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  Subjects -> CHEMISTRY (Total: 845 journals)
    - ANALYTICAL CHEMISTRY (51 journals)
    - CHEMISTRY (595 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (25 journals)
    - INORGANIC CHEMISTRY (41 journals)
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    - PHYSICAL CHEMISTRY (67 journals)

CHEMISTRY (595 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 34)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 24)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 246)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 51)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 56)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 15)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 21)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 67)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 27)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 199)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 218)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 310)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 118)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 91)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 4)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 7)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 14)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 72)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 24)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 20)
Chemical Reviews     Full-text available via subscription   (Followers: 181)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 58)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 26)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 146)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 255)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 17)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 61)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 3)
Environmental Chemistry     Hybrid Journal   (Followers: 7)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)

        1 2 3 | Last

Journal Cover Biochemical Pharmacology
  [SJR: 2.263]   [H-I: 160]   [10 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-2952
   Published by Elsevier Homepage  [3051 journals]
  • Tobacco and alcohol use during adolescence: Interactive mechanisms in
           animal models
    • Authors: Yael Abreu-Villaça; Alex C. Manhães; Thomas E. Krahe; Claudio C. Filgueiras; Anderson Ribeiro-Carvalho
      Pages: 1 - 17
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Yael Abreu-Villaça, Alex C. Manhães, Thomas E. Krahe, Claudio C. Filgueiras, Anderson Ribeiro-Carvalho
      There is a strong association between tobacco smoking and the consumption of alcoholic beverages. When compared to the effects of either drug on its own, the combined use may lead to worsened outcomes, such as less successful quitting attempts and increased likelihood of developing mood disorders. Co-consumption most frequently begins during adolescence, a developmental period that is characterized by an increased risk for substance use disorders. However, to date, most studies that have contributed to the current state of knowledge on the mechanisms that underlie tobacco or alcohol use/abuse, and their consequences, adopted adult animal models. Besides, the available literature hardly addresses the effects of co-exposure, irrespective of age. Since adolescence is a period of transition between infancy and adulthood that is characterized by unique brain maturational events and behavioral traits, the mechanisms that drive drug use/abuse in adolescents differ in several aspects from those proposed to underlie adult consumption. This review summarizes and consolidates recent findings on common molecular targets and neuropharmacological mechanisms of action associated with nicotine/tobacco smoke and ethanol co-exposure in animal models, highlighting the effects that culminate in behavioral dysfunctions. To that effect, we discuss the role of mesocorticolimbic system maturation events, cross-tolerance and cross-reinforcement, stress, and sex differences in the context of adolescent co-exposure, identifying gaps in knowledge regarding the interactions between these habit-forming drugs. Finally, we suggest future directions for research on epigenetic mechanisms associated with nicotine and ethanol co-exposure as well as on potential pharmacological therapies for co-addiction.
      Graphical abstract image

      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.06.113
      Issue No: Vol. 144 (2017)
       
  • Improving the efficacy of hormone therapy in breast cancer: The role of
           cholesterol metabolism in SERM-mediated autophagy, cell differentiation
           and death
    • Authors: Julie Leignadier; Florence Dalenc; Marc Poirot; Sandrine Silvente-Poirot
      Pages: 18 - 28
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Julie Leignadier, Florence Dalenc, Marc Poirot, Sandrine Silvente-Poirot
      Breast cancer (BC) is one of the most common female cancers in the world, with estrogen receptor (ER)-positive BC the most frequent subtype. Tamoxifen (Tam) is an effective drug that competitively binds to the ER and is routinely used for the treatment of ER-positive BC. However, a number of ER-positive BC do not respond to Tam treatment and acquired resistance is often observed, constituting a major challenge for extending patient life expectancy. The mechanisms responsible for these treatment failures remain unclear, indicating the requirement for other targets and better predictors for patient response to Tam. One of Tam's off-targets of interest is the microsomal antiestrogen binding site (AEBS), a multiproteic complex made up of the cholesterol-5,6-epoxide hydrolase (ChEH) enzymes that are involved in the late stages of cholesterol biosynthesis. Tam and other selective ER modulators stimulate oxidative stress and inhibit the ChEH subunits at pharmacological doses, triggering the production and accumulation of cholesterol-5,6-epoxide metabolites responsible for BC cell differentiation and death. However, inhibition of the cholesterogenic activity of the AEBS subunits also induces the accumulation of sterol precursors, which triggers a survival autophagy to impair Tam's efficacy. Altogether, these studies have highlighted the involvement of cholesterol metabolism in the pharmacology of Tam that has provided new clues on how to improve its therapeutic efficacy in both BC and other cancers as well as offering a new rationale for developing more efficient drugs for BC treatment.
      Graphical abstract image

      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.06.120
      Issue No: Vol. 144 (2017)
       
  • Transcription factor decoy technology: A therapeutic update
    • Authors: Markus Hecker; Andreas H. Wagner
      Pages: 29 - 34
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Markus Hecker, Andreas H. Wagner
      Targeting transcription factors represents one possibility to interfere with a known activated regulatory pathway that promotes disease. Double-stranded transcription factor decoy (TFD) oligodeoxynucleotides (ODN) are therapeutic drug candidates, which are able to specifically target and neutralize key transcription factors involved in the pathogenesis of a given disease. These short double-stranded TFD molecules mimic the consensus DNA binding site of a specific transcription factor in the promoter region of its target genes. Therefore, it is possible to exploit this nucleic acid-based drug class for the treatment of diseases caused by aberrant expression of such target genes the products of which are involved in disease initiation and progression. This research update focuses firstly on the mechanism of action of TFD molecules. Long-term effects of such ODNs depend on their stability and the efficiency by which they are delivered to the target tissue and taken up by their target cells. Hence structural modifications like e.g., single-stranded TFD molecules hybridising to itself to form an intramolecular hairpin molecule or circular ODNs assuming a dumbbell configuration, intended to enhance both stability and efficacy, are addressed. Also specific drug delivery methods like ultrasound-targeted microbubble destruction with TFD ODN-coated microbubbles or adeno-associated viral (AAV) vectors for tissue-specific transduction and long-term TFD molecule expression in non-dividing cells will be discussed. Finally, current therapeutic applications of TFD ODN will be summarized.
      Graphical abstract image

      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.06.122
      Issue No: Vol. 144 (2017)
       
  • Potent influenza A virus entry inhibitors targeting a conserved region of
           hemagglutinin
    • Authors: Dongguo Lin; Yinzhu Luo; Guang Yang; Fangfang Li; Xiangkun Xie; Daiwei Chen; Lifang He; Jingyu Wang; Chunfeng Ye; Shengsheng Lu; Lin Lv; Shuwen Liu; Jian He
      Pages: 35 - 51
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Dongguo Lin, Yinzhu Luo, Guang Yang, Fangfang Li, Xiangkun Xie, Daiwei Chen, Lifang He, Jingyu Wang, Chunfeng Ye, Shengsheng Lu, Lin Lv, Shuwen Liu, Jian He
      Influenza A viruses (IAVs) induce acute respiratory disease and cause significant morbidity and mortality throughout the world. With the emergence of drug-resistant viral strains, new and effective anti-IAV drugs with different modes of action are urgently needed. In this study, by conjugating cholesterol to the N-terminus of the short peptide KKWK, a lipopeptide named S-KKWK was created. The anti-IAV test indicated that S-KKWK and its derivatives displayed potent antiviral activities against a broad variety of influenza A viral strains including oseltamivir-resistant strains and clinically relevant isolates with IC50 values ranging from 0.7 to 3.0µM. An extensive mechanistic study showed that these peptides functioned as viral “entry blockers” by inhibiting the conformational rearrangements of HA2 subunit, thereby interrupting the fusion of virus-host cell membranes. Significantly, a computer-aided docking simulation and protein sequence alignment identified conserved residues in the stem region of HA2 as the possible binding site of S-KKWK, which may be employed as a potential drug target for designing anti-IAVs with a broad-spectrum of activity. By targeting this region, a potent anti-IAV agent was subsequently created. In addition, the anti-IAV activity of S-KKWK was assessed by experiments with influenza A virus-infected mice, in which S-KKWK reduced the mortality of infected animals and extended survival time significantly. Overall, in addition to providing a strategy for designing broad-spectrum anti-IAV agents, these results indicate that S-KKWK and its derivatives are prospective candidates for potent antivirals.
      Graphical abstract image

      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.07.023
      Issue No: Vol. 144 (2017)
       
  • Ascites interferes with the activity of lurbinectedin and trabectedin:
           Potential role of their binding to alpha 1-acid glycoprotein
    • Authors: E. Erba; M. Romano; M. Gobbi; M. Zucchetti; M. Ferrari; C. Matteo; N. Panini; B. Colmegna; G. Caratti; L. Porcu; R. Fruscio; M.V. Perlangeli; D. Mezzanzanica; D. Lorusso; F. Raspagliesi; M. D'Incalci
      Pages: 52 - 62
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): E. Erba, M. Romano, M. Gobbi, M. Zucchetti, M. Ferrari, C. Matteo, N. Panini, B. Colmegna, G. Caratti, L. Porcu, R. Fruscio, M.V. Perlangeli, D. Mezzanzanica, D. Lorusso, F. Raspagliesi, M. D'Incalci
      Trabectedin and its analogue lurbinectedin are effective drugs used in the treatment of ovarian cancer. Since the presence of ascites is a frequent event in advanced ovarian cancer we asked the question whether ascites could modify the activity of these compounds against ovarian cancer cells. The cytotoxicity induced by trabectedin or lurbinectedin against A2780, OVCAR-5 cell lines or primary culture of human ovarian cancer cells was compared by performing treatment in regular medium or in ascites taken from either nude mice or ovarian cancer patients. Ascites completely abolished the activity of lurbinectedin at up to 10nM (in regular medium corresponds to the IC90), strongly reduced that of trabectedin, inhibited the cellular uptake of lurbinectedin and, to a lesser extent, that of trabectedin. Since α1-acid glycoprotein (AGP) is present in ascites at relatively high concentrations, we tested if the binding of the drugs to this protein could be responsible for the reduction of their activity. Adding AGP to the medium at concentration range of those found in ascites, we reproduced the anticytotoxic effect of ascites. Erythromycin partially restored the activity of the drugs, presumably by displacing them from AGP. Equilibrium dialysis experiments showed that both drugs bind AGP, but the affinity of binding of lurbinectedin was much greater than that of trabectedin. KD values are 8±1.7 and 87±14nM for lurbinectedin and trabectedin, respectively. The studies intimate the possibility that AGP present in ascites might reduce the activity of lurbinectedin and to a lesser extent of trabectedin against ovarian cancer cells present in ascites. AGP plasma levels could influence the distribution of these drugs and thus they should be monitored in patients receiving these compounds.
      Graphical abstract image

      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.08.001
      Issue No: Vol. 144 (2017)
       
  • Development of resistance to photodynamic therapy (PDT) in human breast
           cancer cells is photosensitizer-dependent: Possible mechanisms and
           approaches for overcoming PDT-resistance
    • Authors: Cathrine Elisabeth Olsen; Anette Weyergang; Victoria Tudor Edwards; Kristian Berg; Andreas Brech; Sabine Weisheit; Anders Høgset; Pål Kristian Selbo
      Pages: 63 - 77
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Cathrine Elisabeth Olsen, Anette Weyergang, Victoria Tudor Edwards, Kristian Berg, Andreas Brech, Sabine Weisheit, Anders Høgset, Pål Kristian Selbo
      Here we report on the induction of resistance to photodynamic therapy (PDT) in the ABCG2-high human breast cancer cell line MA11 after repetitive PDT, using either Pheophorbide A (PhA) or di-sulphonated meso-tetraphenylchlorin (TPCS2a) as photosensitizer. Resistance to PhA-PDT was associated with enhanced expression of the efflux pump ABCG2. TPCS2a-PDT-resistance was neither found to correspond with lower TPCS2a-accumulation nor reduced generation of reactive oxygen species (ROS). Cross-resistance to chemotherapy (doxorubicin) or radiotherapy was not observed. TPCS2a-PDT-resistant cells acquired a higher proliferation capacity and an enhanced expression of EGFR and ERK1/2. p38 MAPK was found to be a death-signalling pathway in the MA11 cells post TPCS2a-PDT, contrasting the MA11/TR cells in which PDT generated a sustained phosphorylation of p38 that had lost its death-mediated signalling, and an abrogated activation of its downstream effector MAPKAPK2. No difference in apoptosis, necrosis or autophagy responses was found between the treated cell lines. Development of TPCS2a-PDT resistance in the MDA-MB-231 cell line was also established, however, p38 MAPK did not play a role in the PDT-resistance. MCF-7 cells did not develop TPCS2a-PDT-resistance. Photochemical internalisation (PCI) of 1 pM of EGF-saporin induced equal strong cytotoxicity in both MA11 and MA11/TR cells. In conclusion, loss of p38 MAPK-inducing death signalling is the main mechanism of resistance to TPCS2a-PDT in the MA11/TR cell line. This work provides mechanistic knowledge of intrinsic and acquired PDT-resistance which is dependent on choice of photosensitizer, and suggests PCI as a rational therapeutic intervention for the elimination of PDT-resistant cells.
      Graphical abstract image

      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.08.002
      Issue No: Vol. 144 (2017)
       
  • Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor
           suppressor protein phosphatase 2A in non-small cell lung cancer cells
    • Authors: Myeong-ok Kim; Min Ho Choe; Yi Na Yoon; Jiyeon Ahn; Minjin Yoo; Kwan-Young Jung; Sungkwan An; Sang-Gu Hwang; Jeong Su Oh; Jae-Sung Kim
      Pages: 78 - 89
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Myeong-ok Kim, Min Ho Choe, Yi Na Yoon, Jiyeon Ahn, Minjin Yoo, Kwan-Young Jung, Sungkwan An, Sang-Gu Hwang, Jeong Su Oh, Jae-Sung Kim
      Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC.
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      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.08.009
      Issue No: Vol. 144 (2017)
       
  • Azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through
           the modulation of ACE-2/ANG 1–7/Mas receptor cascade
    • Authors: Vijayakumar Sukumaran; Hirotsugu Tsuchimochi; Eisuke Tatsumi; Mikiyasu Shirai; James T. Pearson
      Pages: 90 - 99
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Vijayakumar Sukumaran, Hirotsugu Tsuchimochi, Eisuke Tatsumi, Mikiyasu Shirai, James T. Pearson
      Hyperglycemia up-regulates intracellular angiotensin II (ANG-II) production in cardiac myocytes. This study investigated the hemodynamic and metabolic effects of azilsartan (AZL) treatment in a mouse model of diabetic cardiomyopathy and whether the cardioprotective effects of AZL are mediated by the angiotensin converting enzyme (ACE)-2/ANG 1–7/Mas receptor (R) cascade. Control db/+ and db/db mice (n=5 per group) were treated with vehicle or AZL (1 or 3mg/kg/d oral gavage) from the age of 8 to 16weeks. Echocardiography was then performed and myocardial protein levels of ACE-2, Mas R, AT1R, AT2R, osteopontin, connective tissue growth factor (CTGF), atrial natriuretic peptide (ANP) and nitrotyrosine were measured by Western blotting. Oxidative DNA damage and inflammatory markers were assessed by immunofluorescence of 8-hydroxy-2′-deoxyguanosine (8-OHdG), tumor necrosis factor (TNF)-α and interleukin 6 (IL-6). Compared with db/+ mice, the vehicle-treated db/db mice developed obesity, hyperglycemia, hyperinsulinemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis. AZL treatment lowered blood pressure, fasting blood glucose and reduced peak plasma glucose during an oral glucose tolerance test. AZL-3 treatment resulted in a significant decrease in the expression of cytokines, oxidative DNA damage and cardiac dysfunction. Moreover, AZL-3 treatment significantly abrogated the downregulation of ACE-2 and Mas R protein levels in db/db mice. Furthermore, AZL treatment significantly reduced cardiac fibrosis, hypertrophy and their marker molecules (osteopontin, CTGF, TGF-β1 and ANP). Short-term treatment with AZL-3 reversed abnormal cardiac structural remodeling and partially improved glucose metabolism in db/db mice by modulating the ACE-2/ANG 1–7/Mas R pathway.
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      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.07.022
      Issue No: Vol. 144 (2017)
       
  • Insight into the role of urotensin II-related peptide tyrosine residue in
           UT activation
    • Authors: Etienne Billard; Myriam Létourneau; Terence E. Hébert; David Chatenet
      Pages: 100 - 107
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Etienne Billard, Myriam Létourneau, Terence E. Hébert, David Chatenet
      While sharing common biological activity, the two endogenous ligands of the G protein-coupled receptor UT, e.g. urotensin II (UII) and urotensin II-related peptide (URP), also exhibit distinct effects that could be explained by distinct interactions with their cognate receptor (UT). Accordingly, introduction of a similar substitution at the intracyclic Tyr residue in UII and URP led to compounds with divergent pharmacologic profiles. Hypothesizing that the Tyr6 residue of URP is a key-element to understand the specific activation of UT by URP, we undertook a study of the structure-activity relationship in which this particular residue was replaced by non-natural and constrained amino acids. Each compound was evaluated for its ability to bind UT, to induce rat aortic ring contraction and to activate Gq and G12 signaling pathways. We identified [Pep6]URP, that binds UT with an affinity similar to that of URP, but behaves as a biased ligand. Used as an antagonist, this peptide is also able to selectively reduce the maximal aortic contraction of URP but not UII. Our results suggest that the orientation of the Tyr residue can stabilize at least two different conformations of UT, leading to biased signaling and a probe-dependent allosteric effect.
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      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.08.003
      Issue No: Vol. 144 (2017)
       
  • Doxorubicin enhances oxysterol levels resulting in a LXR-mediated
           upregulation of cardiac cholesterol transporters
    • Authors: Judith V. Monzel; Thomas Budde; Henriette E. Meyer zu Schwabedissen; Matthias Schwebe; Sandra Bien-Möller; Dieter Lütjohann; Heyo K. Kroemer; Gabriele Jedlitschky; Markus Grube
      Pages: 108 - 119
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Judith V. Monzel, Thomas Budde, Henriette E. Meyer zu Schwabedissen, Matthias Schwebe, Sandra Bien-Möller, Dieter Lütjohann, Heyo K. Kroemer, Gabriele Jedlitschky, Markus Grube
      The anthracycline-mediated cardiotoxicity is still not completely understood. To examine the impact of cholesterol metabolism and transport in this context, cholesterol and oxysterol levels as well as the expression of the cholesterol transporters ABCA1 and ABCG1 were analyzed in doxorubicin-treated HL-1 murine cardiomyocytes as well as in mouse model for acute doxorubicin-induced cardiotoxicity. Doxorubicin-treated HL-1 cells exhibited enhanced cholesterol (153±20% of control), oxysterol (24S-hydroxycholesterol: 206±29% of control) and cholesterol precursor levels (lathosterol: 122±12% of control; desmosterol: 188±10% of control) indicating enhanced cholesterol synthesis. Moreover, abca1 and abcg1 were upregulated on mRNA, protein and functional level caused by a doxorubicin-mediated activation of the nuclear receptor LXR. In addition, the oxysterols not only induced the abca1 and abcg1 in HL-1 cells but also enhanced the expression of endothelin-1 and transforming growth factor-β, which have already been identified as important factors in doxorubicin-induced cardiotoxicity. These in vitro findings were verified in a murine model for acute doxorubicin-induced cardiotoxicity, demonstrating elevated cardiac (2.1±0.2vs. 3.6±1.0ng/mg) and systemic cholesterol levels (105.0±8.4vs. 130.0±4.3mg/dl), respectively, as well as enhanced oxysterol levels such as cardiac 24S-hydroxycholesterol (2.1±0.2vs. 3.6±1.0ng/mg). In line with these findings cardiac mRNA expression of abca1 (303% of control) and abcg1 (161% of control) was induced. Taken together, our data demonstrate enhanced cholesterol and oxysterol levels by doxorubicin, resulting in a LXR-dependent upregulation of abca1 and abcg1. In this context, the cytotoxic effects of oxysterols and their impact on cardiac gene expression should be considered as an important factor in doxorubicin-induced cardiotoxicity.
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      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.08.008
      Issue No: Vol. 144 (2017)
       
  • Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated
           microglia: Critical role of PPAR-γ signaling pathway
    • Authors: Min-Ji Choi; Eun-Jung Lee; Jin-Sun Park; Su-Nam Kim; Eun-Mi Park; Hee-Sun Kim
      Pages: 120 - 131
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Min-Ji Choi, Eun-Jung Lee, Jin-Sun Park, Su-Nam Kim, Eun-Mi Park, Hee-Sun Kim
      Since microglia-associated neuroinflammation plays a pivotal role in the progression of neurodegenerative diseases, controlling microglial activation has been suggested as a potential therapeutic strategy. Here, we investigated the anti-inflammatory effects of galangin (3,5,7-trihydroxyflavone) in microglia and analyzed the underlying molecular mechanisms. Galangin inhibited the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines and enhanced the expression of anti-inflammatory interleukin (IL)-10 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Galangin also suppressed microglial activation and the expression of pro-inflammatory markers in LPS-injected mouse brains. The results of mechanistic studies have shown that galangin inhibited LPS-induced phosphorylation of p38 mitogen activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K)/Akt, and nuclear factor (NF)-κB activity. On the contrary, galangin increased the activity of transcription factors, such as nuclear factor-E2-related factor 2 (Nrf2), cAMP response element-binding protein (CREB), and peroxisome proliferator-activated receptor (PPAR)-γ, known to play an anti-inflammatory role. In addition, galangin showed antioxidant effects by suppressing the expression of NADPH oxidase subunits p47phox and gp91phox, and by enhancing hemeoxygenase-1. We then investigated whether PPAR-γ was involved in the anti-inflammatory function of galangin. Pretreatment with a PPAR-γ antagonist or siRNA significantly blocked galangin-mediated upregulation of IL-10 and attenuated the inhibition of tumor necrosis factor (TNF)-α, nitric oxide (NO), and IL-6 in LPS-stimulated microglia. Moreover, the PPAR-γ antagonist reversed the effects of galangin on NF-κB, Nrf2, and CREB. Altogether, our data suggest that PPAR-γ plays a key role in mediating the anti-inflammatory effects of galangin by modulating the NF-κB and Nrf2/CREB signaling pathways.
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      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.07.021
      Issue No: Vol. 144 (2017)
       
  • LAT is essential for the mast cell stabilising effect of tHGA in
           IgE-mediated mast cell activation
    • Authors: Ji Wei Tan; Daud Ahmad Israf; Nur Fariesha Md Hashim; Yoke Kqueen Cheah; Hanis Hazeera Harith; Khozirah Shaari; Chau Ling Tham
      Pages: 132 - 148
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Ji Wei Tan, Daud Ahmad Israf, Nur Fariesha Md Hashim, Yoke Kqueen Cheah, Hanis Hazeera Harith, Khozirah Shaari, Chau Ling Tham
      Mast cells play a central role in the pathogenesis of allergic reaction. Activation of mast cells by antigens is strictly dependent on the influx of extracellular calcium that involves a complex interaction between signalling molecules located within the cells. We have previously reported that tHGA, an active compound originally isolated from a local shrub known as Melicope ptelefolia, prevented IgE-mediated mast cell activation and passive systemic anaphylaxis by suppressing the release of interleukin-4 (IL-4) and tumour necrosis factor (TNF)-α from activated rat basophilic leukaemia (RBL)-2H3 cells. However, the mechanism of action (MOA) as well as the molecular target underlying the mast cell stabilising effect of tHGA has not been previously investigated. In this study, DNP-IgE-sensitised RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA. To dissect the MOA of tHGA in IgE-mediated mast cell activation, the effect of tHGA on the transcription of IL-4 and TNF-α mRNA was determined using Real Time-Polymerase Chain Reaction (qPCR) followed by Calcium Influx Assay to confirm the involvement of calcium in the activation of mast cells. The protein lysates were analysed by using Western Blot to determine the effect of tHGA on various important signalling molecules in the LAT-PLCγ-MAPK and PI3K-NFκB pathways. In order to identify the molecular target of tHGA in IgE-mediated mast cell activation, the LAT and LAT2 genes in RBL-2H3 cells were knocked-down by using RNA interference to establish a LAT/LAT2 competition model. The results showed that tHGA inhibited the transcription of IL-4 and TNF-α as a result of the suppression of calcium influx in activated RBL-2H3 cells. The results from Western Blot revealed that tHGA primarily inhibited the LAT-PLCγ-MAPK pathway with partial inhibition on the PI3K-p65 pathway without affecting Syk. The results from RNAi further demonstrated that tHGA failed to inhibit the release of mediators associated with mast cell degranulation under the LAT/LAT2 competition model in the absence of LAT. Collectively, this study concluded that the molecular target of tHGA could be LAT and may provide a basis for the development of a mast cell stabiliser which targets LAT.
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      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.08.010
      Issue No: Vol. 144 (2017)
       
  • Insight into the mode of action and selectivity of PBRM, a covalent
           steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type 1
    • Authors: Alexandre Trottier; René Maltais; Diana Ayan; Xavier Barbeau; Jenny Roy; Martin Perreault; Richard Poulin; Patrick Lagüe; Donald Poirier
      Pages: 149 - 161
      Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144
      Author(s): Alexandre Trottier, René Maltais, Diana Ayan, Xavier Barbeau, Jenny Roy, Martin Perreault, Richard Poulin, Patrick Lagüe, Donald Poirier
      17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the biosynthesis of estradiol, the major bioactive endogenous estrogen in mammals, and constitutes an interesting therapeutic target for estrogen-dependent diseases. A steroidal derivative, 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl} benzamide (PBRM), has recently been described as a non-estrogenic, irreversible inhibitor of 17β-HSD1. However, the mode of action of this inhibitor and its selectivity profile have not yet been elucidated. We assessed PBRM potency via in vitro kinetic measurements. The mechanism of enzyme inactivation was also investigated using interspecies (human, mouse, pig and monkey) comparisons via both in vitro assays and in silico analysis. Mouse and human plasma protein binding of PBRM was determined, whereas its selectivity of action was studied using a wide range of potential off-targets (e.g. GPCR, hERG, CYPs, etc.). The affinity constant (K i =368nM) and the enzyme inactivation rate (k inact =0.087min−1) values for PBRM were determined with purified 17β-HSD1. PBRM was found to be covalently linked to the enzyme. A long delay period (i.e. 3–5days) is required to recover 17β-HSD1 activity following a pretreatment of breast and placenta cell lines with PBRM. Mechanistic analyses showed important interspecies differences of 17β-HSD1 inhibition which support the importance of inactivation for PBRM effect. Evidences of the potency and selectivity of action presented herein for this first non-estrogenic and steroidal covalent irreversible inhibitor of 17β-HSD1 warrant its further development as a potential drug candidate for estrogen-dependent disorders.
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      PubDate: 2017-10-12T07:00:45Z
      DOI: 10.1016/j.bcp.2017.08.004
      Issue No: Vol. 144 (2017)
       
  • Spatial encryption of G protein-coupled receptor signaling in endosomes;
           Mechanisms and applications
    • Authors: Silvia Sposini; Aylin C. Hanyaloglu
      Pages: 1 - 9
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Silvia Sposini, Aylin C. Hanyaloglu
      Within any cellular signaling system membrane trafficking is a critical mechanism for cells to translate complex networks into specific downstream responses, including the signal pathways activated by the superfamily of G protein-coupled receptors (GPCRs). Classically, membrane trafficking is viewed as a mechanism to regulate ligand sensitivity of a target tissue by controlling the level of surface receptors. Recent studies, however, have not only highlighted that GPCR trafficking is a tightly regulated process critical for spatio-temporal control of signaling, but that heterotrimeric G protein signaling can also be reactivated or continue to signal from distinct endocytic compartments, and even endosomal microdomains. The significance of spatio-temporal control will be discussed, not only with respect to how these novel molecular pathways impact our basic understanding of cellular regulation, but also our view of how aberrant signaling can result in disease. Furthermore, these mechanisms offer the potential application for novel therapeutic strategies to identify GPCR compounds with high specificity in their actions.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.04.028
      Issue No: Vol. 143 (2017)
       
  • Challenges and opportunities for the development of new antipsychotic
           drugs
    • Authors: Carlos Forray; Raimund Buller
      Pages: 10 - 24
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Carlos Forray, Raimund Buller
      In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a single diagnostic entity; the needs for in depth clinical phenotyping to leverage the findings of schizophrenia genetics and advance the understanding of the disease biology; the symptom domains that are the major sources of disability in order to improve functional outcomes beyond current treatment options. In spite of the progress achieved during the last century the task ahead is still daunting and will require the efforts of scientists and clinicians through inclusive public-private partnerships and consortia to create the scientific basis for new therapeutic approaches to schizophrenia.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.05.009
      Issue No: Vol. 143 (2017)
       
  • Characterization of potent and selective iodonium-class inhibitors of
           NADPH oxidases
    • Authors: Jiamo Lu; Prabhakar Risbood; Charles T. Kane; Md Tafazzal Hossain; Larry Anderson; Kimberly Hill; Anne Monks; Yongzhong Wu; Smitha Antony; Agnes Juhasz; Han Liu; Guojian Jiang; Erik Harris; Krishnendu Roy; Jennifer L. Meitzler; Mariam Konaté; James H. Doroshow
      Pages: 25 - 38
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Jiamo Lu, Prabhakar Risbood, Charles T. Kane, Md Tafazzal Hossain, Larry Anderson, Kimberly Hill, Anne Monks, Yongzhong Wu, Smitha Antony, Agnes Juhasz, Han Liu, Guojian Jiang, Erik Harris, Krishnendu Roy, Jennifer L. Meitzler, Mariam Konaté, James H. Doroshow
      The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization. The inhibitory activity of the analogs was interrogated through cell viability and clonogenic studies with a colon cancer cell line (HT-29) that depends on NOX for its proliferative potential. Lack of altered cellular respiration at relevant iodonium analog concentrations was also demonstrated. Additionally, inhibition of ROS generation was evaluated with a luminescence assay for superoxide, or by Amplex Red® assay for H2O2 production, in cell models expressing specific NOX isoforms. DPI and four analogs (NSCs 740104, 751140, 734428, 737392) strongly inhibited HT-29 cell growth and ROS production with nanomolar potency in a concentration-dependent manner. NSC 737392 and 734428, which both feature nitro functional groups at the meta position, had >10-fold higher activity against ROS production by cells that overexpress dual oxidase 2 (DUOX2) than the other compounds examined (IC50 ≈200–400nM). Based on these results, we synthesized and tested NSC 780521 with optimized potency against DUOX2. Iodonium analogs with anticancer activity, including the first generation of targeted agents with improved specificity against DUOX2, may provide a novel therapeutic approach to NOX-driven tumors.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.007
      Issue No: Vol. 143 (2017)
       
  • Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole
           and dithiazine compounds for development of anticancer drugs
    • Authors: Lara Napolitano; Mariafrancesca Scalise; Maria Koyioni; Panayiotis Koutentis; Marco Catto; Ivano Eberini; Chiara Parravicini; Luca Palazzolo; Leonardo Pisani; Michele Galluccio; Lara Console; Angelo Carotti; Cesare Indiveri
      Pages: 39 - 52
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Lara Napolitano, Mariafrancesca Scalise, Maria Koyioni, Panayiotis Koutentis, Marco Catto, Ivano Eberini, Chiara Parravicini, Luca Palazzolo, Leonardo Pisani, Michele Galluccio, Lara Console, Angelo Carotti, Cesare Indiveri
      The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [3H]histidine in exchange with intraliposomal histidine. Out of 59 compounds tested, 8 compounds, showing an inhibition higher than 90% at 100µM concentration, were subjected to dose-response analysis. Two of them exhibited IC50 lower than 1µM. Inhibition kinetics, performed on the two best inhibitors, indicated a mixed type of inhibition with respect to the substrate. Furthermore, inhibition of the transporter was still present after removal of the compounds from the reaction mixture, but was reversed on addition of dithioerythritol, a S-S reducing agent, indicating the formation of disulfide(s) between the compounds and the protein. Molecular docking of the two best inhibitors on the hLAT1 homology structural model, highlighted interaction with the substrate binding site and formation of a covalent bond with the residue C407. Indeed, the inhibition was impaired in the hLAT1 mutant C407A confirming the involvement of that Cys residue. Treatment of SiHa cells expressing hLAT1 at relatively high level, with the two most potent inhibitors led to cell death which was not observed after treatment with a compound exhibiting very poor inhibitory effect.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.006
      Issue No: Vol. 143 (2017)
       
  • Global alteration of the drug-binding pocket of human P-glycoprotein
           (ABCB1) by substitution of fifteen conserved residues reveals a negative
           correlation between substrate size and transport efficiency
    • Authors: Shahrooz Vahedi; Eduardo E. Chufan; Suresh V. Ambudkar
      Pages: 53 - 64
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Shahrooz Vahedi, Eduardo E. Chufan, Suresh V. Ambudkar
      P-glycoprotein (P-gp), an ATP-dependent efflux pump, is linked to the development of multidrug resistance in cancer cells. However, the drug-binding sites and translocation pathways of this transporter are not yet well-characterized. We recently demonstrated the important role of tyrosine residues in regulating P-gp ATP hydrolysis via hydrogen bond formations with high affinity modulators. Since tyrosine is both a hydrogen bond donor and acceptor, and non-covalent interactions are key in drug transport, in this study we investigated the global effect of enrichment of tyrosine residues in the drug-binding pocket on the drug binding and transport function of P-gp. By employing computational analysis, 15 conserved residues in the drug-binding pocket of human P-gp that interact with substrates were identified and then substituted with tyrosine, including 11 phenylalanine (F72, F303, F314, F336, F732, F759, F770, F938, F942, F983, F994), two leucine (L339, L975), one isoleucine (I306), and one methionine (M949). Characterization of the tyrosine-rich P-gp mutant in HeLa cells demonstrated that this major alteration in the drug-binding pocket by introducing fifteen additional tyrosine residues is well tolerated and has no measurable effect on total or cell surface expression of this mutant. Although the tyrosine-enriched mutant P-gp could transport small to moderate size (<1000 Daltons) fluorescent substrates, its ability to transport large (>1000 Daltons) substrates such as NBD-cyclosporine A, Bodipy-paclitaxel and Bodipy-vinblastine was significantly decreased. This was further supported by the physico-chemical characterization of seventeen tested substrates, which revealed a negative correlation between drug transport and molecular size for the tyrosine-enriched P-gp mutant.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.014
      Issue No: Vol. 143 (2017)
       
  • Antibacterial activity of chensinin-1b, a peptide with a random coil
           conformation, against multiple-drug-resistant Pseudomonas aeruginosa
    • Authors: Dejing Shang; Xin Meng; Dongdong Zhang; Zhiru Kou
      Pages: 65 - 78
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Dejing Shang, Xin Meng, Dongdong Zhang, Zhiru Kou
      Nosocomial infections caused by Pseudomonas aeruginosa are difficult to treat due to the low permeability of its outer membrane as well as to its remarkable ability to acquire further resistance to antibiotics. Chensinin-1b exhibited antibacterial activity against the tested multiple-drug-resistant bacteria with a MIC ranging between 1.56 and 50μM, except E. cloacae strain 0320 (MREC0320), P. fluorescens strain 0322 (MRPF0322) and E. aerogenes strain 0320 (MREA0320). However, the MIC (25μM) of chensinin-1b to multiple-drug-resistant P. aeruginosa strain (MRPA 0108) was 16-fold higher than that observed to P. aeruginosa susceptible strain CGMCC 1.860 (PA1860). Chensinin-1b was able to disturb the integration of the cytoplasmic membrane of PA1860 and MRPA0108 cells similarly, but the outer membrane permeability of MRPA0108 cells was significantly lower. This low permeability was associated with increased expression of lipopolysaccharide (LPS) in the outer membrane and a decrease in negatively charged phospholipids in the outer membrane leaflet. In addition, the biofilm of MRPA0108 was responsible for the reduced susceptibility to chensinin-1b. A higher concentration of chensinin-1b (12.5µM) was required to maximally inhibit the formation of MRPA0108 biofilm. Notably, chensinin-1b inhibited the formation of MRPA0108 biofilm at concentrations below its MIC value by down-regulating the level of PelA, algD, and PslA gene transcription. Importantly, chensinin-1b had a significant antibacterial effect against MRPA0108 in vivo. Administration of chensinin-1b to mice infected with MRPA 0108 significantly increased survival by 50–70%. Moreover, chensinin-1b reduced the production of pro-inflammatory mediators and correspondingly reduced lung and liver tissue damage in the mouse model of septic shock induced by MRPA 0108. Collectively, these results suggest that chensinin-1b could be an effective antibiotic against multiple-drug-resistant bacterial strains.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.017
      Issue No: Vol. 143 (2017)
       
  • Activation of ALDH1A1 in MDA-MB-468 breast cancer cells that over-express
           CYP2J2 protects against paclitaxel-dependent cell death mediated by
           reactive oxygen species
    • Authors: Sarah E. Allison; Yongjuan Chen; Nenad Petrovic; Jian Zhang; Kirsi Bourget; Peter I. Mackenzie; Michael Murray
      Pages: 79 - 89
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Sarah E. Allison, Yongjuan Chen, Nenad Petrovic, Jian Zhang, Kirsi Bourget, Peter I. Mackenzie, Michael Murray
      Cytochrome P450 2J2 (CYP2J2) expression is elevated in breast and other tumours, and is known to be protective against cytotoxic agents that may be used in cancer chemotherapy. This study evaluated the mechanisms by which MDA-MB-468 breast cancer cells that stably expressed CYP2J2 (MDA-2J2 cells) were protected against killing by the anti-cancer agent paclitaxel. Compared to control cells caspase-3/7 activation by paclitaxel was lower in MDA-2J2 cells, while cell proliferation and colony formation following paclitaxel treatment were increased. Basal lipid peroxidation was lower in MDA-2J2 cells than in control cells, and the paclitaxel-mediated increase in peroxidation was attenuated. The mitochondrial complex III inhibitor antimycin A modulated basal and paclitaxel-activated reactive oxygen species (ROS) formation in control cells; paclitaxel-activated ROS production was also modulated by the NADPH oxidase inhibitor diphenyleneiodonium. Paclitaxel increased the formation of protein adducts by the reactive aldehyde 4-hydroxynonenal that is produced by lipid peroxidation; adduct formation was attenuated in MDA-2J2 cells. ALDH1A1 expression and activity was strongly upregulated in MDA-2J2 cells that was attributed to CYP2J2-derived 14,15-epoxyeicosatrienoic acid (14,15-EET); the 8,9- and 11,12-EET regioisomers did not activate ALDH1A1 expression. Silencing of ALDH1A1 restored the sensitivity of MDA-2J2 cells to paclitaxel, as indicated by a more pronounced decrease in proliferation, and greater increases in caspase activity and formation of ROS to levels comparable with control cells. Similar findings were observed with doxorubicin, sorafenib and staurosporine, that also promoted ROS-mediated cell death that was attenuated in MDA-2J2 cells and reversed by ALDH1A1 gene silencing. These findings implicate ALDH1A1 as an important gene that is activated in MDA-MB-468-derived cells that contain high levels of CYP2J2. ALDH1A1 modulates the production of ROS by anti-cancer agents such as paclitaxel and diminishes their efficacy. Future approaches could adapt this information to facilitate the targeting of ALDH1A1 to promote the efficacy of ROS-generating cytotoxic agents and enhance the treatment of breast cancer.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.020
      Issue No: Vol. 143 (2017)
       
  • Downregulation of TIGAR sensitizes the antitumor effect of physapubenolide
           through increasing intracellular ROS levels to trigger apoptosis and
           autophagosome formation in human breast carcinoma cells
    • Authors: Ting Ma; Yi Zhang; Chao Zhang; Jian-Guang Luo; Ling-Yi Kong
      Pages: 90 - 106
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Ting Ma, Yi Zhang, Chao Zhang, Jian-Guang Luo, Ling-Yi Kong
      Physapubenolide (PB) is a cytotoxic withanolide isolated from Physalis angulata that was used as a traditional Chinese medicine. In this study, we investigated the role of TIGAR and ROS in PB-induced apoptosis and autophagosome formation in human breast carcinoma MDA-MB-231 and MCF-7 cells. PB induced apoptosis by decreasing mitochondrial membrane potential and elevating the Bax/Bcl-2 protein expression ratio in MDA-MB-231 and MCF-7 cells. Caspase inhibitor Z-VAD-FMK treatment partly blocked PB induced cytotoxicity, suggesting that apoptosis serves as an important role in the anti-proliferative effect of PB. Meanwhile, PB induced autophagosome formation, as characterized by increased acridine orange-stained positive cells, accumulation of punctate LC3B fluorescence and a greater number of autophagic vacuoles under electron microscopy. Furthermore, PB inhibited autophagic flux as reflected by the overlapping of mCherry and GFP fluorescence when MDA-MB-231 cells were transfected with GFP-mCherry-LC3 plasmid. Depletion of LC3B, ATG5 or ATG7 reduced PB-induced cytotoxicity, indicating that autophagosome associated cell death participated in the anti-cancer effect of PB. Moreover, PB-induced apoptosis and autophagosome formation were linked to the generation of intracellular ROS, and pre-treatment with the antioxidant NAC obviously mitigated the effects. Interestingly, PB treatment slightly increased TIGAR expression at low concentrations but decreased TIGAR expression drastically at high concentrations. Downregulation of TIGAR by small interfering RNA augmented low concentrations of PB-induced apoptosis and autophagosome formation, which contributed to the observed anti-cancer effect of PB and were reversed by NAC pre-treatment. Consistently, in MDA-MB-231 or MCF-7 xenograft mouse model, PB suppressed tumor growth through ROS induced apoptosis and autophagosome associated cell death accompanied with the downregulation of TIGAR. Taken together, these results indicate that downregulation of TIGAR increased PB-induced apoptosis and autophagosomes associated cell death through promoting ROS generation in MDA-MB-231 and MCF-7 cells.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.018
      Issue No: Vol. 143 (2017)
       
  • Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via
           expression of regulator of calcineurin activity 1 (RCAN1)
    • Authors: Eun Hye Lee; Seon Sook Kim; Su Ryeon Seo
      Pages: 107 - 117
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Eun Hye Lee, Seon Sook Kim, Su Ryeon Seo
      Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti-inflammatory effects by inhibiting NF-κB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses. Moreover, we show that the PDTC-mediated inhibitory effect on NF-κB signaling is significantly perturbed by knocking out RCAN1. Our data provide the first evidence that PDTC prevents in vivo expression of pro-inflammatory cytokines by inducing RCAN1 expression.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.011
      Issue No: Vol. 143 (2017)
       
  • Functional characterization of 21 allelic variants of dihydropyrimidinase
    • Authors: Eiji Hishinuma; Fumika Akai; Yoko Narita; Masamitsu Maekawa; Hiroaki Yamaguchi; Nariyasu Mano; Akifumi Oda; Noriyasu Hirasawa; Masahiro Hiratsuka
      Pages: 118 - 128
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Eiji Hishinuma, Fumika Akai, Yoko Narita, Masamitsu Maekawa, Hiroaki Yamaguchi, Nariyasu Mano, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka
      Dihydropyrimidinase (DHP, EC 3.5.2.2), encoded by the gene DPYS, is the second enzyme in the catabolic pathway of pyrimidine and of fluoropyrimidine drugs such as 5-fluorouracil, which are commonly used in anticancer treatment; DHP catalyzes the hydrolytic ring opening of dihydrouracil and dihydro-5-fluorouracil. DPYS mutations are known to contribute to interindividual variations in the toxicity of fluoropyrimidine drugs, but the functional characterization of DHP allelic variants remains inadequate. In this study, in vitro analysis was performed on 22 allelic variants of DHP by transiently expressing wild-type DHP and 21 DHP variants in 293FT cells and characterizing their enzymatic activities by using dihydrouracil and dihydro-5-fluorouracil as substrates. DHP expression levels and oligomeric forms were determined using immunoblotting and blue native PAGE, respectively, and the stability of the DHP variants was assessed by examining the proteins in variant-transfected cells treated with cycloheximide or bortezomib. Moreover, three kinetic parameters, Km , Vmax , and intrinsic clearance (Vmax/Km ), for the hydrolysis of dihydrouracil and dihydro-5-fluorouracil were determined. We found that 5/21 variants showed significantly decreased intrinsic clearance as compared to wild-type DHP, and that 9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation. The band patterns observed in the immunoblotting of blue native gels corresponded to DHP activity, and, notably, 18/21 DHP variants exhibited decreased or null enzymatic activity and these variants also showed a drastically reduced ability to form large oligomers. Thus, detection of DPYS genetic polymorphisms might facilitate the prediction severe adverse effects of fluoropyrimidine-based treatments.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.121
      Issue No: Vol. 143 (2017)
       
  • Cytochrome P450 3A selectively affects the pharmacokinetic interaction
           between erlotinib and docetaxel in rats
    • Authors: Xuan Qin; Jian Lu; Peili Wang; Peipei Xu; Mingyao Liu; Xin Wang
      Pages: 129 - 139
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Xuan Qin, Jian Lu, Peili Wang, Peipei Xu, Mingyao Liu, Xin Wang
      Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the microtubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes. In whole animal studies, erlotinib and docetaxel were given to WT and KO rats individually or jointly, and the pharmacokinetic profiles of these two drugs were analyzed and compared among different groups. The results showed that docetaxel not only inhibited the CYP3A-mediated biotransformation of erlotinib in vitro, but also significantly increased the maximum concentration and systemic exposure of erlotinib in vivo in WT rats. In contrast, the DDI was significantly attenuated in KO rats. On the other hand, erlotinib did not influence docetaxel either in vitro biotransformation or in vivo pharmacokinetic behaviors. These results exhibited the potentials of erlotinib-docetaxel interaction and indicated that the CYP3A played the perpetrating role of docetaxel on erlotinib in rats. A better understanding of this DDI with CYP3A may help the regulation of the use of these two drugs, avoid potential problems, and adjust dose carefully and early in clinic.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.013
      Issue No: Vol. 143 (2017)
       
  • Curcumin attenuates oxidative stress induced NFκB mediated inflammation
           and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes
    • Authors: Kahkashan Rashid; Sayantani Chowdhury; Sumit Ghosh; Parames C. Sil
      Pages: 140 - 155
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Kahkashan Rashid, Sayantani Chowdhury, Sumit Ghosh, Parames C. Sil
      The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65mgkg−1 body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals. Oral administration of curcumin at a dose of 100mgkg−1 body weight daily for 8weeks, however, restored these alterations. Investigation of the mechanism of hyperglycemia induced oxidative stress mediated inflammation showed upregulation of inflammatory cytokines, chemokines, adhesion molecules and increased translocation of NFκB into the nucleus. Moreover, ER stress dependent cell death showed induction of eIF2α and CHOP mediated signalling pathways as well as increment in the expression of GRP78, Caspase-12, Calpain-1, phospho JNK, phospho p38 and phospho p53 in the diabetic group. Alteration of Bax/Bcl-2 ratio; disruption of mitochondrial membrane potential, release of cytochrome-C from mitochondria and upregulation of caspase 3 along with the formation of characteristic DNA ladder in the diabetic animals suggest the involvement of mitochondria dependent apoptotic pathway in the splenic cells. Treatment with curcumin could, however, protect cells from inflammatory damage and ER as well as mitochondrial apoptotic death by restoring the alterations of these parameters. Our results suggest that curcumin has the potential to act as an anti-diabetic, anti-oxidant, anti-inflammatory and anti-apoptotic therapeutic against diabetes mediated splenic damage.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.009
      Issue No: Vol. 143 (2017)
       
  • The impact of cellular senescence in skin ageing: A notion of mosaic and
           therapeutic strategies
    • Authors: Marie Toutfaire; Emilie Bauwens; Florence Debacq-Chainiaux
      Pages: 1 - 12
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Marie Toutfaire, Emilie Bauwens, Florence Debacq-Chainiaux
      Cellular senescence is now recognized as one of the nine hallmarks of ageing. Recent data show the involvement of senescent cells in tissue ageing and some age-related diseases. Skin represents an ideal model for the study of ageing. Indeed, skin ageing varies between individuals depending on their chronological age but also on their exposure to various exogenous factors (mainly ultraviolet rays). If senescence traits can be detected with ageing in the skin, the senescent phenotype varies among the various skin cell types. Moreover, the origin of cellular senescence in the skin is still unknown, and multiple origins are possible. This reflects the mosaic of skin ageing. Senescent cells can interfere with their microenvironment, either via the direct secretion of factors (the senescence-associated secretory phenotype) or via other methods of communication, such as extracellular vesicles. Knowledge regarding the impact of cellular senescence on skin ageing could be integrated into dermatology research, especially to limit the appearance of senescent cells after photo(chemo)therapy or in age-related skin diseases. Therapeutic approaches include the clearance of senescent cells via the use of senolytics or via the cooperation with the immune system.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.04.011
      Issue No: Vol. 142 (2017)
       
  • Repurposing bacterial toxins for intracellular delivery of therapeutic
           proteins
    • Authors: Greg L. Beilhartz; Seiji N. Sugiman-Marangos; Roman A. Melnyk
      Pages: 13 - 20
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Greg L. Beilhartz, Seiji N. Sugiman-Marangos, Roman A. Melnyk
      Despite enormous efforts, achieving efficacious levels of proteins inside mammalian cells remains one of the greatest challenges in biologics-based drug discovery and development. The inability of proteins to readily cross biological membranes precludes access to the wealth of intracellular targets and applications that lie within mammalian cells. Existing methods of delivery commonly suffer from an inability to target specific cells and tissues, poor endosomal escape, and limited in vivo efficacy. The aim of the present commentary is to highlight the potential of certain classes of bacterial toxins, which naturally deliver a large protein into the cytosolic compartment of target cells after binding a host cell-surface receptor with high affinity, as robust protein delivery platforms. We review the progress made in recent years toward demonstrating the utility of these systems at delivering a wide variety of protein cargo, with special attention paid to three distinct toxin-based platforms. We contend that with recent advances in protein deimmunization strategies, bacterial toxins are poised to introduce biologics into the inner sanctum of cells and treat a wealth of heretofore untreatable diseases with a new generation of therapeutics.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.04.009
      Issue No: Vol. 142 (2017)
       
  • The overexpression of CPR and P450 3A4 in pancreatic cancer cells changes
           the metabolic profile and increases the cytotoxicity and pro-apoptotic
           activity of acridine antitumor agent, C-1748
    • Authors: Barbara Borowa-Mazgaj; Anna Mróz; Ewa Augustin; Ewa Paluszkiewicz; Zofia Mazerska
      Pages: 21 - 38
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Barbara Borowa-Mazgaj, Anna Mróz, Ewa Augustin, Ewa Paluszkiewicz, Zofia Mazerska
      Drug resistance is one of the major causes of pancreatic cancer treatment failure. Thus, it is still imperative to develop new active compounds and novel approach to improve drug efficacy. Here we present 9-amino-1-nitroacridine antitumor agent, C-1748, developed in our laboratory, as a candidate for pancreatic cancer treatment. We examined (i) the cellular response of pancreatic cancer cell lines: Panc-1, MiaPaCa-2, BxPC-3 and AsPC-1, differing in expression levels of commonly mutated genes for this cancer type, to C-1748 treatment and (ii) the role of P450 3A4 isoenzyme and cytochrome P450 reductase (CPR) in the modulation of this response. C-1748 exhibited the highest cytotoxic activity against MiaPaCa-2, while AsPC-1 cells were the most resistant (IC50: 0.015, 0.075µM, respectively). A considerable amount of apoptosis was detected in Panc-1 and MiaPaCa-2 cells but only limited apoptosis was observed in AsPC-1 and BxPC-3 cells as indicated by morphological changes and biochemical markers. Furthermore, only AsPC-1 cells underwent senescence. Since AsPC-1 cells were the most resistant to C-1748 as evidenced by the lowest P450 3A4 and CPR protein levels, this cell line was subjected to transient transfection either with P450 3A4 or CPR gene. The overexpression of P450 3A4 or CPR changed the pro-apoptotic activity of C-1748 and sensitized AsPC-1 cells to this drug compared to wild-type cells. However, metabolism was changed significantly only for CPR overexpressing cells. In conclusion, the antitumor effectiveness of C-1748 would be improved by multi-drug therapy with chemotherapeutics, that are able to induce P450 3A4 and/or CPR gene expression.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.124
      Issue No: Vol. 142 (2017)
       
  • A high throughput assay to identify substrate-selective inhibitors of the
           ERK protein kinases
    • Authors: Chad J. Miller; Yagmur Muftuoglu; Benjamin E. Turk
      Pages: 39 - 45
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Chad J. Miller, Yagmur Muftuoglu, Benjamin E. Turk
      Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates important for survival and proliferation, and their activity is frequently deregulated in tumors. ERK pathway inhibitors have shown clinical efficacy as anti-cancer drugs, but most patients eventually relapse due to reactivation of the pathway. One factor limiting the efficacy of current therapeutics is the difficulty in reaching clinically effective inhibition of the ERK pathway in the absence of on-target toxicities. Here, we describe an assay suitable for high throughput screening to discover substrate selective ERK1/2 inhibitors, which may have a larger therapeutic window than conventional inhibitors. Specifically, we aim to target a substrate-binding pocket within the ERK1/2 catalytic domain outside of the catalytic cleft. The assay uses an AlphaScreen format to detect phosphorylation of a high-efficiency substrate harboring an essential docking site motif. Pilot screening established that the assay is suitably robust for high-throughput screening. Importantly, the assay can be conducted at high ATP concentrations, which we show reduces the discovery of conventional ATP-competitive inhibitors. These studies provide the basis for high-throughput screens to discover new classes of non-conventional ERK1/2 inhibitors.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.127
      Issue No: Vol. 142 (2017)
       
  • Geranylnaringenin (CG902) inhibits constitutive and inducible STAT3
           activation through the activation of SHP-2 tyrosine phosphatase
    • Authors: Yena Jin; Yae Jin Yoon; Yoon Jung Jeon; Jiyeon Choi; Yu-Jin Lee; Joonku Lee; Sangho Choi; Oyekanmi Nash; Dong Cho Han; Byoung-Mog Kwon
      Pages: 46 - 57
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Yena Jin, Yae Jin Yoon, Yoon Jung Jeon, Jiyeon Choi, Yu-Jin Lee, Joonku Lee, Sangho Choi, Oyekanmi Nash, Dong Cho Han, Byoung-Mog Kwon
      The roles and significance of signal transducer and activator of transcription 3 (STAT3) in human cancers have been extensively studied and STAT3 is a promising therapeutic target for cancer drug discovery. During the screening of natural products to identify STAT3 inhibitors, we identified geranylnaringenin (CG902), which decreased luciferase activity in a dose-dependent manner. CG902 specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cancer cells and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin. Notably, the knockdown of the SHP-2 gene by small interfering RNA suppressed the ability of CG902 to inhibit STAT3 activation and CG902 activated the phosphatase activity of SHP-2 through direct interaction with SHP-2 and induced the phosphorylation of SHP-2. The interactions between CG902 and SHP-2 were confirmed by pull-down assay using biotinylated CG902. The interactions were also further validated by the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). The inhibitory effect of CG902 on cell growth was confirmed using the DU145 mouse xenograft model. We propose that CG902 inhibits STAT3 activity through a mechanism that involves the interactions between CG902 and SHP-2, and the phosphorylation of SHP-2, which leads to SHP-2 activation in DU145 cells. CG902 is the first compound to regulate STAT3 activity via the modulation of SHP-2 activity, and our results suggest that CG902 is a novel inhibitor of the STAT3 pathway and an activator of SHP-2, and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.131
      Issue No: Vol. 142 (2017)
       
  • Eriocalyxin B, a novel autophagy inducer, exerts anti-tumor activity
           through the suppression of Akt/mTOR/p70S6K signaling pathway in breast
           cancer
    • Authors: Xunian Zhou; Grace Gar-Lee Yue; Andrew Man-Lok Chan; Stephen Kwok-Wing Tsui; Kwok-Pui Fung; Handong Sun; Jianxin Pu; Clara Bik-San Lau
      Pages: 58 - 70
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Xunian Zhou, Grace Gar-Lee Yue, Andrew Man-Lok Chan, Stephen Kwok-Wing Tsui, Kwok-Pui Fung, Handong Sun, Jianxin Pu, Clara Bik-San Lau
      Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid presented in the plant Isodon eriocalyx var. laxiflora, has been reported to diminish angiogenesis-dependent breast tumor growth. In the present study, the effects of EriB on human breast cancer and its underlying mechanisms were further investigated. The in vitro anti-breast cancer activity of EriB was determined using MCF-7 and MDA-MB-231 cell lines. MDA-MB-231 xenograft model of human breast cancer was also established to explore the anti-tumor effect in vivo. We found that EriB was able to induce apoptosis accompanied by the activation of autophagy, which was evidenced by the increased accumulation of autophagosomes, acidic vesicular organelles formation, the microtubule-associated protein 1A/1B-light chain 3B-II (LC3B-II) conversion from LC3B-I and p62 degradation. Meanwhile, EriB treatment time-dependently decreased the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), leading to the inhibition of Akt/mTOR/p70S6K signaling pathway. Moreover, the blockage of autophagy obviously sensitized EriB-induced cell death, which suggested the cytoprotective function of autophagy in both MCF-7 and MDA-MB-231 cells. Interestingly, the autophagic features and apoptosis induction were prevented by reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine, indicating that ROS played an essential role in the mediation of EriB-induced cell death. Furthermore, in MDA-MB-231 xenograft model, EriB displayed a significant anti-tumor effect via the activation of autophagy and apoptosis in breast tumor cells. Taken together, our findings firstly demonstrated that EriB suppressed breast cancer cells growth both in vitro and in vivo, and thus could be developed as a promising anti-breast tumor agent.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.133
      Issue No: Vol. 142 (2017)
       
  • Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to
           apoptotic rather than autophagic cell death via ROS/p53 signaling pathways
           in liver cancer
    • Authors: Ya-di Geng; Chao Zhang; Jian-li Lei; Pei Yu; Yuan-zheng Xia; Hao Zhang; Lei Yang; Ling-yi Kong
      Pages: 71 - 86
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Ya-di Geng, Chao Zhang, Jian-li Lei, Pei Yu, Yuan-zheng Xia, Hao Zhang, Lei Yang, Ling-yi Kong
      Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel-7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B-induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other’s production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.134
      Issue No: Vol. 142 (2017)
       
  • A TSPO ligand prevents mitochondrial sterol accumulation and dysfunction
           during myocardial ischemia-reperfusion in hypercholesterolemic rats
    • Authors: Julien Musman; Stéphanie Paradis; Mathieu Panel; Sandrine Pons; Caroline Barau; Claudio Caccia; Valerio Leoni; Bijan Ghaleh; Didier Morin
      Pages: 87 - 95
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Julien Musman, Stéphanie Paradis, Mathieu Panel, Sandrine Pons, Caroline Barau, Claudio Caccia, Valerio Leoni, Bijan Ghaleh, Didier Morin
      A major cause of cell death during myocardial ischemia-reperfusion is mitochondrial dysfunction. We previously showed that the reperfusion of an ischemic myocardium was associated with an accumulation of cholesterol into mitochondria and a concomitant strong generation of auto-oxidized oxysterols. The inhibition of mitochondrial accumulation of cholesterol abolished the formation of oxysterols and prevented mitochondrial injury at reperfusion. The aim of this study was to investigate the impact of hypercholesterolemia on sterol and oxysterol accumulation in rat cardiac cytosols and mitochondria and to analyse the effect of the translocator protein ligand 4′-chlorodiazepam on this accumulation and mitochondrial function. Hypercholesterolemic ZDF fa/fa rats or normocholesterolemic lean rats were submitted to 30min of coronary artery occlusion followed by 15min reperfusion where cardiac cytosols and mitochondria were isolated. Hypercholesterolemia increased the cellular cardiac concentrations of cholesterol, cholesterol precursors and oxysterols both in cytosol and mitochondria in non-ischemic conditions. It also amplified the accumulation of all these compounds in cardiac cells and the alteration of mitochondrial function with ischemia-reperfusion. Administration of 4′-chlorodiazepam to ZDF fa/fa rats had no effect on the enhancement of sterols and oxysterols observed in the cytosols but inhibited cholesterol transfer to the mitochondria. It also alleviated the mitochondrial accumulation of all the investigated sterols and oxysterols. This was associated with a restoration of oxidative phosphorylation and a prevention of mitochondrial transition pore opening. The inhibition of cholesterol accumulation with TSPO ligands represents an interesting strategy to protect the mitochondria during ischemia-reperfusion in hypercholesterolemic conditions.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.125
      Issue No: Vol. 142 (2017)
       
  • Receptor activity-modifying protein dependent and independent activation
           mechanisms in the coupling of calcitonin gene-related peptide and
           adrenomedullin receptors to Gs
    • Authors: Michael J. Woolley; Christopher A. Reynolds; John Simms; Christopher S. Walker; Juan Carlos Mobarec; Michael L. Garelja; Alex C. Conner; David R. Poyner; Debbie L. Hay
      Pages: 96 - 110
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Michael J. Woolley, Christopher A. Reynolds, John Simms, Christopher S. Walker, Juan Carlos Mobarec, Michael L. Garelja, Alex C. Conner, David R. Poyner, Debbie L. Hay
      Calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors are heteromers of the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor, and one of three receptor activity-modifying proteins (RAMPs). How CGRP and AM activate CLR and how this process is modulated by RAMPs is unclear. We have defined how CGRP and AM induce Gs-coupling in CLR-RAMP heteromers by measuring the effect of targeted mutagenesis in the CLR transmembrane domain on cAMP production, modeling the active state conformations of CGRP and AM receptors in complex with the Gs C-terminus and conducting molecular dynamics simulations in an explicitly hydrated lipidic bilayer. The largest effects on receptor signaling were seen with H295A5.40b, I298A5.43b, L302A5.47b, N305A5.50b, L345A6.49b and E348A6.52b, F349A6.53b and H374A7.47b (class B numbering in superscript). Many of these residues are likely to form part of a group in close proximity to the peptide binding site and link to a network of hydrophilic and hydrophobic residues, which undergo rearrangements to facilitate Gs binding. Residues closer to the extracellular loops displayed more pronounced RAMP or ligand-dependent effects. Mutation of H3747.47b to alanine increased AM potency 100-fold in the CGRP receptor. The molecular dynamics simulation showed that TM5 and TM6 pivoted around TM3. The data suggest that hydrophobic interactions are more important for CLR activation than other class B GPCRs, providing new insights into the mechanisms of activation of this class of receptor. Furthermore the data may aid in the understanding of how RAMPs modulate the signaling of other class B GPCRs.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.005
      Issue No: Vol. 142 (2017)
       
  • Sodium butyrate regulates Th17/Treg cell balance to ameliorate uveitis via
           the Nrf2/HO-1 pathway
    • Authors: Xiaoqing Chen; Wenru Su; Taoshang Wan; Jianfeng Yu; Wenjie Zhu; Fen Tang; Guangming Liu; Nancy Olsen; Dan Liang; Song Guo Zheng
      Pages: 111 - 119
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Xiaoqing Chen, Wenru Su, Taoshang Wan, Jianfeng Yu, Wenjie Zhu, Fen Tang, Guangming Liu, Nancy Olsen, Dan Liang, Song Guo Zheng
      Autoimmune uveitis, a group of potentially blinding intraocular inflammatory diseases, remains a therapeutic challenge for ophthalmologists. Butyrates, which belong to the short-chain fatty acid family, possess immunomodulatory properties and therapeutic potential in several inflammatory disorders. However, the roles of butyrates in uveitis and their underlying immunomodulatory mechanisms remain elusive. Here, we report that treatment with sodium butyrate (NaB) significantly attenuated the ocular inflammatory response in mice with experimental autoimmune uveitis (EAU) at 14days after immunization, with significant decreases in inflammatory cell infiltration and inflammatory cytokine production in the retinas. Furthermore, NaB treatment decreased the frequency and number of Th17 cells and increased the frequency and number of T regulatory (Treg) cells in both draining lymph nodes and spleens of EAU mice. In vitro, NaB treatment directly converted the differentiation of naive T cells from Th17 cells toward Treg cells. Mechanistically, the NaB-mediated inhibition of Th17 cell differentiation may occur via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/interleukin-6 receptor pathway. Moreover, the NaB-mediated inhibition on Th17 cell differentiation and uveitis were abrogated when an HO-1 inhibitor, SnPP, was used. These findings suggest that NaB inverts the differentiation of Th17 cells toward Treg cells and attenuates experimental autoimmune uveitis by modulating the Nrf2/HO-1 pathway.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.136
      Issue No: Vol. 142 (2017)
       
  • 4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide
           receptor 1 (FPR1) antagonists
    • Authors: Liliya N. Kirpotina; Igor A. Schepetkin; Andrei I. Khlebnikov; Olga I. Ruban; Yunjun Ge; Richard D. Ye; Douglas J. Kominsky; Mark T. Quinn
      Pages: 120 - 132
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Liliya N. Kirpotina, Igor A. Schepetkin, Andrei I. Khlebnikov, Olga I. Ruban, Yunjun Ge, Richard D. Ye, Douglas J. Kominsky, Mark T. Quinn
      Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics for modulating innate immunity and treating inflammatory diseases. Previously, 1H-pyrrol-2(5H)-ones were reported to be potent and competitive FPR1 antagonists. In the present studies, 42 additional 1H-pyrrol-2(5H)-one analogs were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced intracellular Ca2+ mobilization in FPR1-transfected HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-transfected RBL cells. The most active pyrroles inhibited human neutrophil Ca2+ flux, chemotaxis, and adhesion to human epithelial cells, with the most potent being compounds 14 (4-benzoyl-1-hexyl-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-2,5-dihydro-1H-pyrrol-2-one) and 17 (4-benzoyl-5-(2,5-dimethoxyphenyl)-3-hydroxy-1-(2-methoxyethyl)-2,5-dihydro-1H-pyrrol-2-one). In addition, these FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells, differentiated HL-60 cells, and human neutrophils. Most of the antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, or interleukin 8-induced Ca2+ flux in human neutrophils. Moreover, molecular modeling showed that the active pyrroles had a significantly higher degree of similarity with the FPR1 antagonist pharmacophore template as compared to inactive analogs. Thus, the 4-aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one scaffold represents an important backbone for the development of novel FPR1 antagonists and could provide important clues for understanding the molecular structural requirements of FPR1 antagonists.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.004
      Issue No: Vol. 142 (2017)
       
  • Suppressing mPGES-1 expression by sinomenine ameliorates inflammation and
           arthritis
    • Authors: Hua Zhou; Jian-Xin Liu; Jin-Fang Luo; Chun-Song Cheng; Elaine Lai-Han Leung; Ying Li; Xiao-Hui Su; Zhong-Qiu Liu; Ting-Bo Chen; Fu-Gang Duan; Yan Dong; Yi-Han Zuo; Chong Li; Chon Kit Lio; Ting Li; Pei Luo; Ying Xie; Xiao-Jun Yao; Pei-Xun Wang; Liang Liu
      Pages: 133 - 144
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Hua Zhou, Jian-Xin Liu, Jin-Fang Luo, Chun-Song Cheng, Elaine Lai-Han Leung, Ying Li, Xiao-Hui Su, Zhong-Qiu Liu, Ting-Bo Chen, Fu-Gang Duan, Yan Dong, Yi-Han Zuo, Chong Li, Chon Kit Lio, Ting Li, Pei Luo, Ying Xie, Xiao-Jun Yao, Pei-Xun Wang, Liang Liu
      Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that sinomenine (SIN) decreased prostaglandin (PG)E2 levels without affecting prostacyclin (PG)I2 and thromboxane (TX)A2 synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs. In addition, mPGES-1 protein expression was down-regulated by SIN treatment in the inflamed paw tissues both in carrageenan-induced edema model in rats and the collagen-II induced arthritis (CIA) model in DBA mice. More interestingly, SIN suppressed the last step of mPGES-1 gene expression by decreasing the DNA binding ability of NF-κB, paving a new way for drug discovery.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.010
      Issue No: Vol. 142 (2017)
       
  • Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway
           in human retinal endothelial cells by blocking the effect of AGE/RAGE
    • Authors: Giovanni Giurdanella; Francesca Lazzara; Nunzia Caporarello; Gabriella Lupo; Carmelina Daniela Anfuso; Chiara M. Eandi; Gian Marco Leggio; Filippo Drago; Claudio Bucolo; Salvatore Salomone
      Pages: 145 - 154
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Giovanni Giurdanella, Francesca Lazzara, Nunzia Caporarello, Gabriella Lupo, Carmelina Daniela Anfuso, Chiara M. Eandi, Gian Marco Leggio, Filippo Drago, Claudio Bucolo, Salvatore Salomone
      Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE2 pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA2, an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE2 pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.130
      Issue No: Vol. 142 (2017)
       
  • Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as
           long-acting hypoglycemic and insulinotropic agents with significant
           therapeutic potential
    • Authors: Jing Han; Xinyu Chen; Yiyun Wang; Yingying Fei; Feng Zhou; Ying Zhang; Lin Liu; Pengbin Si; Junjie Fu
      Pages: 155 - 167
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Jing Han, Xinyu Chen, Yiyun Wang, Yingying Fei, Feng Zhou, Ying Zhang, Lin Liu, Pengbin Si, Junjie Fu
      We here report the discovery and therapeutic efficacy of a novel series of glucagon-like peptide-1 (GLP-1) receptor agonists derived from Xenopus GLP-1. First, five amino acid-mutated Xenopus GLP-1s were synthesized, and xGLP-3 with the best acute and long-acting hypoglycemic activity was selected for further modification. Next, PEGylation of xGLP-3 was performed at specific sites, which were determined using cysteine mutagenesis scanning. Twelve PEGylated conjugates tethered with Mal-PEGs of 1, 2, and 5kDa were synthesized. Conjugates 7b and 7c, which exhibited comparable hypoglycemic and insulinotropic effects to Gly8-GLP-1, were selected for in-depth evaluation. It was found that 7b and 7c exhibited prolonged in vivo half-life and improved pharmacokinetic behaviors. The long-term hypoglycemic effects of 7b and 7c were further confirmed by pre-OGTT and multiple OGTT. Importantly, long-term administration of 7b or 7c in db/db mice achieved beneficial effects on body weight loss, food intake and HbA1c reduction, and glucose tolerance normalization. These preclinical studies indicate the promising role of 7b and 7c as long-acting type 2 diabetes therapeutics. In addition, our research demonstrated the feasibility of developing novel antidiabetic agents based on Xenopus GLP-1.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.132
      Issue No: Vol. 142 (2017)
       
  • Study of new interactions of glitazone’s stereoisomers and the
           endogenous ligand 15d-PGJ2 on six different PPAR gamma proteins
    • Authors: Samuel Álvarez-Almazán; Martiniano Bello; Feliciano Tamay-Cach; Marlet Martínez-Archundia; Diana Alemán-González-Duhart; José Correa-Basurto; Jessica Elena Mendieta-Wejebe
      Pages: 168 - 193
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Samuel Álvarez-Almazán, Martiniano Bello, Feliciano Tamay-Cach, Marlet Martínez-Archundia, Diana Alemán-González-Duhart, José Correa-Basurto, Jessica Elena Mendieta-Wejebe
      Diabetes mellitus is a chronic disease characterized by hyperglycemia, insulin resistance and hyperlipidemia. Glitazones or thiazolidinediones (TZD) are drugs that act as insulin-sensitizing agents whose molecular target is the peroxisome proliferator-activated receptor gamma (PPARγ). The euglycemic action of TZD has been linked with the induction of type 4 glucose transporter. However, it has been shown that the effect of TZD depends on the specific stereoisomer that interacts with PPARγ. Therefore, this work is focused on exploring the interactions and geometry adopted by glitazone's stereoisomers and one endogenous ligand on different conformations of the six crystals of the PPARγ protein using molecular docking and molecular dynamics (MD) simulations accompanied by the MMGBSA approach. Specifically, the 2,4-thiazolidinedione ring, pioglitazone (PIO), rosiglitazone (ROSI) and troglitazone (TRO) stereoisomers (exogenous ligands), as well as the endogenous ligand 15d-PGJ2, were evaluated. The six crystallographic structures of PPARγ are available at Protein Data Bank as the PDB entries 2PRG, 4PRG, 3T03, 1I7I, 1FM6, and 4EMA. According to the results, a boomerang shape and a particular location of ligands were found with low variations according to the protein conformations. The 15d-PGJ2, TZD, PIO, ROSI and (S,S)-TRO enantiomers were mostly stabilized by twenty hydrophobic residues: Phe226, Pro227, Leu228, Ile281, Phe282, Cys285, Ala292, Ile296, Ile326, Tyr327, Met329, Leu330, Leu333, Met334, Val339, Ile341, Met348, Leu353, Phe363 and Met364. Most hydrogen bond interactions were found between the polar groups of ligands with Arg288, Ser289, Lys367, Gln286, His323, Glu343 and His449 residues. An energetic analysis revealed binding free energy trends that supported known experimental findings of other authors describing better binding properties for PIO, ROSI and (S,S)-TRO than for 15d-PGJ2 and the TZD ring.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.012
      Issue No: Vol. 142 (2017)
       
  • Pregnane X receptor (PXR) deficiency improves high fat diet-induced
           obesity via induction of fibroblast growth factor 15 (FGF15) expression
    • Authors: Li-Yang Zhao; Jia-Yi Xu; Zhe Shi; Neal A. Englert; Shu-Yun Zhang
      Pages: 194 - 203
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Li-Yang Zhao, Jia-Yi Xu, Zhe Shi, Neal A. Englert, Shu-Yun Zhang
      Obesity has become a significant global health problem, and is a high risk factor for a variety of metabolic diseases. Fibroblast growth factor (FGF) 15 plays an important role in the regulation of metabolism. Xenobiotic-sensing nuclear receptors pregnane X receptor (PXR/NR1I2) and constitutive androstane receptor (CAR/NR1I3) play important roles in xenobiotic detoxification and metabolism, and also are involved in the regulation of energy metabolism. However, the effects that PXR and CAR have on the regulation of FGF15 are unknown. Here, we found that body weight, hepatic triglyceride levels, liver steatosis, and hepatic mRNA expression levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1), the key enzymes in the bile acid classical synthesis pathway, were significantly decreased in high fat diet (HFD)-fed PXR knockout (KO) mice compared to HFD-fed wild-type mice. Interestingly, intestinal FGF15 expression levels were significantly elevated in HFD-fed PXR KO mice compared with HFD-fed wild-type mice. Additionally, serum total bile acid levels were significantly decreased in PXR KO mice than those in wild-type mice when fed a control diet or HFD. Total lipids in feces were significantly increased in HFD-fed PXR KO mice compared to HFD-fed wild-type mice. However, these alterations were not found in HFD-fed CAR KO mice. These results indicate that PXR deficiency improves HFD-induced obesity via induction of FGF15 expression, resulting in suppression of bile acid synthesis and reduction of lipid absorption, hepatic lipid accumulation and liver triglyceride levels. Our findings suggest that PXR may negatively regulate FGF15 expression and represent a potential therapeutic target for the treatment for metabolic disorders such as obesity.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.019
      Issue No: Vol. 142 (2017)
       
  • Inhibitor mechanisms in the S1 binding site of the dopamine transporter
           defined by multi-site molecular tethering of photoactive cocaine analogs
    • Authors: Danielle Krout; Akula Bala Pramod; Rejwi Acharya Dahal; Michael J. Tomlinson; Babita Sharma; James D. Foster; Mu-Fa Zou; Comfort Boatang; Amy Hauck Newman; John R. Lever; Roxanne A. Vaughan; L. Keith Henry
      Pages: 204 - 215
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Danielle Krout, Akula Bala Pramod, Rejwi Acharya Dahal, Michael J. Tomlinson, Babita Sharma, James D. Foster, Mu-Fa Zou, Comfort Boatang, Amy Hauck Newman, John R. Lever, Roxanne A. Vaughan, L. Keith Henry
      Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2β position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane, MFZ 2–24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2–24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2–24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (−)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site and the importance of the tropane moiety in competitive mechanisms of DA uptake inhibition. These findings set a structure-function baseline for comparison of typical and atypical DAT inhibitors and how their interactions with DAT could lead to the loss of cocaine-like behaviors.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.015
      Issue No: Vol. 142 (2017)
       
  • Differential changes in the pharmacokinetics of statins in
           collagen-induced arthritis rats
    • Authors: Chun-Han Lin; Ke-Wei Hsu; Chia-Hao Chen; Yow-Shieng Uang; Chun-Jung Lin
      Pages: 216 - 228
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Chun-Han Lin, Ke-Wei Hsu, Chia-Hao Chen, Yow-Shieng Uang, Chun-Jung Lin
      The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT-qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.118
      Issue No: Vol. 142 (2017)
       
  • The neurotoxicant PCB-95 by increasing the neuronal transcriptional
           repressor REST down-regulates caspase-8 and increases Ripk1, Ripk3 and
           MLKL expression determining necroptotic neuronal death
    • Authors: Natascia Guida; Giusy Laudati; Angelo Serani; Luigi Mascolo; Pasquale Molinaro; Paolo Montuori; Gianfranco Di Renzo; Lorella M.T. Canzoniero; Luigi Formisano
      Pages: 229 - 241
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Natascia Guida, Giusy Laudati, Angelo Serani, Luigi Mascolo, Pasquale Molinaro, Paolo Montuori, Gianfranco Di Renzo, Lorella M.T. Canzoniero, Luigi Formisano
      Our previous study showed that the environmental neurotoxicant non-dioxin-like polychlorinated biphenyl (PCB)-95 increases RE1-silencing transcription factor (REST) expression, which is related to necrosis, but not apoptosis, of neurons. Meanwhile, necroptosis is a type of a programmed necrosis that is positively regulated by receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) and negatively regulated by caspase-8. Here we evaluated whether necroptosis contributes to PCB-95-induced neuronal death through REST up-regulation. Our results demonstrated that in cortical neurons PCB-95 increased RIPK1, RIPK3, and MLKL expression and decreased caspase-8 at the gene and protein level. Furthermore, the RIPK1 inhibitor necrostatin-1 or siRNA-mediated RIPK1, RIPK3 and MLKL expression knockdown significantly reduced PCB-95-induced neuronal death. Intriguingly, PCB-95-induced increases in RIPK1, RIPK3, MLKL expression and decreases in caspase-8 expression were reversed by knockdown of REST expression with a REST-specific siRNA (siREST). Notably, in silico analysis of the rat genome identified a REST consensus sequence in the caspase-8 gene promoter (Casp8-RE1), but not the RIPK1, RIPK3 and MLKL promoters. Interestingly, in PCB-95-treated neurons, REST binding to the Casp8-RE1 sequence increased in parallel with a reduction in its promoter activity, whereas under the same experimental conditions, transfection of siREST or mutation of the Casp8-RE1 sequence blocked PCB-95-induced caspase-8 reduction. Since RIPK1, RIPK3 and MLKL rat genes showed no putative REST binding site, we assessed whether the transcription factor cAMP Responsive Element Binding Protein (CREB), which has a consensus sequence in all three genes, affected neuronal death. In neurons treated with PCB-95, CREB protein expression decreased in parallel with a reduction in binding to the RIPK1, RIPK3 and MLKL gene promoter sequence. Furthermore, CREB overexpression was associated with reduced promoter activity of the RIPK1, RIPK3 and MLKL genes. Collectively, these results indicate that PCB-95 was associated with REST-induced necroptotic cell death by increasing RIPK1, RIPK3 and MLKL expression and reducing caspase-8 levels. In addition, since REST is involved in several neurological disorders, therapies that block REST-induced necroptosis could be a new strategy to revert the neurodetrimental effects associated to its overexpression.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.135
      Issue No: Vol. 142 (2017)
       
  • The Ca2+ / CaMKK2 Axis Mediates the Telbivudine Induces Upregulation of
           Creatine Kinase: Implications for mechanism of Antiviral Nucleoside
           Analogs Side Effect
    • Authors: Long Jianfei; Wang Min; Ma Chunlai; Chen Bicui; Zhang Jiming; Wang Bin
      Abstract: Publication date: Available online 14 October 2017
      Source:Biochemical Pharmacology
      Author(s): Long Jianfei, Wang Min, Ma Chunlai, Chen Bicui, Zhang Jiming, Wang Bin
      Telbivudine (LdT), a widely prescribed anti-hepatitis B virus (HBV) drug for the treatment of chronic Hepatitis B (CHB), causes adverse reactions ranging from creatine kinase (CK) elevation to myopathy. The purpose of this study was to explore the mechanism(s) of LdT induced CK elevation. The effects of LdT on mitochondrial morphology and proteins (TK2 and β-actin), oxidative stress, intracellular Ca2+ levels, Ca2+-related signaling pathway (CaMKK2/AMPK), and Ca2+-related biomarkers such as superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed in human skeletal muscle cells (HSKMCs). The results showed that LdT induced a dose-dependent increase in CK activity in HSKMCs, without affecting mitochondrial morphology, and TK2 and β-actin protein levels, following 72h of treatment. In addition, LdT increased Ca2+ production, ROS generation, MDA and lipid peroxide (LPO) levels, and activated the CaMKK2/AMPK signaling pathway. Moreover, these effects were attenuated by the BAPIA-AM (the calcium chelator). We also confirmed the presence of relevant markers (MDA, LPO, and SOD) in serum from CHB patients after LdT treatment, and found that CK was positively correlated with MDA and LPO, and negatively associated with SOD. These findings indicate that LdT induces CK elevation and oxidative stress associated with imbalance of intracellular Ca2+ in HSKMCs, suggesting that Ca2+/CaMKK2 axis imbalance may underlie human LdT-induced CK elevation. The present findings provide a solid basis for assessing the mechanism of drug-induced CK elevation, which can help develop new tools for the prevention and treatment of diseases associated with drug-induced CK elevation.
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      PubDate: 2017-10-14T13:45:17Z
      DOI: 10.1016/j.bcp.2017.10.005
       
  • Camptothecin and its analog SN-38, the active metabolite of irinotecan,
           inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to
           its DNA target sequence FUSE
    • Authors: Sabrina Khageh Hosseini; Stefanie Kolterer; Marlene Steiner; Victoria von Manstein; Katharina Gerlach; Jörg Trojan; Oliver Waidmann; Stefan Zeuzem; Jörg O. Schulze; Steffen Hahn; Dieter Steinhilber; Volker Gatterdam; Robert Tampé; Ricardo M. Biondi; Ewgenij Proschak; Martin Zörnig
      Abstract: Publication date: Available online 13 October 2017
      Source:Biochemical Pharmacology
      Author(s): Sabrina Khageh Hosseini, Stefanie Kolterer, Marlene Steiner, Victoria von Manstein, Katharina Gerlach, Jörg Trojan, Oliver Waidmann, Stefan Zeuzem, Jörg O. Schulze, Steffen Hahn, Dieter Steinhilber, Volker Gatterdam, Robert Tampé, Ricardo M. Biondi, Ewgenij Proschak, Martin Zörnig
      The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Both molecules prevent in vitro the binding of FUBP1 to its single-stranded target DNA FUSE, and they induce deregulation of FUBP1 target genes in HCC cells. Our results suggest the interference with the FUBP1/FUSE interaction as a further molecular mechanism that, in addition to the inactivation of TOP1, may contribute to the therapeutic potential of CPT/SN-38. Targeting of FUBP1 in HCC therapy with SN-38/irinotecan may be a particularly interesting option because of the high FUBP1 levels in HCC cells and their dependency on FUBP1 expression.
      Graphical abstract image

      PubDate: 2017-10-14T13:45:17Z
      DOI: 10.1016/j.bcp.2017.10.003
       
  • BCRP/ABCG2 and high-alert medications: biochemical, pharmacokinetic,
           pharmacogenetic, and clinical implications
    • Authors: Daiki Hira; Tomohiro Terada
      Abstract: Publication date: Available online 13 October 2017
      Source:Biochemical Pharmacology
      Author(s): Daiki Hira, Tomohiro Terada
      The human breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette efflux transporter that uses ATP hydrolysis to expel xenobiotics from cells, including anti-cancer medications. It is expressed in the gastrointestinal tract, liver, kidney, and brain endothelium. Thus, ABCG2 functions as a tissue barrier to drug transport that strongly influences the pharmacokinetics of substrate medications. Genetic polymorphisms of ABCG2 are closely related to inter-individual variations in therapeutic performance. The common single nucleotide polymorphism c.421C>A, p.Q141K reduces cell surface expression of ABCG2 protein, resulting in lower efflux of substrates. Consequently, a higher plasma concentration of substrate is observed in patients carrying an ABCG2 c.421C>A allele. Detailed pharmacokinetic analyses has revealed that altered intestinal absorption is responsible for the distinct pharmacokinetics of ABCG2 substrates in genetic carriers of the ABCG2 c.421C>A polymorphism. Recent studies have focused on the high-alert medications among ABCG2 substrates (defined as those with high risk of adverse events), such as tyrosine kinase inhibitors (TKIs) and direct oral anti-coagulants (DOACs). For these high-alert medications, inter-individual variation may be closely related to the severity of side effects. In addition, ethnic differences in the frequency of ABCG2 c.421C>A have been reported, with markedly higher frequency in East Asian (∼30%–60%) than Caucasian and African-American populations (∼5%–10%). Therefore, ABCG2 polymorphisms must be considered not only in the drug development phase, but also in clinical practice. In the present review, we provide an update of basic and clinical knowledge on genetic polymorphisms of ABCG2.
      Graphical abstract image

      PubDate: 2017-10-14T13:45:17Z
      DOI: 10.1016/j.bcp.2017.10.004
       
  • Editorial Advisory Board
    • Abstract: Publication date: 15 November 2017
      Source:Biochemical Pharmacology, Volume 144


      PubDate: 2017-10-12T07:00:45Z
       
  • Editorial Advisory Board
    • Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143


      PubDate: 2017-09-21T12:54:46Z
       
  • Editorial Advisory Board
    • Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142


      PubDate: 2017-09-21T12:54:46Z
       
 
 
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