Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model.

Chem Biol Interact. 2017 Nov 10;:

Authors: Helmy SA, El-Mesery M, El-Karef A, Eissa LA, El Gayar AM

Abstract
Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase-3, BCL-2 and TGF-β1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect.

PMID: 29133031 [PubMed - as supplied by publisher]

Neuroleptic drugs in the treatment of tuberculosis: Minimal inhibitory concentrations of different phenothiazines against Mycobacterium tuberculosis.

Tuberculosis (Edinb). 2016 May;98:27-9

Authors: Vesenbeckh S, Krieger D, Bettermann G, Schönfeld N, Bauer TT, Rüssmann H, Mauch H

Abstract
Due to an increase of drug resistant TB, alternative drugs that are not currently listed in the WHO guidelines on MDR TB treatment are currently being evaluated. Our group tested 100 susceptible, 20 MDR and 2 XDR Mtb strains against the phenothiazine derivatives thioridazine, trifluoperazine and triflupromazine. MIC testing was performed on Middlebrook 7H10 agar and was defined as the lowest drug concentration that inhibits ≥99% of the bacterial population. We confirm very good in vitro activity of phenothiazines against Mycobacterium tuberculosis. In >77% of all strains MICs of ≤10 μg/ml were found.

PMID: 27156615 [PubMed - indexed for MEDLINE]

Logical Comparison over RDF Resources in Bio-Informatics.

J Biomed Inform. 2017 Nov 07;:

Authors: Colucci S, Donini FM, Di Sciascio E

Abstract
Comparison of resources is a frequent task in different bio-informatics applications, including drug-target interaction, drug repositioning and mechanism of action understanding, among others. This paper proposes a general method for the logical comparison of resources modeled in Resource Description Framework and shows its distinguishing features with reference to the comparison of drugs. In particular, the method returns a description of the commonalities between resources, rather than a numerical value estimating their similarity and/or relatedness. The approach is domain-independent and may be flexibly adapted to heterogeneous use cases, according to a process for setting parameters which is completely explicit. The paper also presents an experiment using the dataset Bioportal as knowledge source; the experiment is fully reproducible, thanks to the elicitation of criteria and values for parameter customization.

PMID: 29127041 [PubMed - as supplied by publisher]

DrugBank 5.0: a major update to the DrugBank database for 2018.

Nucleic Acids Res. 2017 Nov 08;:

Authors: Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M

Abstract
DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education.

PMID: 29126136 [PubMed - as supplied by publisher]

New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels.

Sci Rep. 2017 Nov 09;7(1):15126

Authors: Sadacca B, Hamy-Petit AS, Laurent C, Gestraud P, Bonsang-Kitzis H, Pinheiro A, Abecassis J, Neuvial P, Reyal F

Abstract
One of the most challenging problems in the development of new anticancer drugs is the very high attrition rate. The so-called "drug repositioning process" propose to find new therapeutic indications to already approved drugs. For this, new analytic methods are required to optimize the information present in large-scale pharmacogenomics datasets. We analyzed data from the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia studies. We focused on common cell lines (n = 471), considering the molecular information, and the drug sensitivity for common drugs screened (n = 15). We propose a novel classification based on transcriptomic profiles of cell lines, according to a biological network-driven gene selection process. Our robust molecular classification displays greater homogeneity of drug sensitivity than cancer cell line grouped based on tissue of origin. We then identified significant associations between cell line cluster and drug response robustly found between both datasets. We further demonstrate the relevance of our method using two additional external datasets and distinct sensitivity metrics. Some associations were still found robust, despite cell lines and drug responses' variations. This study defines a robust molecular classification of cancer cell lines that could be used to find new therapeutic indications to known compounds.

PMID: 29123141 [PubMed - in process]

Anticancer and Immunogenic Properties of Cardiac Glycosides.

Molecules. 2017 Nov 08;22(11):

Authors: Schneider NFZ, Cerella C, Simões CMO, Diederich M

Abstract
Cardiac glycosides (CGs) are natural compounds widely used in the treatment of several cardiac conditions and more recently have been recognized as potential antitumor compounds. They are known to be ligands for Na/K-ATPase, which is a promising drug target in cancer. More recently, in addition to their antitumor effects, it has been suggested that CGs activate tumor-specific immune responses. This review summarizes the anticancer aspects of CGs as new strategies for immunotherapy and drug repositioning (new horizons for old players), and the possible new targets for CGs in cancer cells.

PMID: 29117117 [PubMed - in process]

Comparative analysis of methicillin-sensitive and resistant Staphylococcus aureus exposed to emodin based on proteomic profiling.

Biochem Biophys Res Commun. 2017 Dec 09;494(1-2):318-324

Authors: Ji X, Liu X, Peng Y, Zhan R, Xu H, Ge X

Abstract
Emodin has a strong antibacterial activity, including methicillin-resistant Staphylococcus aureus (MRSA). However, the mechanism by which emodin induces growth inhibition against MRSA remains unclear. In this study, the isobaric tags for relative and absolute quantitation (iTRAQ) proteomics approach was used to investigate the modes of action of emodin on a MRSA isolate and methicillin-sensitive S. aureus ATCC29213(MSSA). Proteomic analysis showed that expression levels of 145 and 122 proteins were changed significantly in MRSA and MSSA, respectively, after emodin treatment. Comparative analysis of the functions of differentially expressed proteins between the two strains was performed via bioinformatics tools blast2go and STRING database. Proteins related to pyruvate pathway imbalance induction, protein synthesis inhibition, and DNA synthesis suppression were found in both methicillin-sensitive and resistant strains. Moreover, Interference proteins related to membrane damage mechanism were also observed in MRSA. Our findings indicate that emodin is a potential antibacterial agent targeting MRSA via multiple mechanisms.

PMID: 29017918 [PubMed - indexed for MEDLINE]

Combating multi-drug resistant pathogens with host-directed non-antibiotic therapeutics.

Antimicrob Agents Chemother. 2017 Nov 06;:

Authors: Andersson JA, Sha J, Kirtley ML, Reyes E, Fitts EC, Dann SM, Chopra AK

Abstract
Earlier, we reported that 3 Food and Drug Administration-approved drugs, trifluoperazine (TFP, anti-psychotic), amoxapine (AXPN, anti-depressant), and doxapram (DXP, breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided 40-60% protection to mice against pneumonic plague when administered at the time of infection for 1-3 days. In this study, the therapeutic potential of these drugs was further evaluated in mice when administered up to 48 h post-infection against pneumonic plague. While efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h post infection, these drugs, when administered in combination with levofloxacin, provided significant, up to 100%, protection to animals against pneumonic or bubonic challenge. Likewise, when used in combination with vancomycin, all three drugs provided 80-100% protection from fatal oral Clostridium difficile infection in mice when administered 24 h post infection. Furthermore, AXPN provided 40-60% protection against respiratory infection with Klebsiella pneumoniae when administered at the time of infection or 24 h post infection. Using the same in vitro cytotoxicity assay, we identified additional 76/780 non-antibiotic drugs effective against K. pneumoniae For Acinetobacter baumannii, 121 non-antibiotic drugs were identified to inhibit bacterial-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited macrophage cytotoxicity with two additional multiple-antibiotic resistant strains. Six of these drugs decreased intracellular survival of all three A. baumannii strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multi-drug resistant pathogens of public health concern.

PMID: 29109161 [PubMed - as supplied by publisher]

Rare Diseases: Drug Discovery and Informatics Resource.

Interdiscip Sci. 2017 Nov 01;:

Authors: Zhao M, Wei DQ

Abstract
A rare disease refers to any disease with very low prevalence individually. Although the impacted population is small for a single disease, more than 6000 rare diseases affect millions of people across the world. Due to the small market size, high cost and possibly low return on investment, only in recent years, the research and development of rare disease drugs have gradually risen globally, in several domains including gene therapy, enzyme replacement therapy, and drug repositioning. Due to the complex etiology and heterogeneous symptoms, there is a large gap between basic research and patient unmet needs for rare disease drug discovery. As computational biology increasingly arises researchers' awareness, the informatics database on rare disease have grown rapidly in the recent years, including drug targets, genetic variant and mutation, phenotype and ontology and patient registries. Along with the advances of informatics database and networks, new computational models will help accelerate the target identification and lead optimization process for rare disease pre-clinical drug development.

PMID: 29094320 [PubMed - as supplied by publisher]

Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment.

JCI Insight. 2017 Nov 02;2(21):

Authors: Mirza AN, Fry MA, Urman NM, Atwood SX, Roffey J, Ott GR, Chen B, Lee A, Brown AS, Aasi SZ, Hollmig T, Ator MA, Dorsey BD, Ruggeri BR, Zificsak CA, Sirota M, Tang JY, Butte A, Epstein E, Sarin KY, Oro AE

Abstract
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Ɩ/ʎ (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.

PMID: 29093271 [PubMed - as supplied by publisher]

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

PLoS One. 2017;12(10):e0186364

Authors: Mogire RM, Akala HM, Macharia RW, Juma DW, Cheruiyot AC, Andagalu B, Brown ML, El-Shemy HA, Nyanjom SG

Abstract
Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens.

PMID: 29088219 [PubMed - in process]

Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues.

Org Biomol Chem. 2017 Oct 31;:

Authors: Jiang H, Xing J, Wang C, Zhang H, Yue L, Wan X, Chen W, Ding H, Xie Y, Tao H, Chen Z, Jiang H, Chen K, Chen S, Zheng M, Zhang Y, Luo C

Abstract
The BET family of bromodomain-containing proteins (BRDs) is believed to be a promising drug target for therapeutic intervention in a number of diseases including cancer, inflammation and cardiovascular diseases. Hence, there is a great demand for novel chemotypes of BET inhibitors. The drug repurposing strategy offers great benefits to find inhibitors with known safety and pharmacokinetic profiles, thus increasing medicinal chemists' interest in recent years. Using the drug repurposing strategy, a BRD4-specific score based virtual screening campaign on an in-house drug library was conducted followed by the ALPHA screen assay test. Nitroxoline, an FDA-approved antibiotic, was identified to effectively disrupt the interaction between the first bromodomain of BRD4 (bromodomain-containing protein 4) and acetylated H4 peptide with IC50 of 0.98 μM. Nitroxoline inhibited all BET family members with good selectivity against non-BET bromodomain-containing proteins, thus it is defined as a selective BET inhibitor. Based on the crystal structure of the nitroxoline-BRD4_BD1 complex, the mechanism of action as well as BET specificity of nitroxoline were determined. Since the anticancer activity of nitroxoline against MLL leukemia, one of the BET related diseases, has not been studied before, we tested whether nitroxoline might serve as a potential repurposing drug candidate for MLL leukemia. Nitroxoline effectively inhibited the proliferation of MLL leukemia cells by inducing cell cycle arrest and apoptosis. The profound efficacy is, at least in part, due to the inhibition of BET and downregulation of target gene transcription. Our discovery of nitroxoline as a BET inhibitor suggests potential application of nitroxoline and its derivatives for clinical translation in BET family related diseases.

PMID: 29087414 [PubMed - as supplied by publisher]

Statins: antimicrobial resistance breakers or makers?

PeerJ. 2017;5:e3952

Authors: Ko HHT, Lareu RR, Dix BR, Hughes JD

Abstract
INTRODUCTION: The repurposing of non-antibiotic drugs as adjuvant antibiotics may help break antimicrobial resistance (AMR). Statins are commonly prescribed worldwide to lower cholesterol. They also possess qualities of AMR "breakers", namely direct antibacterial activity, synergism with antibiotics, and ability to stimulate the host immune system. However, statins' role as AMR breakers may be limited. Their current extensive use for cardiovascular protection might result in selective pressures for resistance, ironically causing statins to be AMR "makers" instead. This review examines statins' potential as AMR breakers, probable AMR makers, and identifies knowledge gaps in a statin-bacteria-human-environment continuum. The most suitable statin for repurposing is identified, and a mechanism of antibacterial action is postulated based on structure-activity relationship analysis.
METHODS: A literature search using keywords "statin" or "statins" combined with "minimum inhibitory concentration" (MIC) was performed in six databases on 7th April 2017. After screening 793 abstracts, 16 relevant studies were identified. Unrelated studies on drug interactions; antifungal or antiviral properties of statins; and antibacterial properties of mevastatin, cerivastatin, antibiotics, or natural products were excluded. Studies involving only statins currently registered for human use were included.
RESULTS: Against Gram-positive bacteria, simvastatin generally exerted the greatest antibacterial activity (lowest MIC) compared to atorvastatin, rosuvastatin, and fluvastatin. Against Gram-negative bacteria, atorvastatin generally exhibited similar or slightly better activity compared to simvastatin, but both were more potent than rosuvastatin and fluvastatin.
DISCUSSION: Statins may serve as AMR breakers by working synergistically with existing topical antibiotics, attenuating virulence factors, boosting human immunity, or aiding in wound healing. It is probable that statins' mechanism of antibacterial activity involves interference of bacterial cell regulatory functions via binding and disrupting cell surface structures such as wall teichoic acids, lipoteichoic acids, lipopolysaccharides, and/or surface proteins. The widespread use of statins for cardiovascular protection may favor selective pressures or co-selection for resistance, including dysbiosis of the human gut microbiota, sublethal plasma concentrations in bacteremic patients, and statin persistence in the environment, all possibly culminating in AMR.
CONCLUSION: Simvastatin appears to be the most suitable statin for repurposing as a novel adjuvant antibiotic. Current evidence better supports statins as potential AMR breakers, but their role as plausible AMR makers cannot be excluded. Elucidating the mechanism of statins' antibacterial activity is perhaps the most important knowledge gap to address as this will likely clarify statins' role as AMR breakers or makers.

PMID: 29085751 [PubMed]

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology.

Nat Genet. 2017 Oct 30;:

Authors: Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, Helmer Q, Tillander A, Ullemar V, van Dongen J, Lu Y, Rüschendorf F, Esparza-Gordillo J, Medway CW, Mountjoy E, Burrows K, Hummel O, Grosche S, Brumpton BM, Witte JS, Hottenga JJ, Willemsen G, Zheng J, Rodríguez E, Hotze M, Franke A, Revez JA, Beesley J, Matheson MC, Dharmage SC, Bain LM, Fritsche LG, Gabrielsen ME, Balliu B, 23andMe Research Team, AAGC collaborators, BIOS consortium, LifeLines Cohort Study, Nielsen JB, Zhou W, Hveem K, Langhammer A, Holmen OL, Løset M, Abecasis GR, Willer CJ, Arnold A, Homuth G, Schmidt CO, Thompson PJ, Martin NG, Duffy DL, Novak N, Schulz H, Karrasch S, Gieger C, Strauch K, Melles RB, Hinds DA, Hübner N, Weidinger S, Magnusson PKE, Jansen R, Jorgenson E, Lee YA, Boomsma DI, Almqvist C, Karlsson R, Koppelman GH, Paternoster L

Abstract
Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10(-8)), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

PMID: 29083406 [PubMed - as supplied by publisher]

In silico repurposing of antipsychotic drugs for Alzheimer's disease.

BMC Neurosci. 2017 Oct 27;18(1):76

Authors: Kumar S, Chowdhury S, Kumar S

Abstract
BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies.
RESULT: A computational method based on ligand-protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski's rule.
CONCLUSION: The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

PMID: 29078760 [PubMed - in process]

Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis.

Expert Opin Ther Targets. 2017 Oct 27;:

Authors: Nuvolone M, Merlini G

Abstract
INTRODUCTION: Systemic amyloidosis occurs when one of a growing list of circulating proteins acquires an abnormal fold, aggregates and gives rise to extracellular amyloid deposits in different body sites, leading to organ dysfunction and eventually death. Current approaches are mainly aimed at lowering the supply of the amyloidogenic precursor or at stabilizing it in a non-amyloidogenic state, thus interfering with the initial phases of amyloid formation and toxicity. Areas covered: Improved understanding of the pathophysiology is indicating novel steps and molecules that could be therapeutically targeted. Here, we will review emerging molecular targets and therapeutic approaches against the main forms of systemic amyloidosis at the early preclinical level. Expert Opinion: Conspicuous efforts in drug design and drug discovery have provided an unprecedented list of potential new drugs or therapeutic strategies, from gene-based therapies to small molecules and peptides, from novel monoclonal antibodies to engineered cell-based therapies. The challenge will now be to validate and optimize the most promising candidates, cross the bridge from the preclinical phase to the clinics and identify, through innovative trials design, the safest and most effective combination therapies, striving for a better care, possibly a definitive cure for these diseases.

PMID: 29076382 [PubMed - as supplied by publisher]

Overcoming Obstacles to Drug Repositioning in Japan.

Front Pharmacol. 2017;8:729

Authors: Nishimura Y, Tagawa M, Ito H, Tsuruma K, Hara H

Abstract
Drug repositioning (DR) is the process of identifying new indications for existing drugs. DR usually focuses on drugs that have cleared phase-I safety trials but has yet to show efficacy for the intended indication. Therefore, DR can probably skip the preclinical and phase-I study, which can reduce the cost throughout drug development. However, the expensive phase-II/III trials are required to establish efficacy. The obstacles to DR include identification of new indications with a high success rate in clinical studies, obtaining funding for clinical studies, patent protection, and approval systems. To tackle these obstacles, various approaches have been applied to DR worldwide. In this perspective, we provide representative examples of DR and discuss the ongoing efforts to overcome obstacles to DR in Japan.

PMID: 29075191 [PubMed]

Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer.

Oncotarget. 2017 Sep 22;8(42):72147-72156

Authors: Kobayashi Y, Kashima H, Rahmanto YS, Banno K, Yu Y, Matoba Y, Watanabe K, Iijima M, Takeda T, Kunitomi H, Iida M, Adachi M, Nakamura K, Tsuji K, Masuda K, Nomura H, Tominaga E, Aoki D

Abstract
Drug repositioning is an alternative strategy redirecting existing drugs for new disease. We have previously reported an antitumor effect of statins, antidyslipidemic drugs, on ovarian cancer in vitro and in vivo. In this study, we investigated the antitumor effects of other mevalonate pathway inhibitors and the mechanism of the antitumor effect from a metabolic perspective. The effects of inhibitors of the mevalonate pathway on tumor cell growth were evaluated in vitro. Bisphosphonates that inhibit this pathway are commonly used as antiosteoporotic drugs, and antitumor effects of the bisphosphonate were examined in vitro and in vivo. Metabolites in SKOV3 ovarian cancer cells were analyzed before and after lovastatin treatment, using capillary electrophoresis-mass spectrometry. All mevalonate pathway inhibitors showed concentration-dependent inhibitory effects on tumor cell growth. Particularly marked effects were obtained with inhibitors of farnesyltransferase and geranylgeranyltransferase. The bisphosphonate was also shown to have an antitumor effect in vivo. The expression of autophagy marker LC3A/3B was increased in cells after treatment. In metabolomics analysis, lovastatin treatment increased the metabolites involved in the tricarboxylic acid cycle while reducing the metabolites associated with glycolysis. Also it decreased glutathione and resulted to work with chemotherapeutic agents synergistically. Inhibition at any point in the mevalonate pathway, and especially of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, suppresses growth of ovarian cancer cells. Inhibition of this pathway may induce autophagy, cause a shift to activation of the tricarboxylic acid cycle and enhance susceptibility to chemotherapy. Drug repositioning targeting mevalonate pathway for ovarian cancer deserves consideration for clinical application.

PMID: 29069775 [PubMed]

A multicenter, randomized, placebo-controlled trial for cilostazol in patients with mild cognitive impairment: The COMCID study protocol.

Alzheimers Dement (N Y). 2016 Nov;2(4):250-257

Authors: Saito S, Kojima S, Oishi N, Kakuta R, Maki T, Yasuno F, Nagatsuka K, Yamamoto H, Fukuyama H, Fukushima M, Ihara M

Abstract
INTRODUCTION: There are currently no effective treatments preventing conversion from mild cognitive impairment (MCI) to Alzheimer's disease. Cilostazol is a selective type-3 phosphodiesterase inhibitor that ameliorates accumulation of amyloid-β and has prevented cognitive decline in rodent models. Furthermore, cilostazol is known to suppress platelet aggregation, protect vascular endothelia, dilate vessels, and increase cerebral blood flow. Beneficial effects have also been shown in observational cohort studies, demonstrating the need for a prospective clinical trial.
METHODS: The Cilostazol for prevention of COnversion from MCI to Dementia (COMCID) study is a double-blind, randomized phase II study of patients with MCI. Participants will receive cilostazol or placebo for 96 weeks. The primary objective is to evaluate whether cilostazol slows down cognitive decline measured by the Mini-Mental State Examination. Secondary objectives are assessing time to conversion from MCI to dementia and assessing incremental changes in several psychological assessment scales.
DISCUSSION: The COMCID trial will identify the therapeutic potential of cilostazol. This trial, which is based on a drug repositioning strategy, may aid the development of a neurovascular treatment for neurocognitive disorders.

PMID: 29067312 [PubMed]

Olanzapine, an Atypical Antipsychotic, Inhibits Survivin Expression and Sensitizes Cancer Cells to Chemotherapeutic Agents.

Anticancer Res. 2017 11;37(11):6177-6188

Authors: Sanomachi T, Suzuki S, Kuramoto K, Takeda H, Sakaki H, Togashi K, Seino S, Yoshioka T, Okada M, Kitanaka C

Abstract
BACKGROUND/AIM: Olanzapine, an atypical antipsychotic, is now increasingly used as an off-label indication for the management of cancer patients with chemotherapy-induced nausea and vomiting (CINV). However, how olanzapine affects cancer cells per se remains poorly understood.
MATERIALS AND METHODS: The effects of olanzapine treatment and survivin knockdown, alone or in combination with chemotherapeutic agents, on survivin expression and cell viability were investigated in human cancer cell lines.
RESULTS: Olanzapine reduced survivin expression in lung and pancreatic cancer stem cell (CSC) lines and sensitized them to chemotherapeutic agents such as 5-fluorouracil, gemcitabine, and cisplatin in a survivin expression-dependent manner. Olanzapine also reduced survivin expression and chemosensitized serum-cultured, non-CSC ovarian cancer cells that expressed survivin.
CONCLUSION: Olanzapine may benefit cancer patients not only as an antiemetic for CINV, but also by enhancing the effects of chemotherapeutic agents through down-regulation of survivin, which has been implicated in multidrug chemoresistance.

PMID: 29061799 [PubMed - in process]