoxicity. With greater understanding of the NMDA-R structure, antagonists with varying degrees of binding-site and subtype selectivity have been developed and put into clinical use. Discovery of target-specific Chinese herbs have also been made in parallel. This article provides an overview of the known active sites on the NMDA-R, followed by a discussion of the relevant herbs and their constituents. Experimental evidence supporting the inhibitory role of the herbal compounds on the NMDA-R is highlighted. For some of the compounds, potential research directions are also proposed to further elucidate the underlying mechanisms of the herbs. It is envisaged that future investigations based on the present data will allow more clinically relevant herbs to be identified. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)
Open AccessReview Characterization of Antimicrobial Peptides toward the Development of Novel Antibiotics
Pharmaceuticals 2013, 6(8), 1055-1081; doi:10.3390/ph6081055
Received: 16 July 2013 / Revised: 2 August 2013 / Accepted: 16 August 2013 / Published: 21 August 2013
Cited by 23 | PDF Full-text (1019 KB) | HTML Full-text | XML Full-text
Abstract
Antimicrobial agents have eradicated many infectious diseases and significantly improved our living environment. However, abuse of antimicrobial agents has accelerated the emergence of multidrug-resistant microorganisms, and there is an urgent need for novel antibiotics. Antimicrobial peptides (AMPs) have attracted attention as a novel
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Antimicrobial agents have eradicated many infectious diseases and significantly improved our living environment. However, abuse of antimicrobial agents has accelerated the emergence of multidrug-resistant microorganisms, and there is an urgent need for novel antibiotics. Antimicrobial peptides (AMPs) have attracted attention as a novel class of antimicrobial agents because AMPs efficiently kill a wide range of species, including bacteria, fungi, and viruses, via a novel mechanism of action. In addition, they are effective against pathogens that are resistant to almost all conventional antibiotics. AMPs have promising properties; they directly disrupt the functions of cellular membranes and nucleic acids, and the rate of appearance of AMP-resistant strains is very low. However, as pharmaceuticals, AMPs exhibit unfavorable properties, such as instability, hemolytic activity, high cost of production, salt sensitivity, and a broad spectrum of activity. Therefore, it is vital to improve these properties to develop novel AMP treatments. Here, we have reviewed the basic biochemical properties of AMPs and the recent strategies used to modulate these properties of AMPs to enhance their safety. Full article
(This article belongs to the Special Issue Antimicrobial Agents)

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