Zingerone Nanotetramer Strengthened the Polypharmacological Efficacy of Zingerone on Human Hepatoma Cell Lines.

ACS Appl Mater Interfaces. 2018 Dec 19;:

Authors: Kung ML, Lin PY, Huang ST, Tai MH, Hsieh SL, Wu CC, Yeh BW, Wu WJ, Hsieh S

Abstract
We base this study on the concept of drug repositioning to reconstitute the natural product of zingerone as zingerone nanoparticles (zingerone NPs) through a one-pot synthesized process. The as-fabricated zingerone NPs were characterized; they possessed a particle size of 1.42 ± 0.67 nm and a reconstituted structure of zingerone nanotetramer. We further validate the effects of zingerone NPs on the antitumor activity and investigate the relative underlying mechanisms on the human hepatoma SK-Hep-1 and Huh7 cell lines. Our results demonstrated that zingerone NPs significantly inhibit Akt activity and NFκB expression as well as activate the caspases cascade signaling pathway which are involved in the antiproliferation, antitumorigenicity, disturbing cell cycle progression, and induction of DNA damage as well as cell apoptosis. These findings were promising to provide a "Nano-chemoprevention" strategy in future cancer therapeutics and medical and clinical applications.

PMID: 30566322 [PubMed - as supplied by publisher]

Systematic polypharmacology and drug repurposing via an integrated L1000-based Connectivity Map database mining.

R Soc Open Sci. 2018 Nov;5(11):181321

Authors: Liu TP, Hsieh YY, Chou CJ, Yang PM

Abstract
Drug repurposing aims to find novel indications of clinically used or experimental drugs. Because drug data already exist, drug repurposing may save time and cost, and bypass safety concerns. Polypharmacology, one drug with multiple targets, serves as a basis for drug repurposing. Large-scale databases have been accumulated in recent years, and utilization and integration of these databases would be highly helpful for polypharmacology and drug repurposing. The Connectivity Map (CMap) is a database collecting gene-expression profiles of drug-treated human cancer cells, which has been widely used for investigation of polypharmacology and drug repurposing. In this study, we integrated the next-generation L1000-based CMap and an analytic Web tool, the L1000FWD, for systematic analyses of polypharmacology and drug repurposing. Two different types of anti-cancer drugs were used as proof-of-concept examples, including histone deacetylase (HDAC) inhibitors and topoisomerase inhibitors. We identified KM-00927 and BRD-K75081836 as novel HDAC inhibitors and mitomycin C as a topoisomerase IIB inhibitor. Our study provides a prime example of utilization and integration of the freely available public resources for systematic polypharmacology analysis and drug repurposing.

PMID: 30564416 [PubMed]

Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer.

Mol Cancer. 2018 Dec 18;17(1):175

Authors: Hong SK, Lee H, Kwon OS, Song NY, Lee HJ, Kang S, Kim JH, Kim M, Kim W, Cha HJ

Abstract
Even when targets responsible for chemoresistance are identified, drug development is often hampered due to the poor druggability of these proteins. We systematically analyzed therapy-resistance with a large-scale cancer cell transcriptome and drug-response datasets and predicted the candidate drugs based on the gene expression profile. Our results implicated the epithelial-mesenchymal transition as a common mechanism underlying resistance to chemotherapeutic drugs. Notably, we identified ITGB3, whose expression was abundant in both drug resistance and mesenchymal status, as a promising target to overcome chemoresistance. We also confirmed that depletion of ITGB3 sensitized cancer cells to conventional chemotherapeutic drugs by modulating the NF-κB signaling pathway. Considering the poor druggability of ITGB3 and the lack of feasible drugs to directly inhibit this protein, we took an in silico screening for drugs mimicking the transcriptome-level changes caused by knockdown of ITGB3. This approach successfully identified atorvastatin as a novel candidate for drug repurposing, paving an alternative path to drug screening that is applicable to undruggable targets.

PMID: 30563517 [PubMed - in process]

[New indications for existing drugs; repurposing in psychiatry and addiction medicine].

Ned Tijdschr Geneeskd. 2018 May 02;162:

Authors: Strous JFM, van den Brink W

Abstract
Repurposing is the discovery - whether or not by accident - of a new use for an existing product, for example, a new indication for a drug. In the past, several psychotropic drugs have received their place in the treatment arsenal via this route. Both in psychiatry and addiction medicine, there is an important need for new treatments with new working mechanisms. Potential new uses in both psychiatry and addiction medicine of several drugs that have already been registered for other indications are currently under study. For example, the anaesthetic ketamine is found to have a strong antidepressant effect. In addition, both the anti-epileptic topiramate and the muscle-relaxant baclofen could possibly prevent relapse in addictive behaviours.

PMID: 30020573 [PubMed - indexed for MEDLINE]

Unexpected Exacerbation of Neuroinflammatory Response After a Combined Therapy in Old Parkinsonian Mice.

Front Cell Neurosci. 2018;12:451

Authors: Gil-Martínez AL, Cuenca L, Estrada C, Sánchez-Rodrigo C, Fernández-Villalba E, Herrero MT

Abstract
The design of therapeutic strategies that focus on the repositioning of anti-inflammatory and antioxidant drugs are a great bet to slow down the progression of neurodegenerative disorders. Despite the fact that Parkinson's disease (PD) is an age-related pathology, almost all experimental studies are carried out in young animals. Here, we evaluated the possible neuroprotective effect of the combination of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory HA-1077 in aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (C57BL/6 mice, 20 months old), whose individual treatment has been shown to have neuroprotective effects in this Parkinsonism model. Interestingly, NAC+HA-1077-based treatment produced a significant increase in dopaminergic neuronal death accompanied by an increase in microglial and astroglial activation in the Substantia Nigra pars compacta (SNpc) and striatum of old-Parkinsonian mice compared to their control group. The astroglial response was also explored by co-immunostaining for GFAP and S100b together with p-JNK and it was found to be particularly exacerbated in the MPTP+NAC+HA-1077 group. The unexpected toxic effects found in the combined use of NAC and HA-1077 in old-Parkinsonian mice highlight the importance of taking into account that in elderly Parkinsonian patients the combination of some drugs (most of them used for other different age-related alterations) can have side effects that may result in the exacerbation of the neurodegenerative process.

PMID: 30559650 [PubMed]

NeoDTI: neural integration of neighbor information from a heterogeneous network for discovering new drug-target interactions.

Bioinformatics. 2019 Jan 01;35(1):104-111

Authors: Wan F, Hong L, Xiao A, Jiang T, Zeng J

Abstract
Motivation: Accurately predicting drug-target interactions (DTIs) in silico can guide the drug discovery process and thus facilitate drug development. Computational approaches for DTI prediction that adopt the systems biology perspective generally exploit the rationale that the properties of drugs and targets can be characterized by their functional roles in biological networks.
Results: Inspired by recent advance of information passing and aggregation techniques that generalize the convolution neural networks to mine large-scale graph data and greatly improve the performance of many network-related prediction tasks, we develop a new nonlinear end-to-end learning model, called NeoDTI, that integrates diverse information from heterogeneous network data and automatically learns topology-preserving representations of drugs and targets to facilitate DTI prediction. The substantial prediction performance improvement over other state-of-the-art DTI prediction methods as well as several novel predicted DTIs with evidence supports from previous studies have demonstrated the superior predictive power of NeoDTI. In addition, NeoDTI is robust against a wide range of choices of hyperparameters and is ready to integrate more drug and target related information (e.g. compound-protein binding affinity data). All these results suggest that NeoDTI can offer a powerful and robust tool for drug development and drug repositioning.
Availability and implementation: The source code and data used in NeoDTI are available at: https://github.com/FangpingWan/NeoDTI.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 30561548 [PubMed - in process]

Spironolactone as an antischistosomal drug capable of clinical repurposing: in vitro and in vivo studies.

Antimicrob Agents Chemother. 2018 Dec 17;:

Authors: Guerra RA, Silva MP, Silva TC, Salvadori MC, Teixeira FS, de Oliveira RN, Rocha JA, Pinto PLS, de Moraes J

Abstract
Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (< 10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harbouring either patent or pre-patent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P<0.05 to P<0.001). Taken together with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for re-purposing.

PMID: 30559137 [PubMed - as supplied by publisher]

Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations.

Biomolecules. 2018 Dec 14;8(4):

Authors: Correia A, Silva D, Correia A, Vilanova M, Gärtner F, Vale N

Abstract
Cancer is a disease that affects and kills millions of people worldwide. Breast cancer, especially, has a high incidence and mortality, and is challenging to treat. Due to its high impact on the health sector, oncological therapy is the subject of an intense and very expensive research. To improve this therapy and reduce its costs, strategies such as drug repurposing and drug combinations have been extensively studied. Drug repurposing means giving new usefulness to drugs which are approved for the therapy of various diseases, but, in this case, are not approved for cancer therapy. On the other hand, the purpose of combining drugs is that the response that is obtained is more advantageous than the response obtained by the single drugs. Using drugs with potential to be repurposed, combined with 5-fluorouracil, the aim of this project was to investigate whether this combination led to therapeutic benefits, comparing with the isolated drugs. We started with a screening of the most promising drugs, with verapamil and itraconazole being chosen. Several cellular viability studies, cell death and proliferation studies, mainly in MCF-7 cells (Michigan Cancer Foundation-7, human breast adenocarcinoma cells) were performed. Studies were also carried out to understand the effect of the drugs at the level of possible therapeutic resistance, evaluating the epithelial-mesenchymal transition. Combining all the results, the conclusion is that the combination of verapamil and itraconazole with 5-fluorouracil had benefits, mainly by decreasing cell viability and proliferation. Furthermore, the combination of itraconazole and 5-fluorouracil seemed to be the most effective, being an interesting focus in future studies.

PMID: 30558247 [PubMed - in process]

Deep Learning in Drug Discovery and Medicine; Scratching the Surface.

Molecules. 2018 Sep 18;23(9):

Authors: Dana D, Gadhiya SV, St Surin LG, Li D, Naaz F, Ali Q, Paka L, Yamin MA, Narayan M, Goldberg ID, Narayan P

Abstract
The practice of medicine is ever evolving. Diagnosing disease, which is often the first step in a cure, has seen a sea change from the discerning hands of the neighborhood physician to the use of sophisticated machines to use of information gleaned from biomarkers obtained by the most minimally invasive of means. The last 100 or so years have borne witness to the enormous success story of allopathy, a practice that found favor over earlier practices of medical purgatory and homeopathy. Nevertheless, failures of this approach coupled with the omics and bioinformatics revolution spurred precision medicine, a platform wherein the molecular profile of an individual patient drives the selection of therapy. Indeed, precision medicine-based therapies that first found their place in oncology are rapidly finding uses in autoimmune, renal and other diseases. More recently a new renaissance that is shaping everyday life is making its way into healthcare. Drug discovery and medicine that started with Ayurveda in India are now benefiting from an altogether different artificial intelligence (AI)-one which is automating the invention of new chemical entities and the mining of large databases in health-privacy-protected vaults. Indeed, disciplines as diverse as language, neurophysiology, chemistry, toxicology, biostatistics, medicine and computing have come together to harness algorithms based on transfer learning and recurrent neural networks to design novel drug candidates, a priori inform on their safety, metabolism and clearance, and engineer their delivery but only on demand, all the while cataloging and comparing omics signatures across traditionally classified diseases to enable basket treatment strategies. This review highlights inroads made and being made in directed-drug design and molecular therapy.

PMID: 30231499 [PubMed - indexed for MEDLINE]

Incretins: Beyond type 2 diabetes.

Diabetes Obes Metab. 2018 02;20 Suppl 1:59-67

Authors: Dandona P, Ghanim H, Chaudhuri A

Abstract
While the use of incretins, including GLP-1 receptor agonists and PDD-IV inhibitors, is well established in the treatment of type 2 diabetes, many other aspects of these agents are yet to be discovered and utilized for their potential clinical benefit. These include the potential role of GLP-1 receptor agonists in the induction of weight loss, blood pressure reduction, anti-inflammatory and nephro- and cardio-protective actions. Their potential benefit in type 1 diabetes is also being investigated. This review will attempt to comprehensively describe novel discoveries in the field of incretin pathophysiology and pharmacology beyond their classical role in the treatment of type 2 diabetes.

PMID: 29364583 [PubMed - indexed for MEDLINE]

An update on Drug Repurposing: Re-written saga of the drug's fate.

Biomed Pharmacother. 2018 Dec 12;110:700-716

Authors: Gns HS, Gr S, Murahari M, Krishnamurthy M

Abstract
Drug repurposing is an unconventional drug discovery approach to explore new therapeutic benefits of existing, shelved and the drugs in clinical trials. This approach is currently emerging to overcome the bottleneck constraints faced during traditional drug discovery in grounds of financial support, timeline and resources. In this direction, several efforts were made for the construction of stratagems based on bioinformatics and computational tools to intensify the repurposing process off-late. Further, advanced research has succeeded in widening its boundaries in identification of gene targets and subsequent molecular interactions of the drugs depending on available omics data. Currently, the advent of data repositories like Connectivity Map (CMap), Library Integrated Network based Cellular Signatures (LINCS), Genome Wide Association Studies (GWAS), Side Effect Resource (SIDER), and Directionality Map (DMAP) has bestowed great oppurtunity to the researchers in improving their drug repurposing research exponentially. On the otherhand, in silico approaches like pharmacophore modelling and docking techniques circumvent the routine tedious in vitro and in vivo techniques involved in former screening phases of the drugs and disease specific targets. This review elaborates on currently designed contemporary tools, databases and strategies with relevant case studies.

PMID: 30553197 [PubMed - as supplied by publisher]

Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis.

Ann Rheum Dis. 2018 Dec 14;:

Authors: Aterido A, Cañete JD, Tornero J, Ferrándiz C, Pinto JA, Gratacós J, Queiró R, Montilla C, Torre-Alonso JC, Pérez-Venegas JJ, Fernández Nebro A, Muñoz-Fernández S, González CM, Roig D, Zarco P, Erra A, Rodríguez J, Castañeda S, Rubio E, Salvador G, Díaz-Torné C, Blanco R, Willisch Domínguez A, Mosquera JA, Vela P, Sánchez-Fernández SA, Corominas H, Ramírez J, de la Cueva P, Fonseca E, Fernández E, Puig L, Dauden E, Sánchez-Carazo JL, López-Estebaranz JL, Moreno D, Vanaclocha F, Herrera E, Blanco F, Fernández-Gutiérrez B, González A, Pérez-García C, Alperi-López M, Olivé Marques A, Martínez-Taboada V, González-Álvaro I, Sanmartí R, Tomás Roura C, García-Montero AC, Bonàs-Guarch S, Mercader JM, Torrents D, Codó L, Gelpí JL, López-Corbeto M, Pluma A, López-Lasanta M, Tortosa R, Palau N, Absher D, Myers R, Marsal S, Julià A

Abstract
OBJECTIVE: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA.
METHODS: We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case-control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA.
RESULTS: We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs.
CONCLUSION: These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.

PMID: 30552173 [PubMed - as supplied by publisher]

The exploration of novel Alzheimer's therapeutic agents from the pool of FDA approved medicines using drug repositioning, enzyme inhibition and kinetic mechanism approaches.

Biomed Pharmacother. 2019 Jan;109:2513-2526

Authors: Hassan M, Raza H, Abbasi MA, Moustafa AA, Seo SY

Abstract
Novel drug development is onerous, time consuming and overpriced process with particularly low success and relatively high enfeebling rates. To overcome this burden, drug repositioning approach is being used to predict the possible therapeutic effects of FDA approved drugs in different diseases. Herein, we designed a computational and enzyme inhibitory mechanistic approach to fetch the promising drugs from the pool of FDA approved drugs against AD. The binding interaction patterns and conformations of screened drugs within active region of AChE were confirmed through molecular docking profiles. The possible associations of selected drugs with AD genes were predicted by pharmacogenomics analysis and confirmed through data mining. The stability behaviour of docked complexes (Drugs-AChE) were checked by MD simulations. The possible therapeutic potential of repositioned drugs against AChE were checked by in vitro analysis. Taken together, Cinitapride displayed a comparable results with standard and can be used as possible therapeutic agent in the treatment of AD.

PMID: 30551512 [PubMed - in process]

21 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 2018/12/14

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.

Basics on the use of acid-sensing ion channels' inhibitors as therapeutics.

Neural Regen Res. 2019 Mar;14(3):395-398

Authors: Dibas J, Al-Saad H, Dibas A

Abstract
Since the discovery of acid-sensing ion channels in 1997, their importance in the health of neurons and other non-neuronal cells has gained significant importance. Acid-sensing ion channels play important roles in mediating pain sensation during diseases such as stroke, inflammation, arthritis, cancer, and recently migraine. More interestingly, acid-sensing ion channels may explain the sex differences in pain between males and females. Also, the ability of acid-sensing ion channel blockers to exert neuroprotective effects in a number of neurodegenerative diseases has added a new dimension to their therapeutic value. The current failure rate of ~45% of new drugs (due to toxicity issues) and saving of up to 7 years in the life span of drug approval makes drug repurposing a high priority. If acid-sensing ion channels' blockers undergo what is known as "drug repurposing", there is a great potential to bring them as medications with known safety profiles to new patient populations. However, the route of administration remains a big challenge due to their poor penetration of the blood brain and retinal barriers. In this review, the promise of using acid-sensing ion channel blockers as neuroprotective drugs is discussed.

PMID: 30539804 [PubMed]

Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum.

Mem Inst Oswaldo Cruz. 2018 Dec 06;113(12):e180279

Authors: Penna-Coutinho J, Aguiar AC, Krettli/ AU

Abstract
BACKGROUND The main strategy to control human malaria still relies on specific drug treatment, limited now by Plasmodium falciparum-resistant parasites, including that against artemisinin derivatives. Despite the large number of active compounds described in the literature, few of them reached full development against human malaria. Drug repositioning is a fast and less expensive strategy for antimalarial drug discovery, because these compounds are already approved for human use. OBJECTIVES To identify new antimalarial drugs from compounds commercially available and used for other indications. METHODS Accuvit®, Ginkgo® and Soyfit®, rich in flavonoids, and also the standard flavonoids, hesperidin, quercetin, and genistein were tested against blood cultures of chloroquine-resistant P. falciparum, as well as chloroquine, a reference antimalarial. Inhibition of parasite growth was measured in immunoenzymatic assay with monoclonal anti-P. falciparum antibodies, specific to the histidine-rich protein II. Tests in mice with P. berghei malaria were based on percent of parasitaemia reduction. These compounds were also evaluated for in vitro cytotoxicity. FINDINGS The inhibition of parasite growth in vitro showed that Accuvit® was the most active drug (IC50 5 ± 3.9 μg/mL). Soyfit® was partially active (IC50 13.6 ± 7.7 μg/mL), and Ginkgo® (IC50 38.4 ± 14 μg/mL) was inactive. All such compounds were active in vivo at a dose of 50 mg/kg body weight. Accuvit® and quercetin induced the highest reduction of P. berghei parasitaemia (63% and 53%, respectively) on day 5 after parasite inoculation. As expected, the compounds tested were not toxic. MAIN CONCLUSIONS The antimalarial activity of Accuvit® was not related to flavonoids only, and it possibly results from synergisms with other compounds present in this drug product, such as multivitamins. Multivitamins in Accuvit® may explain its effect against the malaria parasites. This work demonstrated for the first time the activity of these drugs, which are already marketed.

PMID: 30540020 [PubMed - in process]

miR-9 Upregulation Integrates Post-ischemic Neuronal Survival and Regeneration In Vitro.

Cell Mol Neurobiol. 2018 Dec 11;:

Authors: Nampoothiri SS, Rajanikant GK

Abstract
The irrefutable change in the expression of brain-enriched microRNAs (miRNAs) following ischemic stroke has promoted the development of radical miRNA-based therapeutics encompassing neuroprotection and neuronal restoration. Our previous report on the systems-level prediction of miR-9 in post-stroke-induced neurogenesis served as a premise to experimentally uncover the functional role of miR-9 in post-ischemic neuronal survival and regeneration. The oxygen-glucose deprivation (OGD) in SH-SY5Y cells significantly reduced miR-9 expression, while miR-9 mimic transfection enhanced post-ischemic neuronal cell viability. The next major objective involved the execution of a drug repositioning strategy to augment miR-9 expression via structure-based screening of Food and Drug Administration (FDA)-approved drugs that bind to Histone Deacetylase 4 (HDAC4), a known miR-9 target. Glucosamine emerged as the top hit and its binding potential to HDAC4 was verified by Molecular Dynamics (MD) Simulation, Drug Affinity Responsive Target Stability (DARTS) assay, and MALDI-TOF MS. It was intriguing that the glucosamine treatment 1-h post-OGD was associated with the increased miR-9 level as well as enhanced neuronal viability. miR-9 mimic or post-OGD glucosamine treatment significantly increased the cellular proliferation (BrdU assay), while the neurite outgrowth assay displayed elongated neurites. The enhanced BCL2 and VEGF parallel with the reduced NFκB1, TNF-α, IL-1β, and iNOS mRNA levels in miR-9 mimic or glucosamine-treated cells further substantiated their post-ischemic neuroprotective and regenerative efficacy. Hence, this study unleashes a potential therapeutic approach that integrates neuronal survival and regeneration via small-molecule-based regulation of miR-9 favoring long-term recovery against ischemic stroke.

PMID: 30539420 [PubMed - as supplied by publisher]

GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment.

EMBO Rep. 2018 Dec 11;:

Authors: Cortes E, Sarper M, Robinson B, Lachowski D, Chronopoulos A, Thorpe SD, Lee DA, Del Río Hernández AE

Abstract
The mechanical properties of the tumor microenvironment are emerging as attractive targets for the development of therapies. Tamoxifen, an agonist of the G protein-coupled estrogen receptor (GPER), is widely used to treat estrogen-positive breast cancer. Here, we show that tamoxifen mechanically reprograms the tumor microenvironment through a newly identified GPER-mediated mechanism. Tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells (PSCs) in the tumor microenvironment of pancreatic cancer in an acto-myosin-dependent manner via RhoA-mediated contractility, YAP deactivation, and GPER signaling. This hampers the ability of PSCs to remodel the extracellular matrix and to promote cancer cell invasion. Tamoxifen also reduces the recruitment and polarization to the M2 phenotype of tumor-associated macrophages. Our results highlight GPER as a mechanical regulator of the tumor microenvironment that targets the three hallmarks of pancreatic cancer: desmoplasia, inflammation, and immune suppression. The well-established safety of tamoxifen in clinics may offer the possibility to redirect the singular focus of tamoxifen on the cancer cells to the greater tumor microenvironment and lead a new strategy of drug repurposing.

PMID: 30538117 [PubMed - as supplied by publisher]

10 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 2018/12/12

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.

The Use of Large-Scale Chemically-Induced Transcriptome Data Acquired from LINCS to Study Small Molecules.

Methods Mol Biol. 2019;1888:189-203

Authors: Iwata M, Yamanishi Y

Abstract
Identification of the modes of action of bioactive compounds is an important issue in chemical systems biology. In this chapter we review a recently developed data-driven approach using large-scale chemically induced transcriptome data acquired from the Library of Integrated Network-based Cellular Signatures to elucidate the modes of action of bioactive compounds. First, we present a method for pathway enrichment analyses of regulated genes to reveal biological pathways activated by compounds. Next, we present a method using the pre-knowledge on chemical-protein interactome for predicting potential target proteins, including primary targets and off-targets, with transcriptional similarity. Finally, we present a method based on the target proteins for predicting new therapeutic indications for a variety of diseases. These approaches are expected to be useful for mode-of-action analysis, drug discovery, and drug repositioning.

PMID: 30519948 [PubMed - in process]