Next Issue
Volume 10, June
Previous Issue
Volume 9, December
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.7
4.8
Journals
Pharmaceuticals
Volume 10
Issue 1
share announcement

Pharmaceuticals, Volume 10, Issue 1 (March 2017) – 32 articles

Cover Story (view full-size image): Radiotheranostics combining diagnostic imaging and radiotherapeutic treatment fulfil the criteria of personalized medicine on molecular level. In particular, peptide receptor targeting mechanism has demonstrated strong potential in the clinical management of neuroendocrine neoplasms (NENs) wherein radiolabeled somatostatin analogs targeting somatostatin receptors (SSTR) has entered clinical practice. Other receptors expressed in various NENs such as Glucagon-Like Peptide-1 Receptor and Cholecystokinin-2 receptor approached clinical research, and Glucose-Dependent Insulinotropic Polypeptide (GIP) receptor has the potential for SSTR-negative and GLP-1R-negative NENs. The current status of radiotheranostics in NENs proves that peptide-receptor targeting nuclear imaging and therapy is an indispensable clinical tool in oncology. View this paper
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Reader to open them.
Order results
Result details
Section
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
3 pages, 186 KiB  
Editorial
Aptamers: Biomedical Interest and Applications
by Cristina Romero-López and Alfredo Berzal-Herranz
Pharmaceuticals 2017, 10(1), 32; https://doi.org/10.3390/ph10010032 - 16 Mar 2017
Cited by 8 | Viewed by 6507
Abstract
Aptamers are short DNA or RNA oligonucleotides specialized in the specific and efficient binding to a target molecule. They are obtained by in vitro selection or evolution processes. It was in 1990 that two independent research groups described the bases of a new [...] Read more.
Aptamers are short DNA or RNA oligonucleotides specialized in the specific and efficient binding to a target molecule. They are obtained by in vitro selection or evolution processes. It was in 1990 that two independent research groups described the bases of a new in vitro technology for the identification of RNA molecules able to specifically bind to a target [1,2]. Tuerk and Gold established the principals of the in vitro selection process that was named SELEX (Systematic Evolution of Ligands by Exponential enrichment), which is based on iterative cycles of binding, partitioning, and amplification of oligonucleotides from a pool of variant sequences [2]. Ellington and Szostak coined the term aptamer to define the selected molecules by the application of this method [1]. To date, numerous reports have described the isolation of aptamers directed against a great variety of targets covering a wide diversity of molecules varying in nature, size, and complexity ranging from ions to whole cells, including small molecules (e.g., aminoacids, nucleotides, antibiotics), peptides, proteins, nucleic acids, and viruses, among others (for example, see [3–6]). Modifications and optimization of the SELEX procedure aimed to get newly modified aptamers has also attracted much interest (examples can be found in [7,8]). These advances along with the parallel progresses in the nucleic acids chemistry and cellular delivery fields have allowed for the rise of a new hope in developing aptamers as efficient molecular tools for diagnostics and therapeutics (for recent comprehensive reviews, see [9–11]).
Full article
(This article belongs to the Special Issue Aptamers: Biomedical Interest and Applications)
10 pages, 966 KiB  
Article
Anacardic Acid Constituents from Cashew Nut Shell Liquid: NMR Characterization and the Effect of Unsaturation on Its Biological Activities
by Selene M. Morais, Katherine A. Silva, Halisson Araujo, Icaro G.P. Vieira, Daniela R. Alves, Raquel O.S. Fontenelle and Artur M.S. Silva
Pharmaceuticals 2017, 10(1), 31; https://doi.org/10.3390/ph10010031 - 16 Mar 2017
Cited by 79 | Viewed by 11780
Abstract
Anacardic acids are the main constituents of natural cashew nut shell liquid (CNSL), obtained via the extraction of cashew shells with hexane at room temperature. This raw material presents high technological potential due to its various biological properties. The main components of CNSL [...] Read more.
Anacardic acids are the main constituents of natural cashew nut shell liquid (CNSL), obtained via the extraction of cashew shells with hexane at room temperature. This raw material presents high technological potential due to its various biological properties. The main components of CNSL are the anacardic acids, salicylic acid derivatives presenting a side chain of fifteen carbon atoms with different degrees of unsaturation (monoene–15:1, diene–15:2, and triene–15:3). Each constituent was isolated by column chromatography using silica gel impregnated with silver nitrate. The structures of the compounds were characterized by nuclear magnetic resonance through complete and unequivocal proton and carbon assignments. The effect of the side chain unsaturation was also evaluated in relation to antioxidant, antifungal and anticholinesterase activities, and toxicity against Artemia salina. The triene anacardic acid provided better results in antioxidant activity assessed by the inhibition of the free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), higher cytotoxicity against A. salina, and acetylcholinesterase (AChE) inhibition. Thus, increasing the unsaturation of the side chain of anacardic acid increases its action against free radicals, AChE enzyme, and A. salina nauplii. In relation to antifungal activity, an inverse result was obtained, and the linearity of the molecule plays an important role, with monoene being the most active. In conclusion, the changes in structure of anacardic acids, which cause differences in polarity, contribute to the increase or decrease in the biological activity assessed. Full article
►▼ Show Figures

Figure 1

22 pages, 3094 KiB  
Review
Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms
by Melpomeni Fani, Petra Kolenc Peitl and Irina Velikyan
Pharmaceuticals 2017, 10(1), 30; https://doi.org/10.3390/ph10010030 - 15 Mar 2017
Cited by 46 | Viewed by 12289
Abstract
Abstract: Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as [...] Read more.
Abstract: Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors. Full article
(This article belongs to the Special Issue Emerging Theranostic Tracers in the Context of Radiopharmaceutical Drug Development)
►▼ Show Figures

Figure 1

15 pages, 1806 KiB  
Article
Theranostic Value of Multimers: Lessons Learned from Trimerization of Neurotensin Receptor Ligands and Other Targeting Vectors
by Simone Maschauer, Jürgen Einsiedel, Dominik Reich, Harald Hübner, Peter Gmeiner, Hans-Jürgen Wester, Olaf Prante and Johannes Notni
Pharmaceuticals 2017, 10(1), 29; https://doi.org/10.3390/ph10010029 - 10 Mar 2017
Cited by 17 | Viewed by 6327
Abstract
Neurotensin receptor 1 (NTS1) is overexpressed on a variety of cancer entities; for example, prostate cancer, ductal pancreatic adenocarcinoma, and breast cancer. Therefore, it represents an interesting target for the diagnosis of these cancers types by positron emission tomography (PET) [...] Full article
(This article belongs to the Special Issue Emerging Theranostic Tracers in the Context of Radiopharmaceutical Drug Development)
►▼ Show Figures

Figure 1

11 pages, 233 KiB  
Review
Targeted Drugs as Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Mantle Cell Lymphoma
by Fengting Yan, Ajay K. Gopal and Solomon A. Graf
Pharmaceuticals 2017, 10(1), 28; https://doi.org/10.3390/ph10010028 - 10 Mar 2017
Cited by 19 | Viewed by 4833
Abstract
The treatment landscape for mantle cell lymphoma (MCL) is rapidly evolving toward the incorporation of novel and biologically targeted pharmaceuticals with improved disease activity and gentler toxicity profiles compared with conventional chemotherapeutics. Upfront intensive treatment of MCL includes autologous stem cell transplantation (SCT) [...] Read more.
The treatment landscape for mantle cell lymphoma (MCL) is rapidly evolving toward the incorporation of novel and biologically targeted pharmaceuticals with improved disease activity and gentler toxicity profiles compared with conventional chemotherapeutics. Upfront intensive treatment of MCL includes autologous stem cell transplantation (SCT) consolidation aimed at deepening and lengthening disease remission, but subsequent relapse occurs. Maintenance therapy after autologous SCT in patients with MCL in remission features lower-intensity treatments given over extended periods to improve disease outcomes. Targeted drugs are a natural fit for this space, and are the focus of considerable clinical investigation. This review summarizes recent advances in the field and their potential impact on treatment practices for MCL. Full article
(This article belongs to the Special Issue New Drugs in Hematology)
19 pages, 4693 KiB  
Review
Protein Kinase CK2: Intricate Relationships within Regulatory Cellular Networks
by Teresa Nuñez de Villavicencio-Diaz, Adam J. Rabalski and David W. Litchfield
Pharmaceuticals 2017, 10(1), 27; https://doi.org/10.3390/ph10010027 - 5 Mar 2017
Cited by 80 | Viewed by 9463
Abstract
Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered [...] Read more.
Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered to be a constitutively active enzyme which raises questions about how it can be a regulatory participant in intricately controlled cellular processes. To resolve this apparent paradox, we have performed a systematic analysis of the published literature using text mining as well as mining of proteomic databases together with computational assembly of networks that involve CK2. These analyses reinforce the notion that CK2 is involved in a broad variety of biological processes and also reveal an extensive interplay between CK2 phosphorylation and other post-translational modifications. The interplay between CK2 and other post-translational modifications suggests that CK2 does have intricate roles in orchestrating cellular events. In this respect, phosphorylation of specific substrates by CK2 could be regulated by other post-translational modifications and CK2 could also have roles in modulating other post-translational modifications. Collectively, these observations suggest that the actions of CK2 are precisely coordinated with other constituents of regulatory cellular networks. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

13 pages, 1993 KiB  
Review
CK2 Molecular Targeting—Tumor Cell-Specific Delivery of RNAi in Various Models of Cancer
by Janeen H. Trembley, Betsy T. Kren, Md. Joynal Abedin, Rachel I. Vogel, Claire M. Cannon, Gretchen M. Unger and Khalil Ahmed
Pharmaceuticals 2017, 10(1), 25; https://doi.org/10.3390/ph10010025 - 21 Feb 2017
Cited by 13 | Viewed by 6635
Abstract
Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; [...] Read more.
Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; thus, CK2 has emerged as a plausible target for cancer therapy. Our focus has been to target CK2 catalytic subunits at the molecular level using RNA interference (RNAi) strategies to achieve their downregulation. The delivery of oligonucleotide therapeutic agents warrants that they are protected and are delivered specifically to cancer cells. The latter is particularly important since CK2 is a ubiquitous signal that is essential for survival. To achieve these goals, we have developed a nanocapsule that has the properties of delivering an anti-CK2 RNAi therapeutic cargo, in a protected manner, specifically to cancer cells. Tenfibgen (TBG) is used as the ligand to target tenascin-C receptors, which are elevated in cancer cells. This strategy is effective for inhibiting growth and inducing death in several types of xenograft tumors, and the nanocapsule elicits no safety concerns in animals. Further investigation of this therapeutic approach for its translation is warranted. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

23 pages, 3586 KiB  
Review
The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design
by Giorgio Cozza
Pharmaceuticals 2017, 10(1), 26; https://doi.org/10.3390/ph10010026 - 20 Feb 2017
Cited by 53 | Viewed by 13531
Abstract
Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown [...] Read more.
Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by “trial and error testing”. In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

18 pages, 2433 KiB  
Article
Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice
by Laura Ferrer-Font, Lucia Villamañan, Nuria Arias-Ramos, Jordi Vilardell, Maria Plana, Maria Ruzzene, Lorenzo A. Pinna, Emilio Itarte, Carles Arús and Ana Paula Candiota
Pharmaceuticals 2017, 10(1), 24; https://doi.org/10.3390/ph10010024 - 12 Feb 2017
Cited by 37 | Viewed by 7742
Abstract
Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human [...] Read more.
Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

20 pages, 3451 KiB  
Article
RNA-Eluting Surfaces for the Modulation of Gene Expression as A Novel Stent Concept
by Olivia Koenig, Diane Zengerle, Nadja Perle, Susanne Hossfeld, Bernd Neumann, Andreas Behring, Meltem Avci-Adali, Tobias Walker, Christian Schlensak, Hans Peter Wendel and Andrea Nolte
Pharmaceuticals 2017, 10(1), 23; https://doi.org/10.3390/ph10010023 - 10 Feb 2017
Cited by 8 | Viewed by 6318
Abstract
Presently, a new era of drug-eluting stents is continuing to improve late adverse effects such as thrombosis after coronary stent implantation in atherosclerotic vessels. The application of gene expression–modulating stents releasing specific small interfering RNAs (siRNAs) or messenger RNAs (mRNAs) to the vascular [...] Read more.
Presently, a new era of drug-eluting stents is continuing to improve late adverse effects such as thrombosis after coronary stent implantation in atherosclerotic vessels. The application of gene expression–modulating stents releasing specific small interfering RNAs (siRNAs) or messenger RNAs (mRNAs) to the vascular wall might have the potential to improve the regeneration of the vessel wall and to inhibit adverse effects as a new promising therapeutic strategy. Different poly (lactic-co-glycolic acid) (PLGA) resomers for their ability as an siRNA delivery carrier against intercellular adhesion molecule (ICAM)-1 with a depot effect were tested. Biodegradability, hemocompatibility, and high cell viability were found in all PLGAs. We generated PLGA coatings with incorporated siRNA that were able to transfect EA.hy926 and human vascular endothelial cells. Transfected EA.hy926 showed significant siICAM-1 knockdown. Furthermore, co-transfection of siRNA and enhanced green fluorescent protein (eGFP) mRNA led to the expression of eGFP as well as to the siRNA transfection. Using our PLGA and siRNA multilayers, we reached high transfection efficiencies in EA.hy926 cells until day six and long-lasting transfection until day 20. Our results indicate that siRNA and mRNA nanoparticles incorporated in PLGA films have the potential for the modulation of gene expression after stent implantation to achieve accelerated regeneration of endothelial cells and to reduce the risk of restenosis. Full article
►▼ Show Figures

Figure 1

12 pages, 1787 KiB  
Article
Inhibition of Protein Kinase CK2 Prevents Adipogenic Differentiation of Mesenchymal Stem Cells Like C3H/10T1/2 Cells
by Lisa Schwind, Sarah Schetting and Mathias Montenarh
Pharmaceuticals 2017, 10(1), 22; https://doi.org/10.3390/ph10010022 - 9 Feb 2017
Cited by 12 | Viewed by 5730
Abstract
Protein kinase CK2 as a holoenzyme is composed of two catalytic α- or α’-subunits and two non-catalytic β-subunits. Knock-out experiments revealed that CK2α and CK2β are required for embryonic development. Little is known about the role of CK2 during differentiation of stem cells. [...] Read more.
Protein kinase CK2 as a holoenzyme is composed of two catalytic α- or α’-subunits and two non-catalytic β-subunits. Knock-out experiments revealed that CK2α and CK2β are required for embryonic development. Little is known about the role of CK2 during differentiation of stem cells. Mesenchymal stem cells (MSCs) are multipotent cells which can be differentiated into adipocytes in vitro. Thus, MSCs and in particular C3H/10T1/2 cells are excellent tools to study a possible role of CK2 in adipogenesis. We found downregulation of the CK2 catalytic subunits as well as a decrease in CK2 kinase activity with progression of differentiation. Inhibition of CK2 using the potent inhibitor CX-4945 impeded differentiation of C3H/10T1/2 cells into adipocytes. The inhibited cells lacked the observed decrease in CK2 expression, but showed a constant expression of all three CK2 subunits. Furthermore, inhibition of CK2 resulted in decreased cell proliferation in the early differentiation phase. Analysis of the main signaling cascade revealed an elevated expression of C/EBPβ and C/EBPδ and reduced expression of the adipogenic master regulators C/EBPα and PPARγ2. Thus, CK2 seems to be implicated in the regulation of different steps early in the adipogenic differentiation of MSC. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

8 pages, 4276 KiB  
Review
The Link between Protein Kinase CK2 and Atypical Kinase Rio1
by Konrad Kubiński and Maciej Masłyk
Pharmaceuticals 2017, 10(1), 21; https://doi.org/10.3390/ph10010021 - 7 Feb 2017
Cited by 6 | Viewed by 5960
Abstract
The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the [...] Read more.
The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the first interaction partner of Rio1, identified in yeast cells. The enzyme from various sources undergoes CK2-mediated phosphorylation at several sites and this modification regulates the activity of Rio1. The aim of this review is to present studies of the relationship between the two different kinases, with respect to CK2-mediated phosphorylation of Rio1, regulation of Rio1 activity, and similar susceptibility of the kinases to benzimidazole inhibitors. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

15 pages, 3865 KiB  
Article
In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface
by Benoît Bestgen, Zakia Belaid-Choucair, Thierry Lomberget, Marc Le Borgne, Odile Filhol and Claude Cochet
Pharmaceuticals 2017, 10(1), 16; https://doi.org/10.3390/ph10010016 - 3 Feb 2017
Cited by 16 | Viewed by 6933
Abstract
Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. [...] Read more.
Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

24 pages, 5245 KiB  
Meeting Report
Second International Electronic Conference on Medicinal Chemistry (ECMC-2)
by Annie Mayence and Jean Jacques Vanden Eynde
Pharmaceuticals 2017, 10(1), 20; https://doi.org/10.3390/ph10010020 - 31 Jan 2017
Cited by 4 | Viewed by 7202
Abstract
The second International Electronic Conference on Medicinal Chemistry, organized and sponsored by the publisher MDPI AG and the Journal Pharmaceuticals, took place in November 2016 on the SciForum website (www.sciforum.net/conference/ecmc-12). More than 150 authors from 22 countries participated in the event. Selected works [...] Read more.
The second International Electronic Conference on Medicinal Chemistry, organized and sponsored by the publisher MDPI AG and the Journal Pharmaceuticals, took place in November 2016 on the SciForum website (www.sciforum.net/conference/ecmc-12). More than 150 authors from 22 countries participated in the event. Selected works presented during the scientific meeting are disclosed in this report. Full article
(This article belongs to the Special Issue Selected Papers from the 2nd International Electronic Conference on Medicinal Chemistry)
11 pages, 762 KiB  
Article
Barriers to the Access of Bevacizumab in Patients with Solid Tumors and the Potential Impact of Biosimilars: A Physician Survey
by Bradley J. Monk, Philip E. Lammers, Thomas Cartwright and Ira Jacobs
Pharmaceuticals 2017, 10(1), 19; https://doi.org/10.3390/ph10010019 - 28 Jan 2017
Cited by 47 | Viewed by 8778
Abstract
Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of [...] Read more.
Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non–small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, ~50% of physicians reported they “definitely” or “probably” would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM. Full article
(This article belongs to the Special Issue Choices of the Journal)
►▼ Show Figures

Figure 1

30 pages, 493 KiB  
Review
CK2 in Cancer: Cellular and Biochemical Mechanisms and Potential Therapeutic Target
by Melissa M.J. Chua, Charina E. Ortega, Ayesha Sheikh, Migi Lee, Hussein Abdul-Rassoul, Kevan L. Hartshorn and Isabel Dominguez
Pharmaceuticals 2017, 10(1), 18; https://doi.org/10.3390/ph10010018 - 28 Jan 2017
Cited by 136 | Viewed by 11463
Abstract
CK2 genes are overexpressed in many human cancers, and most often overexpression is associated with worse prognosis. Site-specific expression in mice leads to cancer development (e.g., breast, lymphoma) indicating the oncogenic nature of CK2. CK2 is involved in many key aspects of cancer [...] Read more.
CK2 genes are overexpressed in many human cancers, and most often overexpression is associated with worse prognosis. Site-specific expression in mice leads to cancer development (e.g., breast, lymphoma) indicating the oncogenic nature of CK2. CK2 is involved in many key aspects of cancer including inhibition of apoptosis, modulation of signaling pathways, DNA damage response, and cell cycle regulation. A number of CK2 inhibitors are now available and have been shown to have activity against various cancers in vitro and in pre-clinical models. Some of these inhibitors are now undergoing exploration in clinical trials as well. In this review, we will examine some of the major cancers in which CK2 inhibition has promise based on in vitro and pre-clinical studies, the proposed cellular and signaling mechanisms of anti-cancer activity by CK2 inhibitors, and the current or recent clinical trials using CK2 inhibitors. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

25 pages, 6249 KiB  
Meeting Report
“The 24th Conference” of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A)
by Jean-Jacques Hélesbeux and Olivier Duval
Pharmaceuticals 2017, 10(1), 17; https://doi.org/10.3390/ph10010017 - 28 Jan 2017
Viewed by 6080
Abstract
The GP2A European Conference is a two-day meeting focused on medicinal chemistry and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, MS studies, in vitro in vivo assays, and structure activity [...] Read more.
The GP2A European Conference is a two-day meeting focused on medicinal chemistry and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, MS studies, in vitro in vivo assays, and structure activity relationships. Abstracts of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collated in this report. Full article
(This article belongs to the Special Issue Choices of the Journal)
20 pages, 3604 KiB  
Article
Relationship between Surface Properties and In Vitro Drug Release from Compressed Matrix Containing Polymeric Materials with Different Hydrophobicity Degrees
by Cristhian J. Yarce, Juan D. Echeverri, Mario A. Palacio, Carlos A. Rivera and Constain H. Salamanca
Pharmaceuticals 2017, 10(1), 15; https://doi.org/10.3390/ph10010015 - 24 Jan 2017
Cited by 15 | Viewed by 6730
Abstract
This work is the continuation of a study focused on establishing relations between surface thermodynamic properties and in vitro release mechanisms using a model drug (ampicillin trihydrate), besides analyzing the granulometric properties of new polymeric materials and thus establishing the potential to be [...] Read more.
This work is the continuation of a study focused on establishing relations between surface thermodynamic properties and in vitro release mechanisms using a model drug (ampicillin trihydrate), besides analyzing the granulometric properties of new polymeric materials and thus establishing the potential to be used in the pharmaceutical field as modified delivery excipients. To do this, we used copolymeric materials derived from maleic anhydride with decreasing polarity corresponding to poly(isobutylene-alt-maleic acid) (hydrophilic), sodium salt of poly(maleic acid-alt-octadecene) (amphiphilic), poly(maleic anhydride-alt-octadecene) (hydrophobic) and the reference polymer hydroxyl-propyl-methyl-cellulose (HPMC). Each material alone and in blends underwent spectroscopic characterization by FTIR, thermal characterization by DSC and granulometric characterization using flow and compaction tests. Each tablet was prepared at different polymer ratios of 0%, 10%, 20%, 30% and 40%, and the surface properties were determined, including the roughness by micro-visualization, contact angle and water absorption rate by the sessile drop method and obtaining Wadh and surface free energy (SFE) using the semi-empirical models of Young–Dupré and Owens-Wendt-Rabel-Käelbe (OWRK), respectively. Dissolution profiles were determined simulating physiological conditions in vitro, where the kinetic models of order-zero, order-one, Higuchi and Korsmeyer–Peppas were evaluated. The results showed a strong relationship between the proportion and nature of the polymer to the surface thermodynamic properties and kinetic release mechanism. Full article
►▼ Show Figures

Figure 1

7 pages, 193 KiB  
Meeting Report
Aptamers in Bordeaux, 24–25 June 2016
by Jean-Jacques Toulmé, Paloma H. Giangrande, Günter Mayer, Beatrix Suess, Frédéric Ducongé, Bruce Sullenger, Vittorio De Franciscis, Fabien Darfeuille and Eric Peyrin
Pharmaceuticals 2017, 10(1), 14; https://doi.org/10.3390/ph10010014 - 20 Jan 2017
Cited by 2 | Viewed by 6122
Abstract
The symposium covered the many different aspects of the selection and the characterization of aptamers as well as their application in analytical, diagnostic and therapeutic areas. Natural and artificial riboswitches were discussed. Recent advances for the design of mutated polymerases and of chemically [...] Read more.
The symposium covered the many different aspects of the selection and the characterization of aptamers as well as their application in analytical, diagnostic and therapeutic areas. Natural and artificial riboswitches were discussed. Recent advances for the design of mutated polymerases and of chemically modified nucleic acid bases that provide aptamers with new properties were presented. The power of aptamer platforms for multiplex analysis of biomarkers of major human diseases was described. The potential of aptamers for the treatment of cancer or cardiovascular diseases was also presented. Brief summaries of the lectures presented during the symposium are given in this report. A second edition of “Aptamers in Bordeaux” will take place on September 2017 (http://www.aptamers-in-bordeaux.com/). Full article
(This article belongs to the Special Issue Aptamers: Biomedical Interest and Applications)
8 pages, 1090 KiB  
Review
Exploring the CK2 Paradox: Restless, Dangerous, Dispensable
by Cinzia Franchin, Christian Borgo, Silvia Zaramella, Luca Cesaro, Giorgio Arrigoni, Mauro Salvi and Lorenzo A. Pinna
Pharmaceuticals 2017, 10(1), 11; https://doi.org/10.3390/ph10010011 - 20 Jan 2017
Cited by 39 | Viewed by 7151
Abstract
The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but [...] Read more.
The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its “lateral” implication in a variety of signaling pathways is now soundly documented. At variance with many “onco-kinases”, CK2 is constitutively active, and no oncogenic CK2 mutant is known; still high CK2 activity correlates to neoplasia. Its pleiotropy and essential role may cast doubts on the actual “druggability” of CK2; however, a CK2 inhibitor is now in Phase II clinical trials for the treatment of cancer, and cell clones viable in the absence of CK2 are providing information about the mechanism by which cancer becomes addicted to high CK2 levels. A phosphoproteomics analysis of these CK2 null cells suggests that CK2 pleiotropy may be less pronounced than expected and supports the idea that the phosphoproteome generated by this kinase is flexible and not rigidly pre-determined. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

9 pages, 2044 KiB  
Article
Ablation of Protein Kinase CK2β in Skeletal Muscle Fibers Interferes with Their Oxidative Capacity
by Nane Eiber, Luca Simeone and Said Hashemolhosseini
Pharmaceuticals 2017, 10(1), 13; https://doi.org/10.3390/ph10010013 - 19 Jan 2017
Cited by 8 | Viewed by 5782
Abstract
The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be [...] Read more.
The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be at least required for regular aggregation of nicotinic acetylcholine receptors, which serves as a hallmark for the presence of a postsynaptic apparatus. Here, we set out to determine whether any other feature accompanies CK2β-deficient muscle fibers. Hind limb muscles gastrocnemius, plantaris, and soleus of adult wildtype and CK2β-deficient mice were dissected, cross-sectioned, and stained histochemically by Gomori trichrome and for nicotinamide adenine dinucleotide (NADH) dehydrogenase and succinate dehydrogenase (SDH) enzymatic activities. A reduction of oxidative enzymatic activity was determined for CK2β-deficient muscle fibers in comparison with wildtype controls. Importantly, the CK2β-deficient fibers, muscle fibers that typically exhibit high NADH dehydrogenase and SDH activities, like slow-type fibers, showed a marked reduction in these activities. Altogether, our data indicate additional impairments in the absence of CK2β in skeletal muscle fibers, pointing to an eventual mitochondrial myopathy. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

13 pages, 2885 KiB  
Review
188Re(V) Nitrido Radiopharmaceuticals for Radionuclide Therapy
by Alessandra Boschi, Petra Martini and Licia Uccelli
Pharmaceuticals 2017, 10(1), 12; https://doi.org/10.3390/ph10010012 - 19 Jan 2017
Cited by 21 | Viewed by 8135
Abstract
The favorable nuclear properties of rhenium-188 for therapeutic application are described, together with new methods for the preparation of high yield and stable 188Re radiopharmaceuticals characterized by the presence of the nitride rhenium core in their final chemical structure. 188Re is [...] Read more.
The favorable nuclear properties of rhenium-188 for therapeutic application are described, together with new methods for the preparation of high yield and stable 188Re radiopharmaceuticals characterized by the presence of the nitride rhenium core in their final chemical structure. 188Re is readily available from an 188W/188Re generator system and a parallelism between the general synthetic procedures applied for the preparation of nitride technetium-99m and rhenium-188 theranostics radiopharmaceuticals is reported. Although some differences between the chemical characteristics of the two metallic nitrido fragments are highlighted, it is apparent that the same general procedures developed for the labelling of biologically active molecules with technetium-99m can be applied to rhenium-188 with minor modification. The availability of these chemical strategies, that allow the obtainment, in very high yield and in physiological condition, of 188Re radiopharmaceuticals, gives a new attractive prospective to employ this radionuclide for therapeutic applications. Full article
(This article belongs to the Special Issue Emerging Theranostic Tracers in the Context of Radiopharmaceutical Drug Development)
►▼ Show Figures

Figure 1

16 pages, 3288 KiB  
Article
Structural Hypervariability of the Two Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex Structures with a Flavonol- and a Thieno[2,3-d]pyrimidine-Based Inhibitor
by Karsten Niefind, Nils Bischoff, Andriy G. Golub, Volodymyr G. Bdzhola, Anatoliy O. Balanda, Andriy O. Prykhod’ko and Sergiy M. Yarmoluk
Pharmaceuticals 2017, 10(1), 9; https://doi.org/10.3390/ph10010009 - 11 Jan 2017
Cited by 15 | Viewed by 6911
Abstract
Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog [...] Read more.
Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog CK2α′ in complex with two ATP-competitive inhibitors—based on either a flavonol or a thieno[2,3-d]pyrimidine framework—are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix αD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2α and CK2α′. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

3 pages, 182 KiB  
Editorial
Acknowledgement to Reviewers of Pharmaceuticals in 2016
by Pharmaceuticals Editorial Office
Pharmaceuticals 2017, 10(1), 10; https://doi.org/10.3390/ph10010010 - 10 Jan 2017
Viewed by 3518
Abstract
The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. Full article
13 pages, 3713 KiB  
Article
Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining
by Samer Haidar, Zouhair Bouaziz, Christelle Marminon, Tuomo Laitinen, Antti Poso, Marc Le Borgne and Joachim Jose
Pharmaceuticals 2017, 10(1), 8; https://doi.org/10.3390/ph10010008 - 9 Jan 2017
Cited by 32 | Viewed by 7537
Abstract
Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different [...] Read more.
Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada). This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthene-7,10,12-trione), a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50 value of 1.24 µM. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

17 pages, 643 KiB  
Review
CK2—An Emerging Target for Neurological and Psychiatric Disorders
by Julia Castello, Andre Ragnauth, Eitan Friedman and Heike Rebholz
Pharmaceuticals 2017, 10(1), 7; https://doi.org/10.3390/ph10010007 - 5 Jan 2017
Cited by 68 | Viewed by 8674
Abstract
Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the [...] Read more.
Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full and conditional CK2 knockout mice have further elucidated the importance of CK2 in brain development, neuronal activity, and behavior. This review will discuss recent advances in the field that point to CK2 as a regulator of neuronal functions and as a potential novel target to treat neurological and psychiatric disorders. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

21 pages, 4364 KiB  
Article
Identification of a Potent Allosteric Inhibitor of Human Protein Kinase CK2 by Bacterial Surface Display Library Screening
by Christian Nienberg, Claudia Garmann, Andreas Gratz, Andre Bollacke, Claudia Götz and Joachim Jose
Pharmaceuticals 2017, 10(1), 6; https://doi.org/10.3390/ph10010006 - 5 Jan 2017
Cited by 11 | Viewed by 8054
Abstract
Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to [...] Read more.
Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to identify non-ATP competitive inhibitors, a 12-mer peptide library of 6 × 105 variants was displayed on the surface of E. coli by autodisplay. Screening of this peptide library on variants with affinity to CK2 was performed by fluorophore-conjugated CK2 and subsequent flow cytometry. Single cell sorting of CK2-bound E. coli yielded new peptide variants, which were tested on inhibition of CK2 by a CE-based assay. Peptide B2 (DCRGLIVMIKLH) was the most potent inhibitor of both, CK2 holoenzyme and the catalytic CK2α subunit (IC50 = 0.8 µM). Using different ATP concentrations and different substrate concentrations for IC50 determination, B2 was shown to be neither ATP- nor substrate competitive. By microscale thermophoresis (MST) the KD value of B2 with CK2α was determined to be 2.16 µM, whereas no binding of B2 to CK2β-subunit was detectable. To our surprise, besides inhibition of enzymatic activity, B2 also disturbed the interaction of CK2α with CK2β at higher concentrations (≥25 µM). Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Graphical abstract

14 pages, 1319 KiB  
Article
D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells
by Susanne Schaefer, Tina H. Svenstrup, Mette Fischer and Barbara Guerra
Pharmaceuticals 2017, 10(1), 5; https://doi.org/10.3390/ph10010005 - 1 Jan 2017
Cited by 8 | Viewed by 5043
Abstract
Compelling evidence indicates that protein kinase CK2 plays an important role in many steps of cancer initiation and progression, therefore, the development of effective and cell-permeable inhibitors targeting this kinase has become an important objective for the treatment of a variety of cancer [...] Read more.
Compelling evidence indicates that protein kinase CK2 plays an important role in many steps of cancer initiation and progression, therefore, the development of effective and cell-permeable inhibitors targeting this kinase has become an important objective for the treatment of a variety of cancer types including glioblastoma. We have recently identified 1,3-dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl]dibenzo(b,d)furan-2,7-diol (D11) as a potent and selective inhibitor of protein kinase CK2. In this study, we have further characterized this compound and demonstrated that it suppresses CK2 kinase activity by mixed type inhibition (KI 7.7 nM, KI′ 42 nM). Incubation of glioblastoma cells with D11 induces cell death and upon hypoxia the compound leads to HIF-1α destabilization. The analysis of differential mRNA expression related to human hypoxia signaling pathway revealed that D11-mediated inhibition of CK2 caused strong down-regulation of genes associated with the hypoxia response including ANGPTL4, CA9, IGFBP3, MMP9, SLC2A1 and VEGFA. Taken together, the results reported here support the notion that including D11 in future treatment regimens might turn out to be a promising strategy to target tumor hypoxia to overcome resistance to radio- and chemotherapy. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

30 pages, 22421 KiB  
Review
Drosophila Protein Kinase CK2: Genetics, Regulatory Complexity and Emerging Roles during Development
by Mohna Bandyopadhyay, Scott Arbet, Clifton P. Bishop and Ashok P. Bidwai
Pharmaceuticals 2017, 10(1), 4; https://doi.org/10.3390/ph10010004 - 29 Dec 2016
Cited by 10 | Viewed by 9189
Abstract
CK2 is a Ser/Thr protein kinase that is highly conserved amongst all eukaryotes. It is a well-known oncogenic kinase that regulates vital cell autonomous functions and animal development. Genetic studies in the fruit fly Drosophila are providing unique insights into the roles of [...] Read more.
CK2 is a Ser/Thr protein kinase that is highly conserved amongst all eukaryotes. It is a well-known oncogenic kinase that regulates vital cell autonomous functions and animal development. Genetic studies in the fruit fly Drosophila are providing unique insights into the roles of CK2 in cell signaling, embryogenesis, organogenesis, neurogenesis, and the circadian clock, and are revealing hitherto unknown complexities in CK2 functions and regulation. Here, we review Drosophila CK2 with respect to its structure, subunit diversity, potential mechanisms of regulation, developmental abnormalities linked to mutations in the gene encoding CK2 subunits, and emerging roles in multiple aspects of eye development. We examine the Drosophila CK2 “interaction map” and the eye-specific “transcriptome” databases, which raise the prospect that this protein kinase has many additional targets in the developing eye. We discuss the possibility that CK2 functions during early retinal neurogenesis in Drosophila and mammals bear greater similarity than has been recognized, and that this conservation may extend to other developmental programs. Together, these studies underscore the immense power of the Drosophila model organism to provide new insights and avenues to further investigate developmentally relevant targets of this protein kinase. Full article
(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)
►▼ Show Figures

Figure 1

16 pages, 2057 KiB  
Article
Germinated Thai Black Rice Extract Protects Experimental Diabetic Rats from Oxidative Stress and Other Diabetes-Related Consequences
by Chaiyavat Chaiyasut, Bhagavathi Sundaram Sivamaruthi, Noppawat Pengkumsri, Waranya Keapai, Periyanaina Kesika, Manee Saelee, Parichart Tojing, Sasithorn Sirilun, Khontaros Chaiyasut, Sartjin Peerajan and Narissara Lailerd
Pharmaceuticals 2017, 10(1), 3; https://doi.org/10.3390/ph10010003 - 28 Dec 2016
Cited by 38 | Viewed by 7599
Abstract
Background: Diabetes mellitus (DM), particularly type 2 DM (T2DM), is one of the most common metabolic disorder worldwide. The prevention measures and treatment strategies for DM are improving steadily. The current study explains the impact of germination on phytochemical content of Thai [...] Read more.
Background: Diabetes mellitus (DM), particularly type 2 DM (T2DM), is one of the most common metabolic disorder worldwide. The prevention measures and treatment strategies for DM are improving steadily. The current study explains the impact of germination on phytochemical content of Thai black rice (BR), and the influence of germinated BR extract (GBRE) supplementation on diabetic conditions in rats. Methods: BR was germinated and the phenolic, anthocyanin, and γ-aminobutyric acid (GABA) content of the extract were analyzed using HPLC and spectrophotometric methods. Streptozotocin-induced diabetic rats were supplemented with high and low doses of GBRE. The plasma glucose, insulin, cholesterol, triglyceride levels, antioxidant status, and antioxidant enzyme levels of treated animals were assessed using ELISA and spectrophotometric methods. Results: Germination enhanced the GABA content of BR, and GBRE intervention improved the total antioxidant capacity and antioxidant enzymes levels in diabetic rats. The plasma glucose, cholesterol, triglyceride levels, insulin resistance and glucose tolerance were reduced, and the degree of insulin secretion in rat plasma was significantly increased upon GBRE treatment. Both pre and post-treatment approaches showed the anti-diabetic ability of GBRE. In most of the analyzed parameters, GBRE was quite equal to the performance of drug-metformin. Conclusions: GBRE supplementation helps prevent and manage the consequences of DM. Full article
►▼ Show Figures

Graphical abstract

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-32
Previous Issue
Next Issue
Back to TopTop