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Pharmaceuticals, Volume 6, Issue 11 (November 2013) – 6 articles , Pages 1335-1450

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Article
Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo
by Kathryn E. O'Reilly, Eleazar Vega-Saenz De Miera, Miguel F. Segura, Erica Friedman, Laura Poliseno, Sung Won Han, Judy Zhong, Jiri Zavadil, Anna Pavlick, Eva Hernando and Iman Osman
Pharmaceuticals 2013, 6(11), 1429-1450; https://doi.org/10.3390/ph6111429 - 11 Nov 2013
Cited by 38 | Viewed by 8255
Abstract
Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway [...] Read more.
Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway members and determined the consequences of both genetic and pharmacological inhibition of the hedgehog pathway activator Smoothened (SMO) in melanoma, both in vitro and in vivo. We also examined the relationship between altered expression of hedgehog pathway mediators and survival in a well-characterized cohort of metastatic melanoma patients with prospectively collected follow up information. Studies revealed that over 40% of the melanoma cell lines examined harbored significantly elevated levels of the hedgehog pathway mediators SMO, GLI2, and PTCH1 compared to melanocytes (p < 0.05). SMO inhibition using siRNA and the small molecule inhibitor, NVP-LDE-225, suppressed melanoma growth in vitro, particularly in those cell lines with moderate SMO and GLI2 expression. NVP-LDE-225 also induced apoptosis in vitro and inhibited melanoma growth in a xenograft model. Gene expression data also revealed evidence of compensatory up-regulation of two other developmental pathways, Notch and WNT, in response to hedgehog pathway inhibition. Pharmacological and genetic SMO inhibition also downregulated genes involved in human embryonic stem cell pluripotency. Finally, increased SMO expression and decreased expression of the hedgehog pathway repressor GLI3 correlated with shorter post recurrence survival in metastatic melanoma patients. Our data demonstrate that hedgehog pathway inhibition might be a promising targeted therapy in appropriately selected metastatic melanoma patients. Full article
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Article
Structural Bioinformatics and Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions: Towards Allosteric Inhibition of Protein Kinases by Targeting the Hsp90-Cdc37 Chaperone Machinery
by Nathan Lawless, Kristin Blacklock, Elizabeth Berrigan and Gennady Verkhivker
Pharmaceuticals 2013, 6(11), 1407-1428; https://doi.org/10.3390/ph6111407 - 11 Nov 2013
Cited by 27 | Viewed by 9638
Abstract
A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding [...] Read more.
A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4) kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock) kinase from the system during client loading (release) stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery. Full article
(This article belongs to the Special Issue Allosteric Modulators)
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Article
Longitudinal Assessment of Antimicrobial Susceptibility among Gram-Negative and Gram-Positive Organisms Collected from Italy as Part of the Tigecycline Evaluation and Surveillance Trial between 2004 and 2011
by Stefania Stefani and Michael J. Dowzicky
Pharmaceuticals 2013, 6(11), 1381-1406; https://doi.org/10.3390/ph6111381 - 07 Nov 2013
Cited by 12 | Viewed by 5892
Abstract
The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) was initiated in 2004 to longitudinally monitor the activity of the broad-spectrum glycylcycline antimicrobial tigecycline, and a suite of comparator agents, against an array of clinically important bacterial pathogens worldwide. In this report, we examine the [...] Read more.
The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) was initiated in 2004 to longitudinally monitor the activity of the broad-spectrum glycylcycline antimicrobial tigecycline, and a suite of comparator agents, against an array of clinically important bacterial pathogens worldwide. In this report, we examine the activity of tigecycline and comparators against a collection of 13,245 clinical isolates, both Gram-positive (n = 4,078 and Gram-negative (n = 9,167), collected from 27 centres in Italy between 2004 and 2011. Susceptibility was established according to Clinical Laboratory Standards Institute guidelines. Tigecycline and linezolid exhibited very good activity against Gram-positive pathogens, with MIC90s ranging from 0.06 to 0.25 mg/L and 1–4 mg/L, respectively; vancomycin and the carbapenems also showed good activity against select Gram-positive pathogens. Tigecycline was the most active agent against Gram-negative pathogens (except P. aeruginosa), with MIC90s ranging from 0.25–2 mg/L (16 mg/L for P. aeruginosa). Amikacin and the carbapenems also possessed good activity against many Gram-negative pathogens here. ESBL-positive E. coli increased in prevalence from 2004 to 2011, while ESBL-positive Klebsiella spp., vancomycin-resistant enterococci and MRSA decreased in prevalence. Linezolid, tigecycline and vancomycin susceptibility were very stable over the course of this study, while susceptibility to ampicillin, piperacillin-tazobactam, ceftriaxone and levofloxacin varied over time according to pathogen; minocycline and cefepime susceptibility among several pathogens decreased during this study. Full article
(This article belongs to the Special Issue Antimicrobial Agents)
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Review
Nanoparticles as Drug Delivery Systems in Cancer Medicine: Emphasis on RNAi-Containing Nanoliposomes
by Mónica Rivera Díaz and Pablo E. Vivas-Mejia
Pharmaceuticals 2013, 6(11), 1361-1380; https://doi.org/10.3390/ph6111361 - 04 Nov 2013
Cited by 117 | Viewed by 12201
Abstract
Nanomedicine is a growing research field dealing with the creation and manipulation of materials at a nanometer scale for the better treatment, diagnosis and imaging of diseases. In cancer medicine, the use of nanoparticles as drug delivery systems has advanced the bioavailability, in [...] Read more.
Nanomedicine is a growing research field dealing with the creation and manipulation of materials at a nanometer scale for the better treatment, diagnosis and imaging of diseases. In cancer medicine, the use of nanoparticles as drug delivery systems has advanced the bioavailability, in vivo stability, intestinal absorption, solubility, sustained and targeted delivery, and therapeutic effectiveness of several anticancer agents. The expansion of novel nanoparticles for drug delivery is an exciting and challenging research filed, in particular for the delivery of emerging cancer therapies, including small interference RNA (siRNA) and microRNA (miRNAs)-based molecules. In this review, we focus on the currently available drug delivery systems for anticancer agents. In addition, we will discuss the promising use of nanoparticles for novel cancer treatment strategies. Full article
(This article belongs to the Special Issue Chemotherapeutic Agents)
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Review
Metabolic Interactions of Purine Derivatives with Human ABC Transporter ABCG2: Genetic Testing to Assess Gout Risk
by Toshihisa Ishikawa, Wanping Aw and Kiyoko Kaneko
Pharmaceuticals 2013, 6(11), 1347-1360; https://doi.org/10.3390/ph6111347 - 04 Nov 2013
Cited by 46 | Viewed by 16121
Abstract
In mammals, excess purine nucleosides are removed from the body by breakdown in the liver and excretion from the kidneys. Uric acid is the end product of purine metabolism in humans. Two-thirds of uric acid in the human body is normally excreted through [...] Read more.
In mammals, excess purine nucleosides are removed from the body by breakdown in the liver and excretion from the kidneys. Uric acid is the end product of purine metabolism in humans. Two-thirds of uric acid in the human body is normally excreted through the kidney, whereas one-third undergoes uricolysis (decomposition of uric acid) in the gut. Elevated serum uric acid levels result in gout and could be a risk factor for cardiovascular disease and diabetes. Recent studies have shown that human ATP-binding cassette transporter ABCG2 plays a role of renal excretion of uric acid. Two non-synonymous single nucleotide polymorphisms (SNPs), i.e., 421C>A (major) and 376C>T (minor), in the ABCG2 gene result in impaired transport activity, owing to ubiquitination-mediated proteosomal degradation and truncation of ABCG2, respectively. These genetic polymorphisms are associated with hyperuricemia and gout. Allele frequencies of those SNPs are significantly higher in Asian populations than they are in African and Caucasian populations. A rapid and isothermal genotyping method has been developed to detect the SNP 421C>A, where one drop of peripheral blood is sufficient for the detection. Development of simple genotyping methods would serve to improve prevention and early therapeutic intervention for high-risk individuals in personalized healthcare. Full article
(This article belongs to the Special Issue Purine and Its Derivatives)
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Review
A Review of Ten Years of the Study for Monitoring Antimicrobial Resistance Trends (SMART) from 2002 to 2011
by Ian Morrissey, Meredith Hackel, Robert Badal, Sam Bouchillon, Stephen Hawser and Douglas Biedenbach
Pharmaceuticals 2013, 6(11), 1335-1346; https://doi.org/10.3390/ph6111335 - 01 Nov 2013
Cited by 189 | Viewed by 15736
Abstract
Surveillance of antimicrobial agent resistance provides important information to guide microbiologists and infectious disease specialists understanding of the control and the spread of resistance mechanisms within the local environment. Continued monitoring of antimicrobial resistance patterns in the community and in local hospital environments [...] Read more.
Surveillance of antimicrobial agent resistance provides important information to guide microbiologists and infectious disease specialists understanding of the control and the spread of resistance mechanisms within the local environment. Continued monitoring of antimicrobial resistance patterns in the community and in local hospital environments is essential to guide effective empiric therapy. The Study for Monitoring Antimicrobial Resistance Trends (SMART) has monitored the in vitro susceptibility patterns of clinical Gram-negative bacilli to antimicrobial agents collected worldwide from intra-abdominal infections since 2002 and urinary tract infections since 2009. Resistance trends, with a particular focus on carbapenem resistance and the rate of extended-spectrum β-lactamases (ESBLs), were analyzed. Isolates from intra-abdominal infections (n = 92,086) and urinary-tract infections (n = 24,705) were collected and tested using Clinical and Laboratory Standards Institute methods. This review presents carbapenem susceptibility and ESBL rates over ten years of SMART study analysis, including key publications during this period. The SMART study has proved to be a valuable resource in determining pathogen prevalence and antibiotic susceptibility over the last ten years and continues to provide evidence for regulatory susceptibility breakpoints and clinical decision making. Full article
(This article belongs to the Special Issue Antimicrobial Agents)
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