From ancient herb to versatile, modern drug: Artemisia annua and artemisinin for cancer therapy.

Semin Cancer Biol. 2017 Feb 27;:

Authors: Efferth T

Abstract
Artemisia annua L. is used throughout Asia and Africa as tea and press juice to treat malaria and related symptomes (fever, chills). Its active ingredient, artemisinin (ARS), has been developed as antimalarial drug and is used worldwide. Interestingly, the bioactivity is not restricted to malaria treatment. We and others found that ARS-type drugs also reveal anticancer in vitro and in vivo. In this review, we give a systematic overview of the literature published over the past two decades until the end of 2016. Like other natural products, ARS acts in a multi-specific manner against tumors. The cellular response of ARS and its derivatives (dihydroartemisinin, artesunate, artemether, arteether) towards cancer cells include oxidative stress response by reactive oxygen species and nitric oxide, DNA damage and repair (base excision repair, homologous recombination, non-homologous end-joining), various cell death modes (apoptosis, autophagy, ferroptosis, necrosis, necroptosis, oncosis), inhibition of angiogenesis and tumor-related signal transduction pathways (e.g. Wnt/β-catenin pathway, AMPK pathway, metastatic pathways, and others) and signal transducers (NF-κB, MYC/MAX, AP-1, CREBP, mTOR etc). ARS-type drugs are at the stairways to the clinics. Several published case reports and pilot phase I/II trials indicate clinical anticancer activity of these compounds. Because of unexpected cases of hepatotoxicity, combinations of ARS-type drugs with complementary and alternative medicines are not recommended, until controlled clinical trials will prove the safety of non-approved combination treatments.

PMID: 28254675 [PubMed - as supplied by publisher]

Systematic Identification and Assessment of Therapeutic Targets for Breast Cancer Based on Genome-Wide RNA Interference Transcriptomes.

Genes (Basel). 2017 Feb 24;8(3):

Authors: Liu Y, Yin X, Zhong J, Guan N, Luo Z, Min L, Yao X, Bo X, Dai L, Bai H

Abstract
With accumulating public omics data, great efforts have been made to characterize the genetic heterogeneity of breast cancer. However, identifying novel targets and selecting the best from the sizeable lists of candidate targets is still a key challenge for targeted therapy, largely owing to the lack of economical, efficient and systematic discovery and assessment to prioritize potential therapeutic targets. Here, we describe an approach that combines the computational evaluation and objective, multifaceted assessment to systematically identify and prioritize targets for biological validation and therapeutic exploration. We first establish the reference gene expression profiles from breast cancer cell line MCF7 upon genome-wide RNA interference (RNAi) of a total of 3689 genes, and the breast cancer query signatures using RNA-seq data generated from tissue samples of clinical breast cancer patients in the Cancer Genome Atlas (TCGA). Based on gene set enrichment analysis, we identified a set of 510 genes that when knocked down could significantly reverse the transcriptome of breast cancer state. We then perform multifaceted assessment to analyze the gene set to prioritize potential targets for gene therapy. We also propose drug repurposing opportunities and identify potentially druggable proteins that have been poorly explored with regard to the discovery of small-molecule modulators. Finally, we obtained a small list of candidate therapeutic targets for four major breast cancer subtypes, i.e., luminal A, luminal B, HER2+ and triple negative breast cancer. This RNAi transcriptome-based approach can be a helpful paradigm for relevant researches to identify and prioritize candidate targets for experimental validation.

PMID: 28245581 [PubMed - in process]

Combination treatment with naftopidil increases the efficacy of radiotherapy in PC-3 human prostate cancer cells.

J Cancer Res Clin Oncol. 2017 Feb 27;:

Authors: Iwamoto Y, Ishii K, Kanda H, Kato M, Miki M, Kajiwara S, Arima K, Shiraishi T, Sugimura Y

Abstract
PURPOSE: Clinically, radiotherapy (RT) often leads to the development of prostate cancer (PCa) resistance because of protective responses in cancer cells. One of the mechanisms includes the upregulation of RT-induced antioxidant enzymes. Thus, combination therapy with RT and certain pharmaceutical drugs targeting antioxidant enzymes may be ideal for increasing the efficacy of RT with minimum side effects. Naftopidil is a subtype-selective α1D-adrenoceptor antagonist used for the treatment of benign prostatic hyperplasia (BPH). In our drug repositioning study, naftopidil showed not only unique growth-inhibitory effects but also AKT phosphorylation-inhibitory effects in PC-3 human PCa cells. Here, we examined the efficacy of additive naftopidil treatment in combination with RT in PC-3 cells.
METHODS: The effects of combination therapy with RT plus naftopidil were analyzed using an animal model of PC-3 xenografts in BALB/c nude mice. The expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was evaluated by western blotting.
RESULTS: Combination therapy with RT plus naftopidil induced a more efficacious delay in PC-3 xenograft tumor growth as compared with monotherapy with naftopidil or RT. In PC-3 tumors, combination therapy with RT plus naftopidil suppressed the upregulation of RT-induced MnSOD expression. In vitro, neither AKT inhibitor IV nor naftopidil directly altered MnSOD expression. Upregulation of RT-induced MnSOD expression was markedly suppressed by combination treatment with RT plus AKT inhibitor IV or naftopidil.
CONCLUSIONS: These results suggest that additive naftopidil treatment in combination with RT may increase the efficacy of RT for the treatment of PCa.

PMID: 28243746 [PubMed - as supplied by publisher]

Drug voyager: a computational platform for exploring unintended drug action.

BMC Bioinformatics. 2017 Feb 28;18(1):131

Authors: Oh M, Ahn J, Lee T, Jang G, Park C, Yoon Y

Abstract
BACKGROUND: The dominant paradigm in understanding drug action focuses on the intended therapeutic effects and frequent adverse reactions. However, this approach may limit opportunities to grasp unintended drug actions, which can open up channels to repurpose existing drugs and identify rare adverse drug reactions. Advances in systems biology can be exploited to comprehensively understand pharmacodynamic actions, although proper frameworks to represent drug actions are still lacking.
RESULTS: We suggest a novel platform to construct a drug-specific pathway in which a molecular-level mechanism of action is formulated based on pharmacologic, pharmacogenomic, transcriptomic, and phenotypic data related to drug response ( http://databio.gachon.ac.kr/tools/ ). In this platform, an adoption of three conceptual levels imitating drug perturbation allows these pathways to be realistically rendered in comparison to those of other models. Furthermore, we propose a new method that exploits functional features of the drug-specific pathways to predict new indications as well as adverse reactions. For therapeutic uses, our predictions significantly overlapped with clinical trials and an up-to-date drug-disease association database. Also, our method outperforms existing methods with regard to classification of active compounds for cancers. For adverse reactions, our predictions were significantly enriched in an independent database derived from the Food and Drug Administration (FDA) Adverse Event Reporting System and meaningfully cover an Adverse Reaction Database provided by Health Canada. Lastly, we discuss several predictions for both therapeutic indications and side-effects through the published literature.
CONCLUSIONS: Our study addresses how we can computationally represent drug-signaling pathways to understand unintended drug actions and to facilitate drug discovery and screening.

PMID: 28241745 [PubMed - in process]

Lysine Deacetylase Inhibitors in Parasites: Past, Present and Future Perspectives.

J Med Chem. 2017 Feb 27;:

Authors: Hailu GS, Robaa D, Forgione M, Sippl W, Rotili D, Mai A

Abstract
Current therapies for human parasite infections rely on a few drugs, most of which have severe side effects, and their helpfulness is being seriously compromised by the drug resistance problem. Globally, this is pushing discovery research of anti-parasitic drugs towards new agents endowed with new mechanisms of action. By using a "drug repurposing" strategy, histone deacetylase inhibitors (HDACi), which are presently clinically approved for cancer use, are now under investigation for various parasite infections. Since parasitic Zn2+- and NAD+-dependent HDACs play crucial roles in the modulation of parasite gene expression, and many of them are pro-survival for several parasites under various conditions, they are now emerging as novel potential anti-parasitic targets. This Perspective summarizes the state of knowledge of HDACi (both class I/II HDACi and sirtuin inhibitors) targeted to the main human parasitic diseases (schistosomiasis, malaria, trypanosomiasis, leishmaniasis and toxoplasmosis) and provides visions into the main issues that challenge their development as anti-parasitic agents.

PMID: 28241112 [PubMed - as supplied by publisher]

The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma.

Nat Commun. 2017 Feb 27;8:4565

Authors: Zhai W, Lim TK, Zhang T, Phang ST, Tiang Z, Guan P, Ng MH, Lim JQ, Yao F, Li Z, Ng PY, Yan J, Goh BK, Chung AY, Choo SP, Khor CC, Soon WW, Sung KW, Foo RS, Chow PK

Abstract
Hepatocellular carcinoma (HCC) has one of the poorest survival rates among cancers. Using multi-regional sampling of nine resected HCC with different aetiologies, here we construct phylogenetic relationships of these sectors, showing diverse levels of genetic sharing, spanning early to late diversification. Unlike the variegated pattern found in colorectal cancers, a large proportion of HCC display a clear isolation-by-distance pattern where spatially closer sectors are genetically more similar. Two resected intra-hepatic metastases showed genetic divergence occurring before and after primary tumour diversification, respectively. Metastatic tumours had much higher variability than their primary tumours, suggesting that intra-hepatic metastasis is accompanied by rapid diversification at the distant location. The presence of co-existing mutations offers the possibility of drug repositioning for HCC treatment. Taken together, these insights into intra-tumour heterogeneity allow for a comprehensive understanding of the evolutionary trajectories of HCC and suggest novel avenues for personalized therapy.

PMID: 28240289 [PubMed - in process]

Phenome-wide association studies: A new method for functional genomics in humans.

J Physiol. 2017 Feb 23;:

Authors: Roden DM

Abstract
In experimental physiology research, a common study design for examining the functional role of a gene or a genetic variant is to introduce that genetic variant into a model organism (such as yeast or mouse) and then to search for phenotypic consequences. The development of DNA biobanks linked to dense phenotypic information enables such an experiment to be applied to human subjects in form of a phenome-wide association study (PheWAS). The PheWAS paradigm takes advantage of a curated medical phenome, often derived from electronic health records, to search for associations between "input functions" and phenotypes in an unbiased fashion. The most commonly studied input function to date has been single nucleotide polymorphisms (SNPs), but other inputs, such as sets of SNPs or a disease or drug exposure, are now being explored to probe the genetic and phenotypic architecture of human traits. Potential outcomes of these approaches include defining subsets of complex diseases (that can then be targeted by specific therapies) or drug repurposing.

PMID: 28229460 [PubMed - as supplied by publisher]

Repurposing Cationic Amphiphilic Antihistamines for Cancer Treatment.

EBioMedicine. 2016 Jul;9:130-9

Authors: Ellegaard AM, Dehlendorff C, Vind AC, Anand A, Cederkvist L, Petersen NH, Nylandsted J, Stenvang J, Mellemgaard A, Østerlind K, Friis S, Jäättelä M

Abstract
Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. In search for new NSCLC treatment options, we screened a cationic amphiphilic drug (CAD) library for cytotoxicity against NSCLC cells and identified several CAD antihistamines as inducers of lysosomal cell death. We then performed a cohort study on the effect of CAD antihistamine use on mortality of patients diagnosed with non-localized cancer in Denmark between 1995 and 2011. The use of the most commonly prescribed CAD antihistamine, loratadine, was associated with significantly reduced all-cause mortality among patients with non-localized NSCLC or any non-localized cancer when compared with use of non-CAD antihistamines and adjusted for potential confounders. Of the less frequently described CAD antihistamines, astemizole showed a similar significant association with reduced mortality as loratadine among patients with any non-localized cancer, and ebastine use showed a similar tendency. The association between CAD antihistamine use and reduced mortality was stronger among patients with records of concurrent chemotherapy than among those without such records. In line with this, sub-micromolar concentrations of loratadine, astemizole and ebastine sensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistamines may improve the efficacy of cancer chemotherapy.

PMID: 27333030 [PubMed - indexed for MEDLINE]

Current Care and Investigational Therapies in Achondroplasia.

Curr Osteoporos Rep. 2017 Feb 21;:

Authors: Unger S, Bonafé L, Gouze E

Abstract
PURPOSE OF REVIEW: The goal of this review is to evaluate the management options for achondroplasia, the most common non-lethal skeletal dysplasia. This disease is characterized by short stature and a variety of complications, some of which can be quite severe.
RECENT FINDINGS: Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications. Achondroplasia is the most common non-lethal skeletal dysplasia. It is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications.

PMID: 28224446 [PubMed - as supplied by publisher]

Human enterovirus 71 protein interaction network prompts antiviral drug repositioning.

Sci Rep. 2017 Feb 21;7:43143

Authors: Han L, Li K, Jin C, Wang J, Li Q, Zhang Q, Cheng Q, Yang J, Bo X, Wang S

Abstract
As a predominant cause of human hand, foot, and mouth disease, enterovirus 71 (EV71) infection may lead to serious diseases and result in severe consequences that threaten public health and cause widespread panic. Although the systematic identification of physical interactions between viral proteins and host proteins provides initial information for the recognition of the cellular mechanism involved in viral infection and the development of new therapies, EV71-host protein interactions have not been explored. Here, we identified interactions between EV71 proteins and host cellular proteins and confirmed the functional relationships of EV71-interacting proteins (EIPs) with virus proliferation and infection by integrating a human protein interaction network and by functional annotation. We found that most EIPs had known interactions with other viruses. We also predicted ATP6V0C as a broad-spectrum essential host factor and validated its essentiality for EV71 infection in vitro. EIPs and their interacting proteins were more likely to be targets of anti-inflammatory and neurological drugs, indicating their potential to serve as host-oriented antiviral targets. Thus, we used a connectivity map to find drugs that inhibited EIP expression. We predicted tanespimycin as a candidate and demonstrated its antiviral efficiency in vitro. These findings provide the first systematic identification of EV71-host protein interactions, an analysis of EIP protein characteristics and a demonstration of their value in developing host-oriented antiviral therapies.

PMID: 28220872 [PubMed - in process]

Drug Repurposing of Histone Deacetylase Inhibitors that Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis.

J Med Chem. 2017 Feb 20;:

Authors: Lu W, Yao X, Ouyang P, Dong N, Wu D, Jiang X, Wu Z, Zhang C, Xu Z, Tang Y, Zou S, Liu M, Li J, Zeng MH, Lin P, Cheng F, Huang J

Abstract
Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analog 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray Crystallographic investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were determined in vivo. Collectively, 1 and 2 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.

PMID: 28218840 [PubMed - as supplied by publisher]

Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment.

Curr Opin Neurol. 2017 Feb 15;:

Authors: Symonds JD, Zuberi SM, Johnson MR

Abstract
PURPOSE OF REVIEW: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery.
RECENT FINDINGS: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed. Examples of precision medicine in epilepsy targeting gain-of-function mutations in KCNT1, GRIN2A, GRIN2D and SCN8A are presented. Potential reasons for the paucity of examples of precision medicine for loss-of-function mutations or in non-ion channel epilepsy genes are explored. We highlight how systems genetics and gene network analyses have suggested that pathways disrupted in epilepsy overlap with those of other neurodevelopmental traits including human cognition. We review how network-based computational approaches are now being applied to epilepsy drug discovery.
SUMMARY: We are living in an unparalleled era of epilepsy gene discovery. Advances in clinical care from this progress are already materializing through improved clinical diagnosis and stratified medicine. The application of targeted drug repurposing based on single gene defects has shown promise for epilepsy arising from gain-of-function mutations in ion-channel subunit genes, but important barriers remain to translating these approaches to non-ion channel epilepsy genes and loss-of-function mutations. Gene network analysis offers opportunities to discover new pathways for epilepsy, to decipher epilepsy's relationship to other neurodevelopmental traits and to frame a new approach to epilepsy drug discovery.

PMID: 28212175 [PubMed - as supplied by publisher]

New applications for known drugs: Human glycogen synthase kinase 3 inhibitors as modulators of Aspergillus fumigatus growth.

Eur J Med Chem. 2016 Jun 30;116:281-9

Authors: Sebastián V, Manoli MT, Pérez DI, Gil C, Mellado E, Martínez A, Espeso EA, Campillo NE

Abstract
Invasive aspergillosis (IA) is one of the most severe forms of fungi infection. IA disease is mainly due to Aspergillus fumigatus, an air-borne opportunistic pathogen. Mortality rate caused by IA is still very high (50-95%), because of difficulty in early diagnostics and reduced antifungal treatment options, thus new and efficient drugs are necessary. The aim of this work is, using Aspergillus nidulans as non-pathogen model, to develop efficient drugs to treat IA. The recent discovered role of glycogen synthase kinase-3 homologue, GskA, in A. fumigatus human infection and our previous experience on human GSK-3 inhibitors focus our attention on this kinase as a target for the development of antifungal drugs. With the aim to identify effective inhibitors of colonial growth of A. fumigatus we use A. nidulans as an accurate model for in vivo and in silico studies. Several well-known human GSK-3β inhibitors were tested for inhibition of A. nidulans colony growth. Computational tools as docking studies and binding site prediction was used to explain the different biological profile of the tested inhibitors. Three of the five tested hGSK3β inhibitors are able to reduce completely the colonial growth by covalent bind to the enzyme. Therefore these compounds may be useful in different applications to eradicate IA.

PMID: 27131621 [PubMed - indexed for MEDLINE]

Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning.

J Psychopharmacol. 2017 Jan 01;:269881117691467

Authors: Powell TR, Murphy T, Lee SH, Price J, Thuret S, Breen G

Abstract
Current pharmacological treatments for major depressive disorder (MDD) are ineffective in a significant proportion of patients, and the identification of new antidepressant compounds has been difficult. 'Connectivity mapping' is a method that can be used to identify drugs that elicit similar downstream effects on mRNA levels when compared to current treatments, and thus may point towards possible repositioning opportunities. We investigated genome-wide transcriptomic changes to human hippocampal progenitor cells treated with therapeutically relevant concentrations of a tricyclic antidepressant (nortriptyline) and a selective serotonin reuptake inhibitor (escitalopram). We identified mRNA changes common to both drugs to create an 'antidepressant mRNA signature'. We used this signature to probe the Library of Integrated Network-based Cellular Signatures (LINCS) and to identify other compounds that elicit similar changes to mRNA in neural progenitor cells. Results from LINCS revealed that the tricyclic antidepressant clomipramine elicited mRNA changes most similar to our mRNA signature, and we identified W-7 and vorinostat as functionally relevant drug candidates, which may have repositioning potential. Our results are encouraging and represent the first attempt to use connectivity mapping for drug repositioning in MDD.

PMID: 28208023 [PubMed - as supplied by publisher]

Systematic analyses of drugs and disease indications in RepurposeDB reveal pharmacological, biological and epidemiological factors influencing drug repositioning.

Brief Bioinform. 2017 Feb 15;:

Authors: Shameer K, Glicksberg BS, Hodos R, Johnson KW, Badgeley MA, Readhead B, Tomlinson MS, O'Connor T, Miotto R, Kidd BA, Chen R, Ma'ayan A, Dudley JT

PMID: 28200013 [PubMed - as supplied by publisher]

DeSigN: connecting gene expression with therapeutics for drug repurposing and development.

BMC Genomics. 2017 Jan 25;18(Suppl 1):934

Authors: Lee BK, Tiong KH, Chang JK, Liew CS, Abdul Rahman ZA, Tan AC, Khang TF, Cheong SC

Abstract
BACKGROUND: The drug discovery and development pipeline is a long and arduous process that inevitably hampers rapid drug development. Therefore, strategies to improve the efficiency of drug development are urgently needed to enable effective drugs to enter the clinic. Precision medicine has demonstrated that genetic features of cancer cells can be used for predicting drug response, and emerging evidence suggest that gene-drug connections could be predicted more accurately by exploring the cumulative effects of many genes simultaneously.
RESULTS: We developed DeSigN, a web-based tool for predicting drug efficacy against cancer cell lines using gene expression patterns. The algorithm correlates phenotype-specific gene signatures derived from differentially expressed genes with pre-defined gene expression profiles associated with drug response data (IC50) from 140 drugs. DeSigN successfully predicted the right drug sensitivity outcome in four published GEO studies. Additionally, it predicted bosutinib, a Src/Abl kinase inhibitor, as a sensitive inhibitor for oral squamous cell carcinoma (OSCC) cell lines. In vitro validation of bosutinib in OSCC cell lines demonstrated that indeed, these cell lines were sensitive to bosutinib with IC50 of 0.8-1.2 μM. As further confirmation, we demonstrated experimentally that bosutinib has anti-proliferative activity in OSCC cell lines, demonstrating that DeSigN was able to robustly predict drug that could be beneficial for tumour control.
CONCLUSIONS: DeSigN is a robust method that is useful for the identification of candidate drugs using an input gene signature obtained from gene expression analysis. This user-friendly platform could be used to identify drugs with unanticipated efficacy against cancer cell lines of interest, and therefore could be used for the repurposing of drugs, thus improving the efficiency of drug development.

PMID: 28198666 [PubMed - in process]

Repositioning of amprenavir as a novel extracellular signal-regulated kinase-2 inhibitor and apoptosis inducer in MCF-7 human breast cancer.

Int J Oncol. 2017 Jan 24;:

Authors: Jiang W, Li X, Li T, Wang H, Shi W, Qi P, Li C, Chen J, Bao J, Huang G, Wang Y

Abstract
Computational drug repositioning by virtually screening existing drugs for additional therapeutic usage could efficiently accelerate anticancer drug discovery. Herein, a library of 1447 Food and Drug Administration (FDA)-approved small molecule drugs was screened in silico for inhibitors of extracellular signal-regulated kinase 2 (ERK2). Then, in vitro kinase assay demonstrated amprenavir, a HIV-1 protease inhibitor, as a potential kinase inhibitor of ERK2. The in vivo kinase assay indicated that amprenavir could inhibit ERK2-mediated phosphorylation of BimEL at Ser69. Amprenavir could suppress this phosphorylation in MCF-7 cells, which may further facilitate the association of BimEL with several pro-survival molecules. Additionally, inhibition of ERK2-BimEL signaling pathway by amprenavir could contribute to its anti-proliferative and apoptosis-inducing activity in MCF-7 cells. Finally, in vivo tumor growth and immunohistochemical studies confirmed that amprenavir remarkably suppressed tumor proliferation and induce apoptosis in MCF-7 xenografts. Taken together, amprenavir can effectively inhibit the kinase activity of ERK2, and thus induces apoptosis and inhibits tumor growth in human MCF-7 cancer cells both in vitro and in vivo, making amprenavir a promising candidate for future anticancer therapeutics.

PMID: 28197631 [PubMed - as supplied by publisher]

Mefloquine and its oxazolidine derivative compound are active against drug-resistant Mycobacterium tuberculosis strains and in a murine model of tuberculosis infection.

Int J Antimicrob Agents. 2016 Aug;48(2):203-7

Authors: Rodrigues-Junior VS, Villela AD, Gonçalves RS, Abbadi BL, Trindade RV, López-Gavín A, Tudó G, González-Martín J, Basso LA, de Souza MV, Campos MM, Santos DS

Abstract
Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. In this work, we demonstrate for the first time the activities of mefloquine and its oxazolidine derivative compound 1E in a murine model of TB infection following administration of both drugs by the oral route. The effects of associations between mefloquine or 1E with the clinically used antituberculosis drugs isoniazid, rifampicin, ethambutol, moxifloxacin and streptomycin were also investigated. Importantly, combination of mefloquine with isoniazid and of 1E with streptomycin showed a two-fold decrease in their minimum inhibitory concentrations (MICs). Moreover, no tested combinations demonstrated antagonist interactions. Here we describe novel evidence on the activity of mefloquine and 1E against a series of quinolone-resistant M. tuberculosis strains. These data show MICs against quinolone-resistant strains (0.5-8 µg/mL) similar to or lower than those previously reported for multidrug-resistant strains. Taking these results together, we can suggest the use of mefloquine or 1E in combination with clinically available drugs, especially in the case of resistant forms of TB.

PMID: 27364701 [PubMed - indexed for MEDLINE]

In vitro screening of an FDA-Approved Library against ESKAPE pathogens.

Curr Pharm Des. 2017 Feb 09;:

Authors: Younis W, AbdelKhalek A, Mayhoub AS, Seleem MN

Abstract
Bacterial resistance to conventional antibiotics is an increasingly serious threat to public health worldwide that requires immediate exploration and the development of novel antimicrobial compounds. Drug repurposing is an inexpensive and untapped source of new antimicrobial leads, and it holds many attractive features warranting further attention for antimicrobial drug discovery. In an effort to repurpose drugs and explore new leads in the field of antimicrobial drug discovery, we performed a whole-cell screening assay of 1,600 Food and Drug Administration (FDA) approved drugs against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae (ESKAPE) pathogens. The in vitro screening identified 49 non-antimicrobial drugs that were active against at least one species of ESKAPE pathogen. Although some of these drugs were known to have antibacterial activity, many have never been reported before. In particular, sulfonamide-containing structures represent a novel drug scaffold that should be investigated further. The characteristics of these drugs as antimicrobial agents may offer a safe, effective, and quick supplement to current approaches to treating bacterial infections.

PMID: 28190396 [PubMed - as supplied by publisher]

Novel antiviral activity and mechanism of bromocriptine as a Zika virus NS2B-NS3 protease inhibitor.

Antiviral Res. 2017 Feb 06;:

Authors: Chan JF, Chik KK, Yuan S, Yip CC, Zhu Z, Tee KM, Tsang JO, Chan CC, Poon VK, Lu G, Zhang AJ, Lai KK, Chan KH, Kao RY, Yuen KY

Abstract
Zika virus (ZIKV) infection is associated with congenital malformations in infected fetuses and severe neurological and other systemic complications in adults. There are currently limited anti-ZIKV treatment options that are readily available and safe for use in pregnancy. In this drug repurposing study, bromocriptine was found to have inhibitory effects on ZIKV replication in cytopathic effect inhibition, virus yield reduction, and plaque reduction assays. Time-of-drug-addition assay showed that bromocriptine exerted anti-ZIKV activity between 0 and 12 h post-ZIKV inoculation, corroborating with post-entry events in the virus replication cycle prior to budding. Our docking model showed that bromocriptine interacted with several active site residues of the proteolytic cavity involving H51 and S135 in the ZIKV-NS2B-NS3 protease protein, and might occupy the active site and inhibit the protease activity of the ZIKV-NS2B-NS3 protein. A fluorescence resonance energy transfer-based enzymatic assay confirmed that bromocriptine inhibited ZIKV protease activity. Moreover, bromocriptine exhibited synergistic effect with interferon-α2b against ZIKV replication in cytopathic effect inhibition assay. The availability of per vagina administration of bromocriptine as suppositories or vaginoadhesive discs and the synergistic anti-ZIKV activity between bromocriptine and type I interferon may make bromocriptine a potentially useful and readily available treatment option for ZIKV infection. The anti-ZIKV effects of bromocriptine should be evaluated in a suitable animal model.

PMID: 28185815 [PubMed - as supplied by publisher]