Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning.

Front Pharmacol. 2018;9:6

Authors: Langhans SA

Abstract
Drug development is a lengthy and costly process that proceeds through several stages from target identification to lead discovery and optimization, preclinical validation and clinical trials culminating in approval for clinical use. An important step in this process is high-throughput screening (HTS) of small compound libraries for lead identification. Currently, the majority of cell-based HTS is being carried out on cultured cells propagated in two-dimensions (2D) on plastic surfaces optimized for tissue culture. At the same time, compelling evidence suggests that cells cultured in these non-physiological conditions are not representative of cells residing in the complex microenvironment of a tissue. This discrepancy is thought to be a significant contributor to the high failure rate in drug discovery, where only a low percentage of drugs investigated ever make it through the gamut of testing and approval to the market. Thus, three-dimensional (3D) cell culture technologies that more closely resemble in vivo cell environments are now being pursued with intensity as they are expected to accommodate better precision in drug discovery. Here we will review common approaches to 3D culture, discuss the significance of 3D cultures in drug resistance and drug repositioning and address some of the challenges of applying 3D cell cultures to high-throughput drug discovery.

PMID: 29410625 [PubMed]

Repurposing psychiatric drugs as anti-cancer agents.

Cancer Lett. 2018 Feb 01;419:257-265

Authors: Huang J, Zhao D, Liu Z, Liu F

Abstract
Cancer is a major public health problem and one of the leading contributors to the global disease burden. The high cost of development of new drugs and the increasingly severe burden of cancer globally have led to increased interest in the search and development of novel, affordable anti-neoplastic medications. Antipsychotic drugs have a long history of clinical use and tolerable safety; they have been used as good targets for drug repurposing. Being used for various psychiatric diseases for decades, antipsychotic drugs are now reported to have potent anti-cancer properties against a wide variety of malignancies in addition to their antipsychotic effects. In this review, an overview of repurposing various psychiatric drugs for cancer treatment is presented, and the putative mechanisms for the anti-neoplastic actions of these antipsychotic drugs are reviewed.

PMID: 29414306 [PubMed - as supplied by publisher]

Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells.

Oncotarget. 2016 Apr 26;7(17):23772-84

Authors: Aguirre-Alvarado C, Segura-Cabrera A, Velázquez-Quesada I, Hernández-Esquivel MA, García-Pérez CA, Guerrero-Rodríguez SL, Ruiz-Moreno AJ, Rodríguez-Moreno A, Pérez-Tapia SM, Velasco-Velázquez MA

Abstract
CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24- cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists.

PMID: 27009862 [PubMed - indexed for MEDLINE]

Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules.

Pharmaceuticals (Basel). 2018 Feb 05;11(1):

Authors: Gouveia MJ, Brindley PJ, Gärtner F, Costa JMCD, Vale N

Abstract
Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ.

PMID: 29401734 [PubMed]

Microglial role in the development of chronic pain.

Curr Opin Anaesthesiol. 2016 Oct;29(5):584-9

Authors: Suter MR

Abstract
PURPOSE OF REVIEW: The review aims to present the latest research into microglia and their role in pain.
RECENT FINDINGS: Microglia affect sex and age-dependent differences in pain. The various microglial phenotypes make their involvement in pain more complex but provide more potential as pain modulators.
SUMMARY: Glial cells, composed of microglia, astrocytes, and oligodendrocytes, outnumber neurons in the central nervous system. The crosstalk between these cells and neurons is now established as participating in the development of chronic pain. There has been a great advance in the description of microglia reactivity from pro to anti-inflammatory phenotypes. The modulation of these phenotypes could be a potential target for pain therapy. Recently, different microglial reactivity between man and woman and between neonates and adults, in response to nerve injury were described, which could explain some of the sex differences in pain sensitivity and the absence of neuropathic pain development in neonates. Clinical trials using microglia as a target have been carried out in various neurological diseases and pain, with limited efficacy in the latter, but there are nonetheless, indications that with some improvement in study strategies microglia could be a future target for pain control.

PMID: 27496572 [PubMed - indexed for MEDLINE]

Understanding organellar protein folding capacities and assessing their pharmacological modulation by small molecules.

Eur J Cell Biol. 2018 Jan 10;:

Authors: Sharma R, Pramanik MMD, Chandramouli B, Rastogi N, Kumar N

Abstract
Dysfunctional organellar protein quality control machinery leads to protein misfolding associated cardiovascular, neurodegenerative, metabolic and secretory disorders. To understand organellar homeostasis, suitable tools are required which can sense changes in their respective protein folding capacity upon exposure to environmental and pharmacological perturbations. Herein, we have assessed protein folding capacity of cellular organelles using a metastable sensor selectively targeted to cytosol, nucleus, mitochondria, endoplasmic reticulum, golgi and peroxisomes. Microscopy and biochemical data revealed that these sensors report both acute and organelle-specific cellular insults. It also provided insights into contrasting refolding capacities of cellular organelles to recover from proteotoxic challenges. Further, we used these metastable sensors to evaluate pharmacological modulation of organellar protein folding capacity by small molecules. We observed pyrazole based scaffolds increased organellar protein folding capacity through upregulation of chaperones, mainly HSP90 and its co-chaperone HOP which coordinate refolding of misfolded/aggregated species. Overall, our data highlights the potential use of organelle-specific metastable sensors to understand protein folding capacity of sub-cellular compartments and assess pharmacological correction of their proteostasis imbalance. This study also provides additional avenue for use of these organelle-specific metastable sensors in drug discovery programs for identification of novel pharmacophores and drug repositioning of promising scaffolds for protein conformational diseases associated with different cellular organelles.

PMID: 29395478 [PubMed - as supplied by publisher]

Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes.

Invest New Drugs. 2018 Feb 02;:

Authors: Amaral MEA, Nery LR, Leite CE, de Azevedo Junior WF, Campos MM

Abstract
Background Breast cancer is highly prevalent among women worldwide. It is classified into three main subtypes: estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive (HER2+), and triple negative breast cancer (TNBC). This study has evaluated the effects of aspirin and metformin, isolated or in a combination, in breast cancer cells of the different subtypes. Methods The breast cancer cell lines MCF-7, MDA-MB-231, and SK-BR-3 were treated with aspirin and/or metformin (0.01 mM - 10 mM); functional in vitro assays were performed. The interactions with the estrogen receptors (ER) were evaluated in silico. Results Metformin (2.5, 5 and 10 mM) altered the morphology and reduced the viability and migration of the ER+ cell line MCF-7, whereas aspirin triggered this effect only at 10 mM. A synergistic effect for the combination of metformin and aspirin (2.5, 5 or 10 mM each) was observed in the TNBC cell subtype MDA-MB-231, according to the evaluation of its viability and colony formation. Partial inhibitory effects were observed for either of the drugs in the HER2+ cell subtype SK-BR-3. The effects of metformin and aspirin partly relied on cyclooxygenase-2 (COX-2) upregulation, without the production of lipoxins. In silico, metformin and aspirin bound to the ERα receptor with the same energy. Conclusion We have provided novel evidence on the mechanisms of action of aspirin and metformin in breast cancer cells, showing favorable outcomes for these drugs in the ER+ and TNBC subtypes.

PMID: 29392539 [PubMed - as supplied by publisher]

Systematical analysis of lncRNA-mRNA competing endogenous RNA network in breast cancer subtypes.

Breast Cancer Res Treat. 2018 Feb 01;:

Authors: Zhou S, Wang L, Yang Q, Liu H, Meng Q, Jiang L, Wang S, Jiang W

Abstract
BACKGROUND: Breast cancer is one of the most common solid tumors in women involving multiple subtypes. However, the mechanism for subtypes of breast cancer is still complicated and unclear. Recently, several studies indicated that long non-coding RNAs (lncRNAs) could act as sponges to compete miRNAs with mRNAs, participating in various biological processes.
METHODS: We concentrated on the competing interactions between lncRNAs and mRNAs in four subtypes of breast cancer (basal-like, HER2+, luminal A and luminal B), and analyzed the impacts of competing endogenous RNAs (ceRNAs) on each subtype systematically. We constructed four breast cancer subtype-related lncRNA-mRNA ceRNA networks by integrating the miRNA target information and the expression data of lncRNAs, miRNAs and mRNAs.
RESULTS: We constructed the ceRNA network for each breast cancer subtype. Functional analysis revealed that the subtype-related ceRNA networks were enriched in cancer-related pathways in KEGG, such as pathways in cancer, miRNAs in cancer, and PI3k-Akt signaling pathway. In addition, we found three common lncRNAs across the four subtype-related ceRNA networks, NEAT1, OPI5-AS1 and AC008124.1, which played specific roles in each subtype through competing with diverse mRNAs. Finally, the potential drugs for treatment of basal-like subtype could be predicted through reversing the differentially expressed lncRNA in the ceRNA network.
CONCLUSION: This study provided a novel perspective of lncRNA-involved ceRNA network to dissect the molecular mechanism for breast cancer.

PMID: 29388017 [PubMed - as supplied by publisher]

[Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases].

Yakugaku Zasshi. 2018;138(2):185-190

Authors: Uesawa Y

Abstract
　Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.

PMID: 29386432 [PubMed - in process]

Re-activation of cAMP pathway by PDE4D inhibition represents a novel druggable axis for overcoming tamoxifen resistance in ER-positive breast cancer.

Clin Cancer Res. 2018 Jan 31;:

Authors: Mishra RR, Belder N, Ansari SA, Kayhan M, Bal H, Raza U, Ersan PG, Tokat ÜM, Eyüpoğlu E, Saatci Ö, Jandaghi P, Wiemann S, Üner A, Cekic C, Riazalhosseini Y, Şahin Ö

Abstract
PURPOSE: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer (BC); however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.
EXPERIMENTAL DESIGN: Whole transcriptome sequencing, downstream pathway analysis and drug repositioning approaches were used to identify novel modulators (here: PDE4D) of tamoxifen resistance. Clinical data involving tamoxifen-treated ER-positive BC patients were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.
RESULTS: PDE4D, which hydrolyzes cAMP, was significantly overexpressed in both MCF-7 and T47D tamoxifen resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated BC patients (n=469, P=0.0036 for DMFS; n=561, P= 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n=132, P=0.049). Inhibition of PDE4D by either siRNAs or pharmacological inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded-protein-response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, aspirin was predicted to be a tamoxifen sensitizer using a drug re-positioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo.
CONCLUSIONS: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis.

PMID: 29386221 [PubMed - as supplied by publisher]

Discovering drugs to overcome chemoresistance in ovarian cancers based on the cancer genome atlas tumor transcriptome profile.

Oncotarget. 2017 Dec 29;8(70):115102-115113

Authors: Wang F, Chang JT, Zhang Z, Morrison G, Nath A, Bhutra S, Huang RS

Abstract
Ovarian cancer accounts for the highest mortality among gynecologic cancers, mainly due to intrinsic or acquired chemoresistance. While mechanistic-based methods have been used to identify compounds that can overcome chemoresistance, an effective comprehensive drug screening has yet to be developed. We applied a transcriptome based drug sensitivity prediction method, to the Cancer Genome Atlas (TCGA) ovarian cancer dataset to impute patient tumor response to over 100 different drugs. By stratifying patients based on their predicted response to standard of care (SOC) chemotherapy, we identified drugs that are likely more sensitive in SOC resistant ovarian tumors. Five drugs (ABT-888, BIBW2992, gefitinib, AZD6244 and lenalidomide) exhibit higher efficacy in SOC resistant ovarian tumors when multi-platform of transcriptome profiling methods were employed. Additional in vitro and clinical sample validations were carried out and verified the effectiveness of these agents. Our candidate drugs hold great potential to improve clinical outcome of chemoresistant ovarian cancer.

PMID: 29383145 [PubMed]

Diabetes Drug Receives New Indication.

Am J Nurs. 2017 Apr;117(4):24-25

Authors: Aschenbrenner DS

PMID: 28333738 [PubMed - indexed for MEDLINE]

Structural Basis of Antisickling Effects of Selected FDA Approved Drugs: A Drug Repurposing Study.

Curr Comput Aided Drug Des. 2018 Jan 29;:

Authors: Olubiyi OO, Olagunju MO, Oni JO, Olubiyi AO

Abstract
Sickle cell disease is characterized by a point mutation involving substitution of glutamic acid at position 6 to valine. Encoded in this hydrophobic mutation is both an intrinsic capacity for the beta globin molecules to assemble into thermodynamically favoured polymeric states as well as a rational way of interrupting the aggregation. In this work, starting with a theoretical model that employs occlusive binding onto the beta globin aggregation surface and using a range of computational methods and an effective energy for screening, a number of FDA approved drugs with computed aggregation inhibitory activities were identified. The validity of the model was confirmed using sickling tests, after which pharmacophore models as well the structural basis for the observed antisickling effects were identified.

PMID: 29380703 [PubMed - as supplied by publisher]

CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM).

PLoS Negl Trop Dis. 2017 12;11(12):e0006104

Authors: Debnath A, Calvet CM, Jennings G, Zhou W, Aksenov A, Luth MR, Abagyan R, Nes WD, McKerrow JH, Podust LM

Abstract
Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.

PMID: 29284029 [PubMed - indexed for MEDLINE]

PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy.

Eur J Pharmacol. 2018 Jan 26;:

Authors: To KKW, Wu WKK, Loong HHF

Abstract
We aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of non-small cell lung cancer (NSCLC). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates phosphatase and tensin homolog (PTEN) to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to resistance to EGFR TKIs. Therefore, PPARγ agonists are hypothesized to overcome EGFR TKI resistance. Using human NSCLC cell models with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARγ agonists was evaluated. PPARγ agonists were found to upregulate PTEN, subsequently inhibiting the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI). Chemical and genetic inhibition of PPARγ were shown to prevent this potentiation of anticancer activity by PPARγ agonists, thus confirming the crucial role played by PPARγ activation. Interestingly, the tested PPARγ agonists were also found to induce autophagy, as evidenced by the increased expression of an autophagy marker LC3-II and the autophagic degradation of p62/SQSTM1. PPARγ agonists-induced autophagic cell death was believed to contribute to the circumvention of resistance in PTEN-deficient cells because the genetic silencing of ATG5 (an autophagy mediator) was found to eliminate the drug potentiation effect by the PPARγ agonists. Our findings thus provide the basis for the rational and personalized use of PPARγ agonists in combination with EGFR TKIs in lung cancer patients.

PMID: 29378193 [PubMed - as supplied by publisher]

Autophagy Induced by Naftopidil Inhibits Apoptosis of Human Gastric Cancer Cells.

Anticancer Res. 2018 Feb;38(2):803-809

Authors: Nakamura A, Matsunaga W, Gotoh A

Abstract
AIM: Naftopidil is used to treat benign prostate hyperplasia. Moreover, previous studies have shown that naftopidil reduced viability of many types of cancer cells. Therefore, we investigated the antitumor mechanism of naftopidil in this study.
MATERIALS AND METHODS: We used the HGC27 human gastric cancer cell line. It was treated with naftopidil, pan-caspase inhibitor, and chloroquine diphosphate (CQ). Cell viability and cell death were investigated by the assay and annexin V/ propidium iodide assay. Phosphorylation of protein kinase B (AKT) (Ser473) was measured by western blotting. Alteration of light chain 3B (LC3B) was investigated by western blotting and immunofluorescence.
RESULTS: Naftopidil reduced phospho-AKT (Ser473) and altered LC3B. Combination of naftopidil and CQ reduced cell viability and phospho-AKT (Ser 473).
CONCLUSION: Naftopidil induces apoptosis and autophagy of HGC27 cells, however, autophagy is considered to inhibit apoptosis. We concluded naftopidil and CQ have a synergistic antitumor effect.

PMID: 29374705 [PubMed - in process]

The Architecture and Function of Monoclonal Antibody-Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention.

Small. 2016 05;12(19):2595-608

Authors: Gao Y, Gu S, Zhang Y, Xie X, Yu T, Lu Y, Zhu Y, Chen W, Zhang H, Dong H, Sinko PJ, Jia L

Abstract
The circulating tumor cells (CTCs) existing in cancer survivors are considered the root cause of cancer metastasis. To prevent the devastating metastasis cascade from initiation, we hypothesize that a biodegradable nanomaterial loaded with the abortifacient mifepristone (MIF) and conjugated with the epithelial cell adhesion molecule antibody (aEpCAM) may serve as a safe and effective cancer metastatic preventive agent by targeting CTCs and preventing their adhesion-invasion to vascular intima. It is demonstrated that MIF-loaded mesoporous silica nanoparticles (MSN) coated with aEpCAM (aE-MSN-M) can specifically target and bind colorectal cancer cells in either cell medium or blood through EpCAM recognition proven by quantitative flow cytometric detection and free aEpCAM competitive assay. The specific binding results in downregulation of the captured cells and drives them into G0/G1 phase primarily attributed to the effect of aEpCAM. The functional nanoparticles significantly inhibit the heteroadhesion between cancer cells and endothelial cells, suggesting the combined inhibition effects of aEpCAM and MIF on E-selectin and ICAM-1 expression. The functionalized nanoparticles circulate in mouse blood long enough to deliver MIF and inhibit lung metastasis. The present proof-of-concept study shows that the aE-MSN-M can prevent cancer metastasis by restraining CTC activity and their adhesion-invasion to vascular intima.

PMID: 27027489 [PubMed - indexed for MEDLINE]

Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials.

Nat Commun. 2018 Jan 24;9(1):358

Authors: Korbee CJ, Heemskerk MT, Kocev D, van Strijen E, Rabiee O, Franken KLMC, Wilson L, Savage NDL, Džeroski S, Haks MC, Ottenhoff THM

Abstract
Antibiotic resistance poses rapidly increasing global problems in combatting multidrug-resistant (MDR) infectious diseases like MDR tuberculosis, prompting for novel approaches including host-directed therapies (HDT). Intracellular pathogens like Salmonellae and Mycobacterium tuberculosis (Mtb) exploit host pathways to survive. Only very few HDT compounds targeting host pathways are currently known. In a library of pharmacologically active compounds (LOPAC)-based drug-repurposing screen, we identify multiple compounds, which target receptor tyrosine kinases (RTKs) and inhibit intracellular Mtb and Salmonellae more potently than currently known HDT compounds. By developing a data-driven in silico model based on confirmed targets from public databases, we successfully predict additional efficacious HDT compounds. These compounds target host RTK signaling and inhibit intracellular (MDR) Mtb. A complementary human kinome siRNA screen independently confirms the role of RTK signaling and kinases (BLK, ABL1, and NTRK1) in host control of Mtb. These approaches validate RTK signaling as a drugable host pathway for HDT against intracellular bacteria.

PMID: 29367740 [PubMed - in process]

Insights from Second-Line Treatments for Idiopathic Dilated Cardiomyopathy.

J Cardiovasc Dev Dis. 2017 Aug 23;4(3):

Authors: Luciani M, Del Monte F

Abstract
BACKGROUND: Dilated cardiomyopathy (DCM) is an independent nosographic entity characterized by left ventricular dilatation and contractile dysfunction leading to heart failure (HF). The idiopathic form of DCM (iDCM) occurs in the absence of coronaropathy or other known causes of DCM. Despite being different from other forms of HF for demographic, clinical, and prognostic features, its current pharmacological treatment does not significantly diverge.
METHODS: In this study we performed a Pubmed library search for placebo-controlled clinical investigations and a post-hoc analysis recruiting iDCM from 1985 to 2016. We searched for second-line pharmacologic treatments to reconsider drugs for iDCM management and pinpoint pathological mechanisms.
RESULTS: We found 33 clinical studies recruiting a total of 3392 patients of various durations and sizes, as well as studies that tested different drug classes (statins, pentoxifylline, inotropes). A metanalysis was unfeasible, although a statistical significance for changes upon treatment for molecular results, morphofunctional parameters, and clinical endpoints was reported. Statins appeared to be beneficial in light of their pleiotropic effects; inotropes might be tolerated more for longer times in iDCM compared to ischemic patients. General anti-inflammatory therapies do not significantly improve outcomes. Metabolic and growth modulation remain appealing fields to be investigated.
CONCLUSIONS: The evaluation of drug effectiveness based on direct clinical benefit is an inductive method providing evidence-based insights. This backward approach sheds light on putative and underestimated pathologic mechanisms and thus therapeutic targets for iDCM management.

PMID: 29367542 [PubMed]

Computational Drug Repositioning using Low-Rank Matrix Approximation and Randomized Algorithms.

Bioinformatics. 2018 Jan 22;:

Authors: Luo H, Li M, Wang S, Liu Q, Li Y, Wang J

Abstract
Motivation: Computational drug repositioning is an important and efficient approach towards identifying novel treatments for diseases in drug discovery. The emergence of large-scale, heterogeneous biological and biomedical datasets has provided an unprecedented opportunity for developing computational drug repositioning methods. The drug repositioning problem can be modeled as a recommendation system that recommends novel treatments based on known drug-disease associations. The formulation under this recommendation system is matrix completion, assuming that the hidden factors contributing to drug-disease associations are highly correlated and thus the corresponding data matrix is low-rank. Under this assumption, the matrix completion algorithm fills out the unknown entries in the drug-disease matrix by constructing a low-rank matrix approximation, where new drug-disease associations having not been validated can be screened.
Results: In this work, we propose a drug repositioning recommendation system (DRRS) to predict novel drug indications by integrating related data sources and validated information of drugs and diseases. Firstly, we construct a heterogeneous drug-disease interaction network by integrating drug-drug, disease-disease, and drug-disease networks. The heterogeneous network is represented by a large drug-disease adjacency matrix, whose entries include drug pairs, disease pairs, known drug-disease interaction pairs and unknown drug-disease pairs. Then, we adopt a fast Singular Value Thresholding (SVT) algorithm to complete the drug-disease adjacency matrix with predicted scores for unknown drug-disease pairs. The comprehensive experimental results show that DRRS improves the prediction accuracy compared with the other state-of-the-art approaches. In addition, case studies for several selected drugs further demonstrate the practical usefulness of the proposed method.
Availability: http://bioinformatics.csu.edu.cn/resources/softs/DrugRepositioning/DRRS/index.html.
Contact: yaohang@cs.odu.edu or jxwang@mail.csu.edu.cn.
Supplementary Information: Supplementary data are available at Bioinformatics online.

PMID: 29365057 [PubMed - as supplied by publisher]