Targeting Mevalonate Pathway in Cancer Treatment: Repurposing of Statins.

Recent Pat Anticancer Drug Discov. 2018;13(2):184-200

Authors: Iannelli F, Lombardi R, Milone MR, Pucci B, De Rienzo S, Budillon A, Bruzzese F

Abstract
BACKGROUND: Modifications of lipid metabolism have been progressively accepted as a hallmark of tumor cells and in particular, an elevated lipogenesis has been described in various types of cancers.
OBJECTIVE: Important or deregulated activity of the mevalonate pathway has been demonstrated in different tumors and a wide range of studies have suggested that tumor cells are more dependent on the unceasing availability of mevalonate pathway metabolites than their non-malignant complements.
METHODS: This study provides an overview of the state of the art of statins treatment on human cancer.
RESULTS: In recent times, various actions have been proposed for statins in different physiological and pathological conditions beyond anti-inflammation and neuroprotection activity. Statins have been shown to act through mevalonate-dependent and -independent mechanisms able to affect several tissue functions and modulating specific signal transduction pathways that could account for statin pleiotropic effect. Based on their characteristics, statins represent ideal candidates for repositioning in cancer therapy.
CONCLUSION: In this review article, we provide an overview of the current preclinical and clinical status of statins as antitumor agents. In addition, we evaluated various patents that describe the role of mevalonate pathway inhibitors and methods to determine if cancer cells are sensitive to statins treatment.

PMID: 29189178 [PubMed - indexed for MEDLINE]

The Linked Clinical Trials Initiative (LCT) for Parkinson's disease.

Eur J Neurosci. 2018 Sep 30;:

Authors: Brundin P, Wyse RK

Abstract
The Linked Clinical Trials (LCT) initiative is a drug repurposing program specifically aimed at identifying drugs that can slow the progression of Parkinson's disease (PD). Tom Isaacs was one of the key people behind the idea of LCT in 2011. He ensured it became a priority of The Cure Parkinson's Trust (CPT), a philanthropic funding body based in the UK which Tom had co-founded 7 years earlier. During the latter six years of his life, Tom Isaacs was heavily involved in the LCT initiative and held the program dear to his heart. This article describes the genesis of LCT and how the LCT scientific committee evaluates candidate drugs. From 2012, this committee has met annually to prioritize drugs suitable for repurposing in PD. This article does not catalog every clinical trial within the LCT program, but describes the 10 clinical trials that emerged either directly, or as an offspring from discussions, at the first meeting of the LCT scientific committee. Some, but not all, are funded by CPT, and all 10 trials are now either completed or on-going. These trials use drugs developed to address one of four therapeutic targets: glucagon-like peptide 1 receptor, HMG-CoA reductase, iron, and c-abl tyrosine kinase. We conclude the LCT program has already sparked a large number of promising clinical trials aimed at slowing PD progression. In doing so, it is a major legacy of Tom Isaacs, carrying the torch he once lit and conveying a sense of urgency for new and life-transforming therapies for people with Parkinson's disease. This article is protected by copyright. All rights reserved.

PMID: 30269406 [PubMed - as supplied by publisher]

PISTON: Predicting drug indications and side effects using topic modeling and natural language processing.

J Biomed Inform. 2018 Sep 27;:

Authors: Jang G, Lee T, Hwang S, Park C, Ahn J, Seo S, Hwang Y, Yoon Y

Abstract
The process of discovering novel drugs to treat diseases requires a long time and high cost. It is important to understand side effects of drugs as well as their therapeutic effects, because these can seriously damage the patients due to unexpected actions of the derived candidate drugs. In order to overcome these limitations, computational methods for predicting the therapeutic effects and side effects have been proposed. In particular, text mining is a widely used technique in the field of systems biology, because it can discover hidden relationships between drugs, genes and diseases from a large amount of literature data. Compared with in vivo/in vitro experiments, text mining derives meaningful results with less time and cost. In this study, we propose an algorithm for predicting novel drug-phenotype associations and drug-side effect associations using topic modeling and natural language processing (NLP). We extract sentences in which drugs and genes co-occur from the abstracts of the literature and identify words that describe the relationship between them using NLP. Considering the characteristics of the identified words, we determine if the drug has an up-regulation effect or a down-regulation effect on the gene. Based on genes that affect drugs and their regulatory relationships, we group the frequently occurring genes and regulatory relationships into topics, and build a drug-topic probability matrix by calculating the score that the drug will have a topic using topic modeling. Using the matrix, a classifier is constructed for predicting the novel indications and side effects of drugs considering the characteristics of known drug-phenotype associations or drug-side effect associations. The proposed method predicts both indications and side effects with a single algorithm, and it can exclude drugs with serious side effects or side effects that patients do not want to experience from among the candidate drugs provided for the treatment of the phenotype. Furthermore, lists of novel candidate drugs for phenotypes and side effects can be continuously updated with our algorithm every time a document is added. More than a thousand documents are produced per day, and it is possible for our algorithm to efficiently derive candidate drugs because it requires less cost than the existing drug repositioning methods. The resource of PISTON is available at databio.gachon.ac.kr/tools/PISTON.

PMID: 30268842 [PubMed - as supplied by publisher]

A Large-Scale Gene Expression Intensity-Based Similarity Metric for Drug Repositioning.

iScience. 2018 Sep 28;7:40-52

Authors: Huang CT, Hsieh CH, Oyang YJ, Huang HC, Juan HF

Abstract
Biological systems often respond to a specific environmental or genetic perturbation without pervasive gene expression changes. Such robustness to perturbations, however, is not reflected on the current computational strategies that utilize gene expression similarity metrics for drug discovery and repositioning. Here we propose a new expression-intensity-based similarity metric that consistently achieved better performance than other state-of-the-art similarity metrics with respect to the gold-standard clustering of drugs with known mechanisms of action. The new metric directly emphasizes the genes exhibiting the greatest changes in expression in response to a perturbation. Using the new framework to systematically compare 3,332 chemical and 3,934 genetic perturbations across 10 cell types representing diverse cellular signatures, we identified thousands of recurrent and cell type-specific connections. We also experimentally validated two drugs identified by the analysis as potential topoisomerase inhibitors. The new framework is a valuable resource for hypothesis generation, functional testing, and drug repositioning.

PMID: 30267685 [PubMed]

The thiol-polyamine metabolism of Trypanosoma cruzi: molecular targets and drug repurposing strategies.

Curr Med Chem. 2018 Sep 26;:

Authors: Talevi A, Carrillo C, Comini MA

Abstract
Chagas´ disease continues to be a challenging and neglected public health problem in many American countries. The etiologic agent, Trypanosoma cruzi, develops intracellularly in the mammalian host, which hinders treatment efficacy. Progress in the knowledge of parasite biology and host-pathogen interaction has not been paralleled by the development of novel, safe and effective therapeutic options. It is then urgent to seek for novel therapeutic candidates and to implement drug discovery strategies that may accelerate the discovery process. The most appealing targets for pharmacological intervention are those essential for the pathogen and, whenever possible, absent or significantly different from the host homolog. The thiol-polyamine metabolism of T. cruzi offers interesting candidates for a rational design of selective drugs. In this respect, here we critically review the state of the art of the thiol-polyamine metabolism of T. cruzi and the pharmacological potential of its components. On the other hand, drug repurposing emerged as a valid strategy to identify new biological activities for drugs in clinical use, while significantly shortening the long time and high cost associated with de novo drug discovery approaches. Thus, we also discuss the different drug repurposing strategies available with a special emphasis in their applications to the identification of drug candidates targeting essential components of the thiol-polyamine metabolism of T. cruzi.

PMID: 30259812 [PubMed - as supplied by publisher]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

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6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2018/09/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Auranofin and its Analogues Show Potent Antimicrobial Activity Covering Multiresistant Pathogens: Structure-Activity Relationships.

ChemMedChem. 2018 Sep 25;:

Authors: Marzo T, Cirri D, Pollini S, Prato M, Fallani S, Cassetta MI, Novelli A, Rossolini GM, Messori L

Abstract
Due to the so called "antibiotic resistance crisis" new antibacterial agents are urgently sought to treat multi-resistant pathogens. A group of gold- or silver-based complexes, of general formula M(PEt3)X (with M=Au or Ag, and X=Cl, Br or I), alongside with three complexes bearing a positive or negative charge, i.e. [Au(PEt3)2]Cl, K[Au(CN)2] and [Ag(PEt3)2]NO3, have been prepared and comparatively tested with Auranofin (AF) toward a representative panel of pathogens including Gram-positive, Gram-negative and Candida strains. Interestingly, all tested gold and silver complexes are active on Gram-positive strains, with the gold complexes presenting a greater efficacy. The effects of the gold compounds are potentiated to a larger extent than silver compounds when tested in combination with a permeabilizing agent. A few relevant structure-activity relationships emerge from comparative analysis of the obtained antibacterial profiles shedding new light on the underlying molecular mechanisms.

PMID: 30252208 [PubMed - as supplied by publisher]

Synergistic combination of flavopiridol and carfilzomib targets commonly dysregulated pathways in adrenocortical carcinoma and has biomarkers of response.

Oncotarget. 2018 Aug 31;9(68):33030-33042

Authors: Nilubol N, Boufraqech M, Zhang L, Gaskins K, Shen M, Zhang YQ, Gara SK, Austin CP, Kebebew E

Abstract
Drug repurposing is an effective approach to identify active drugs with known toxicity profiles for rare cancers such as ACC. The objective of this study was to determine the anticancer activity of combination treatment for ACC from previously identified candidate agents using quantitative high-throughput screening (qHTS). In this study, we evaluated the anticancer activity of flavopiridol and carfilzomib in three ACC cell lines in vitro and in vivo. Human ACC samples were analyzed for drug-target analysis, and cancer-related pathway arrays were used to identify biomarkers of treatment response. Because flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor, we found significantly higher CDK1 and CDK2 mRNA expression in three independent cohorts human ACC (p<0.01) and CDK1 protein by immunohistochemistry (p<0.01) in human ACC samples. In vitro treatment with flavopiridol and carfilzomib in all three ACC cell lines resulted in a dose-dependent, anti-proliferative effect, and the combination had synergistic activity as well as in three-dimensional tumor spheroids. We observed increased G2M cell-cycle arrest and apoptosis with combination treatment compared to other groups in vitro. The combination treatment decreased XIAP protein expression in ACC cell lines. Mice with human ACC xenografts treated with flavopiridol and carfilzomib had significantly lower tumor burden, compared to other groups (p<0.05). We observed increased cleaved-caspase expression and decreased XIAP in tumor xenografts of mice treated with combined agents. Our preclinical data supports the evaluation of combination therapy with flavopiridol and carfilzomib in patients with advanced ACC.

PMID: 30250647 [PubMed]

Proscillaridin A exerts anti-tumor effects through GSK3β activation and alteration of microtubule dynamics in glioblastoma.

Cell Death Dis. 2018 Sep 24;9(10):984

Authors: Berges R, Denicolai E, Tchoghandjian A, Baeza-Kallee N, Honore S, Figarella-Branger D, Braguer D

Abstract
Glioblastoma (GBM) is characterized by highly aggressive growth and invasive behavior. Due to the highly lethal nature of GBM, new therapies are urgently needed and repositioning of existing drugs is a promising approach. We have previously shown the activity of Proscillaridin A (ProA), a cardiac glycoside inhibitor of the Na(+)/K(+) ATPase (NKA) pump, against proliferation and migration of GBM cell lines. ProA inhibited tumor growth in vivo and increased mice survival after orthotopic grafting of GBM cells. This study aims to decipher the mechanism of action of ProA in GBM tumor and stem-like cells. ProA displayed cytotoxic activity on tumor and stem-like cells grown in 2D and 3D culture, but not on healthy cells as astrocytes or oligodendrocytes. Even at sub-cytotoxic concentration, ProA impaired cell migration and disturbed EB1 accumulation at microtubule (MT) plus-ends and MT dynamics instability. ProA activates GSK3β downstream of NKA inhibition, leading to EB1 phosphorylation on S155 and T166, EB1 comet length shortening and MT dynamics alteration, and finally inhibition of cell migration and cytotoxicity. Similar results were observed with digoxin. Therefore, we disclosed here a novel pathway by which ProA and digoxin modulate MT-governed functions in GBM tumor and stem-like cells. Altogether, our results support ProA and digoxin as potent candidates for drug repositioning in GBM.

PMID: 30250248 [PubMed - in process]

Old wines in new bottles: Repurposing opportunities for Parkinson's disease.

Eur J Pharmacol. 2018 Jul 05;830:115-127

Authors: Kakkar AK, Singh H, Medhi B

Abstract
Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by accumulation of Lewy bodies and profound loss of substantia nigra dopaminergic neurons. PD symptomatology is now recognized to include both cardinal motor as well as clinically significant non-motor symptoms. Despite intensive research, the current understanding of molecular mechanisms underlying neurodegeneration in PD is limited and has hampered the development of novel symptomatic and disease modifying therapies. The currently available treatment options are only partially or transiently effective and fail to restore the lost dopaminergic neurons or retard disease progression. Given the escalating drug development costs, lengthening timelines and declining R&D efficiency, industry and academia are increasingly focusing on ways to repurpose existing molecules as an accelerated route for drug discovery. The field of PD therapeutics is witnessing vigorous repurposing activity supported by big data analytics, computational models, and high-throughput drug screening systems. Here we review the mechanisms, efficacy, and safety of several emerging drugs currently aspiring to be repositioned for PD pharmacotherapy.

PMID: 29689247 [PubMed - indexed for MEDLINE]

Repurposing itraconazole to the benefit of skin cancer treatment: A combined azole-DDAB nanoencapsulation strategy.

Colloids Surf B Biointerfaces. 2018 Jul 01;167:337-344

Authors: Carbone C, Martins-Gomes C, Pepe V, Silva AM, Musumeci T, Puglisi G, Furneri PM, Souto EB

Abstract
In this work, we aimed at developing an improved topical SLN formulation combining itraconazole delivery with a coating layer of didodecyldimethylammonium bromide, thus repurposing the drug effectiveness by synergistic skin anticancer effectiveness. In order to obtain a stable SLN formulation with small homogeneously dispersed particles, a deep formulative study was developed screening three different solid lipids (Suppocire NB, Cetyl Palmitate and Dynasan 114) for the SLN preparation by the phase inversion temperature. A bluishcolored shade formulation, with homogeneous small particles size (<50 nm) was obtained only using Suppocire NB. The cytotoxicity of all SLN was tested after 24 h exposure against three adherent skin cell lines (A431, HaCaT and SK-MEL-5). Results demonstrate that both unloaded and drugloaded SLN did not significantly affect the cell viability of the non-tumoral HaCaT cell line, thus confirming the safe potential topical application of these formulations. A dose-dependent decrease in cell viability was observed for the tumoral cell lines, A431 and SK-MEL-5, with a significant reduction of the A431 cancer cell line viability. The drug molecule addition to the uncoated nanoparticles was able to increase of almost 20% the reduction of the viability of the cancer cells treated. Ours results demonstrate the potentiality of repurposing itraconazole activity by using the combined nanoencapsulation strategy with the positively charged coating layer on SLN, which can be further investigated as a promising stable and safe approach to significantly reduce the viability of skin cancer cells.

PMID: 29684903 [PubMed - indexed for MEDLINE]

Drug repurposing for Ebola virus disease: principles of consideration and the Animal Rule.

J Pharm Sci. 2018 Sep 19;:

Authors: Bai JPF, Hsu CW

Abstract
There are no approved drugs or biologics to treat Ebola virus disease (EVD). Literature reviews identified a list of 141 drugs with reports of preliminary in-vitro potency and/or in-vivo effectiveness in animals or with reports of clinical use/trials in EVD patients. The majority of these drugs have been individually approved by the US Food and Drug Administration for treating various non-EVD diseases. The anti-Ebola potency data of these drugs were curated from literature and publicly accessible databases, along with their individual biopharmaceutical and pharmacokinetic characteristics. To facilitate the development of anti-viral drugs including anti-EVD drugs, highlights include optimization of the exposure response relationship, design of a safe and effective clinical dosing regimen to achieve an adequate high ratio of clinical Cmin to a plasma protein binding-adjusted EC95, and the pharmacokinetic studies needed in animal models (healthy and affected) and in healthy volunteers. The exposure/response relationship for human dose selection is summarized, as described in the FDA "Animal Rule'' guidance when human efficacy studies are not ethical or feasible.

PMID: 30244014 [PubMed - as supplied by publisher]

Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells.

J Exp Clin Cancer Res. 2018 Sep 21;37(1):236

Authors: Veschi S, De Lellis L, Florio R, Lanuti P, Massucci A, Tinari N, De Tursi M, di Sebastiano P, Marchisio M, Natoli C, Cama A

Abstract
BACKGROUND: Pancreatic cancer (PC) is the fourth most common cause of cancer death. Combination therapies with classical chemotherapeutic agents improved treatment of advanced PC at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%. Consequently, new therapeutic options for this disease are urgently needed. In this study, we explored the effect of two repurposed drug candidates nelfinavir and nitroxoline, approved for non-anticancer human use, in PC cell lines. Nelfinavir and nitroxoline were tested as single agents, or in combinations with or without erlotinib, a targeted drug approved for PC treatment.
METHODS: The effects of the drugs on the viability of AsPC-1, Capan-2 and BxPC-3 PC cell lines were assessed by MTT. The impact of the treatments on cell cycle distribution and apoptosis was analyzed by flow cytometry. The effects of treatments on proteins relevant in cell cycle regulation and apoptosis were evaluated by western blot. Self-renewal capacity of PC cell lines after drug treatments was assessed using a clonogenic assay.
RESULTS: When used as single agents, nelfinavir and nitroxoline decreased viability, affected cell cycle and reduced the expression of relevant cell cycle proteins. The effects on apoptosis were variable among PC cell lines. Moreover, these agents drastically impaired clonogenic activity of the three PC cell lines. Combinations of nelfinavir and nitroxoline, with or without erlotinib, resulted in dose- and cell-dependent synergistic effects on cell viability. These effects were paralleled by cell cycle alterations and more consistent apoptosis induction as compared to single agents. Treatments with drug combinations induced drastic impairment of clonogenic activity in the three cell lines.
CONCLUSIONS: This study shows that two non-antitumor drugs, nelfinavir and nitroxoline, as single agents or in combination have antitumor effects that appear comparable, or in some case more pronounced than those of erlotinib in three PC cell lines. Our results support repurposing of these approved drugs as single agents or in combination for PC treatment.

PMID: 30241558 [PubMed - in process]

Interview with Farid Khan, PhD.

Assay Drug Dev Technol. 2016 12;14(10):551-553

Authors:

PMID: 27922743 [PubMed - indexed for MEDLINE]

Application of molecular framework-based data-mining method in the search for beta-secretase 1 inhibitors through drug repurposing.

J Biomol Struct Dyn. 2018 Sep 20;:1-30

Authors: Ion GND, Mihai DP, Lupascu G, Nitulescu GM

Abstract
Targeting beta-secretase 1, also known as beta-amyloid precursor protein cleaving enzyme (BACE-1) for the inhibition of amyloid production has been intensely studied in the last decades in the search for stopping Alzheimer's disease progression. The chances of finding a druggable BACE-1 inhibitor may be increased by drug repurposing, as this kind of molecules already fulfil certain requirements needed for further advancement. The study describes the development and application of a data mining method based on molecular frameworks and descriptor values of tested BACE-1 inhibitors, suitable for filtering large compound databases, in order to find molecules with high potency against this protease. 465 compounds extracted from the literature, tested against BACE-1, were analysed for finding molecular descriptor values and frameworks that ensure a high probability of strong inhibition. Resulting conclusions were used for filtering DrugBank database, containing ∼8700 approved and experimental drugs, obtaining 26 structures characterised by 4 major Bemis-Murcko frameworks: 2-[3-(2-cyclohexylethyl)cyclohexyl]-decahydronaphthalene, 3-(2-cyclohexylethyl)-1,1'-bi(cyclohexane), [5-(cyclohexylmethyl)-8-cyclopentyloctyl]cyclohexane and (3-cyclohexylcyclopentyl)cyclohexane. The compounds were further studied by molecular docking using the structure of the closed form of the enzyme, which revealed 7 compounds already involved in trials targeting BACE-1 inhibition, confirming the method's specificity. The compounds that afforded the best binding energies were DB06925 (tyrosine-protein kinase inhibitor), DB12285 (Verubecestat) and DB08899 (Enzalutamide). Moreover, docking results indicated several other molecules with high in silico inhibitory potency that can be further studied for developing a potential treatment for Alzheimer's disease.

PMID: 30234434 [PubMed - as supplied by publisher]

Elesclomol restores mitochondrial function in genetic models of copper deficiency.

Proc Natl Acad Sci U S A. 2018 08 07;115(32):8161-8166

Authors: Soma S, Latimer AJ, Chun H, Vicary AC, Timbalia SA, Boulet A, Rahn JJ, Chan SSL, Leary SC, Kim BE, Gitlin JD, Gohil VM

Abstract
Copper is an essential cofactor of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Inherited loss-of-function mutations in several genes encoding proteins required for copper delivery to CcO result in diminished CcO activity and severe pathologic conditions in affected infants. Copper supplementation restores CcO function in patient cells with mutations in two of these genes, COA6 and SCO2, suggesting a potential therapeutic approach. However, direct copper supplementation has not been therapeutically effective in human patients, underscoring the need to identify highly efficient copper transporting pharmacological agents. By using a candidate-based approach, we identified an investigational anticancer drug, elesclomol (ES), that rescues respiratory defects of COA6-deficient yeast cells by increasing mitochondrial copper content and restoring CcO activity. ES also rescues respiratory defects in other yeast mutants of copper metabolism, suggesting a broader applicability. Low nanomolar concentrations of ES reinstate copper-containing subunits of CcO in a zebrafish model of copper deficiency and in a series of copper-deficient mammalian cells, including those derived from a patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function of missing transporters and chaperones of copper, and may have potential in treating human disorders of copper metabolism.

PMID: 30038027 [PubMed - indexed for MEDLINE]

Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms.

Anticancer Res. 2018 Sep;38(9):5149-5157

Authors: Kim JY, Son JY, Lee BM, Kim HS, Yoon S

Abstract
BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment.
MATERIALS AND METHODS: Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells.
RESULTS: DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID.
CONCLUSION: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

PMID: 30194162 [PubMed - indexed for MEDLINE]

[Identification of key pathways and drug repurposing for anaplastic thyroid carcinoma by integrated bioinformatics analysis].

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2018 May 25;47(2):187-193

Authors: Pan Z, Fang Q, Zhang Y, Li L, Huang P

Abstract
OBJECTIVE: To identify hub genes and key pathways associated with anaplastic thyroid carcinoma (ATC), and to explore possible intervention strategy.
METHODS: The differentially expressed genes (DEGs) in ATC were identified by Gene Expression Omnibus (GEO) combined with using R language; the pathway enrichment of DEGs were performed by using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The protein-protein interaction (PPI) network of DEGs was constructed by STRING database and visualized by Cytoscape. Furthermore, the hub genes and key nodes were calculated by MCODE. Finally, the drug repurposing was performed by L1000CDS2.
RESULTS: A total of 2087 DEGs were identified. The DEGs were clustered based on functions and pathways with significant enrichment analysis, among which PI3K-Akt signaling pathway, p53 signaling pathway, inflammatory response, extracellular matrix organization were significantly upregulated. The PPI network was constructed and the most significant three modules and nine genes were filtered. Twenty-two potential compounds were repurposed for ATC treatment.
CONCLUSIONS: Using integrated bioinformatics analysis, we have identified hub genes and key pathways in ATC, and provide novel strategy for the treatment of ATC.

PMID: 30226315 [PubMed - in process]

Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen.

Antimicrob Agents Chemother. 2018 Sep 17;:

Authors: Li B, Wang Y, Shen F, Wu M, Li Y, Fang Z, Ye J, Wang L, Gao L, Yuan Z, Chen J

Abstract
Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia, but induce hepatitis B surface antigen (HBsAg) loss in a very few patients and do not much affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, Tazarotene exhibited the most potent anti-HBV effect with an IC50 for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected dHepaRG models, but not in HepG2.215 cells, and HBV genotype A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA, RNAs and the activation of HBV promoters. Moreover, RNA-sequence analysis showed that Tazarotene did not induce an interferon response, but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by specific antagonist significantly attenuated the anti-HBV activity of Tazarotene, suggesting Tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of Tazarotene and Entecavir on HBV-DNA levels was observed. Therefore, RAR agonists as represented by Tazarotene were identified as potential novel anti-HBV agents.

PMID: 30224536 [PubMed - as supplied by publisher]