Therapeutic Potentials and Mechanisms of Artemisinin and its Derivatives for Tumorigenesis and Metastasis.

Anticancer Agents Med Chem. 2020 Jan 19;:

Authors: Li Y, Zhou X, Liu J, Yuan X, He Q

Abstract
BACKGROUND: Tumor recurrence and metastasis are still leading causes of cancer mortality worldwide. The influence of traditional treatment strategies against metastatic tumor may still be limited. To search for novel and powerful agents against tumors become a major research focus. In this study, Artemisinin (ARM), a natural compound isolated from herbs, Artemisia annua L., proceeding from drug repurposing methods, attracts more attention due to its good efficacy and tolerance in antimalarial practices, as well as newly confirmed anticancer activity.
METHODS: We have searched and reviewed the literatures about ARM and its derivatives (ARMs) for cancer using keywords 'artemisinin' until May 2019.
RESULTS: In preclinical studies, ARMs can induce cell cycle arrest and cell death by apoptosis etc., to inhibit the progression of tumors, and suppress EMT and angiogenesis to inhibit the metastasis of tumors. Notably, the complex relationships of ARMs and autophagy is worth exploring. Inspired by the limitations of its antimalarial applications and the mechanical studies of artemisinin and cancer, people are also committed to develop safer and more potent ARM-based modified compounds (ARMs) or combination therapy, such as artemisinin dimers/trimers, artemisinin-derived hybrids. Some clinical trials support artemisinins as promising candidates for cancer therapy.
CONCLUSION: ARMs show potent therapeutic potentials against carcinoma including metastatic tumors. Novel compounds derived from artemisinin and relevant combination therapies are supposed to be promising treatment strategies for tumors, as the important future research directions.

PMID: 31958040 [PubMed - as supplied by publisher]

Drug repositioning in cancer: the current situation in Japan.

Cancer Sci. 2020 Jan 19;:

Authors: Masuda T, Tsuruda Y, Matsumoto Y, Uchida H, Nakayama KI, Mimori K

Abstract
Cancer is a leading cause of mortality worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in recent years. DR now has become a powerful alternative strategy to discover and develop novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics, and bioinformatics has accelerated the pace of activity-based, literature-based, and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

PMID: 31957175 [PubMed - as supplied by publisher]

A Review of Recent Developments and Progress in Computational Drug Repositioning.

Curr Pharm Des. 2020 Jan 16;:

Authors: Shi W, Chen X, Deng L

Abstract
Computational drug repositioning is an efficient approach towards discovering new indications for existing drugs. In recent years, with the accumulation of online health-related information and the extensive use of biomedical databases, computational drug repositioning approaches have achieved significant progress in drug discovery. In this review, we summarize recent advancements in drug repositioning. Firstly, we detailed demonstrate available data source information which is conducive to identifying novel indications. Furthermore, we provide a summary of commonly used computing approaches. For each method, we briefly describe techniques, case studies, and evaluation criteria. Finally, we discuss the limitations of existing computing approaches.

PMID: 31951162 [PubMed - as supplied by publisher]

Expanding the activity spectrum of antiviral agents.

Drug Discov Today. 2019 05;24(5):1224-1228

Authors: Ianevski A, Andersen PI, Merits A, Bjørås M, Kainov D

Abstract
Broad-spectrum antivirals (BSAs) are agents that inhibit replication of several human viruses. Here, we review 108 approved, investigational, and experimental BSAs, for which safety profiles in humans are available. The most effective and tolerable BSAs could reinforce the arsenal of available antiviral therapeutics pending the results of further pre-clinical and clinical studies.

PMID: 30980905 [PubMed - indexed for MEDLINE]

In Silico and In Vitro Experimental Studies of New Dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)-oximes Designed as Potential Antimicrobial Agents.

Molecules. 2020 Jan 13;25(2):

Authors: Vlad IM, Nuta DC, Chirita C, Caproiu MT, Draghici C, Dumitrascu F, Bleotu C, Avram S, Udrea AM, Missir AV, Marutescu LG, Limban C

Abstract
In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a-j) were confirmed by 1H-NMR, 13C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a-j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues.

PMID: 31941125 [PubMed - in process]

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs.

Cancers (Basel). 2020 Jan 13;12(1):

Authors: Wu CP, Hsiao SH, Huang YH, Hung LC, Yu YJ, Chang YT, Hung TH, Wu YS

Abstract
The development of multidrug resistance (MDR) in cancer patients driven by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells presents one of the most daunting therapeutic complications for clinical scientists to resolve. Despite many novel therapeutic strategies that have been tested over the years, there is still no approved treatment for multidrug-resistant cancers to date. We have recently adopted a drug repurposing approach to identify therapeutic agents that are clinically active and at the same time, capable of reversing multidrug resistance mediated by ABCB1 and ABCG2. In the present study, we investigated the effect of sitravatinib, a novel multitargeted receptor tyrosine kinase inhibitor, on human ABCB1 and ABCG2 in multidrug-resistant cancer cell lines. We discovered that at submicromolar concentrations, sitravatinib re-sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. We found that sitravatinib blocks the drug efflux function of ABCB1 and ABCG2 in a concentration-dependent manner but does not significantly alter the protein expression of ABCB1 or ABCG2 in multidrug-resistant cancer cells. In conclusion, we reveal a potential drug repositioning treatment option for multidrug-resistant cancers by targeting ABCB1 and ABCG2 with sitravatinib and should be further investigated in future clinical trials.

PMID: 31941029 [PubMed]

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations.

Int J Mol Sci. 2020 Jan 13;21(2):

Authors: Liguori L, Monticelli M, Allocca M, Hay Mele B, Lukas J, Cubellis MV, Andreotti G

Abstract
The term "pharmacological chaperone" was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

PMID: 31940970 [PubMed - in process]

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Nat Commun. 2020 Jan 14;11(1):255

Authors: Li YR, Glessner JT, Coe BP, Li J, Mohebnasab M, Chang X, Connolly J, Kao C, Wei Z, Bradfield J, Kim C, Hou C, Khan M, Mentch F, Qiu H, Bakay M, Cardinale C, Lemma M, Abrams D, Bridglall-Jhingoor A, Behr M, Harrison S, Otieno G, Thomas A, Wang F, Chiavacci R, Wu L, Hadley D, Goldmuntz E, Elia J, Maris J, Grundmeier R, Devoto M, Keating B, March M, Pellagrino R, Grant SFA, Sleiman PMA, Li M, Eichler EE, Hakonarson H

Abstract
Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

PMID: 31937769 [PubMed - in process]

[Congenital myasthenic syndromes: repurposing does not simplify access de facto - Clinical use of innovative, repurposed or off-label therapies: a real life experience (4)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:28-31

Authors: Eymard B

PMID: 30943158 [PubMed - indexed for MEDLINE]

[Accompanying patients in the arrival of new treatments. The AFM-Téléthon regional services experience - Clinical use of innovative, repurposed or off-label therapies: a real life experience (3)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:26-27

Authors: Merret G

PMID: 30943157 [PubMed - indexed for MEDLINE]

[Nusinersen in SMA children: evolution or revolution? - Clinical use of innovative, repurposed or off-label therapies: a real life experience (2)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:22-25

Authors: Richelme C

PMID: 30943156 [PubMed - indexed for MEDLINE]

[Late-onset Pompe disease: the lessons drawn from the use of Myosime® - Clinical use of innovative, repurposed or off-label therapies: a real life experience (1)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:18-21

Authors: Laforêt P

PMID: 30943155 [PubMed - indexed for MEDLINE]

Development of Inhalable Quinacrine Loaded Bovine Serum Albumin Modified Cationic Nanoparticles: Repurposing Quinacrine for Lung Cancer Therapeutics.

Int J Pharm. 2020 Jan 11;:118995

Authors: Vaidya B, Kulkarni NS, Shukla SK, Parvathaneni V, Chauhan G, Damon JK, Sarode A, V Garcia J, Kunda N, Mitragotri S, Gupta V

Abstract
Drug repurposing is on the rise as an atypical strategy for discovery of new molecules, involving use of pre-existing molecules for a different therapeutic application than the approved indication. Using this strategy, the current study aims to leverage effects of quinacrine (QA), a well-known anti-malarial drug, for treatment of non-small cell lung cancer (NSCLC). For respiratory diseases, designing a QA loaded inhalable delivery system has multiple advantages over invasive delivery. QA-loaded nanoparticles (NPs) were thus prepared using polyethyleneimine (PEI) as a cationic stabilizer. While the use of PEI provided cationic charge on the particles, it also mediated a burst release of QA and demonstrated potential particle toxicity. These concerns were circumvented by coating nanoparticles with bovine serum albumin (BSA), which retained the cationic charge, reduced NP toxicity and modulated QA release. Prepared nanoparticles were characterized for physicochemical properties along with their aerosolization potential. Therapeutic efficacy of the formulations was tested in different NSCLC cells. Mechanism of higher anti-proliferation was evaluated by studying cell cycle profile, apoptosis and molecular markers involved in the progression of lung cancer. BSA coated QA nanoparticles demonstrated good aerosolization potential with a mass median aerodynamic diameter of significantly less than 5µm. Nanoparticles also demonstrated improved therapeutic efficacy against NSCLC cells in terms of low IC50 values, cell cycle arrest at G2/M phase and autophagy inhibition leading to increased apoptosis. BSA coated QA NPs also demonstrated enhanced therapeutic efficacy in a 3D cell culture model. The present study thus lays solid groundwork for pre-clinical and eventual clinical studies as a standalone therapy and in combination with existing chemotherapeutics.

PMID: 31935471 [PubMed - as supplied by publisher]

Repurposing an HIV Drug for Zika Virus Therapy.

Mol Ther. 2019 12 04;27(12):2064-2066

Authors: Xie X, Shi PY

PMID: 31624014 [PubMed - indexed for MEDLINE]

Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa.

ACS Infect Dis. 2019 01 11;5(1):141-151

Authors: Hubble VB, Hubbard BA, Minrovic BM, Melander RJ, Melander C

Abstract
A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection.

PMID: 30444345 [PubMed - indexed for MEDLINE]

Antibacterial activity of griseofulvin analogs as example of drug repurposing.

Int J Antimicrob Agents. 2020 Jan 10;:105884

Authors: Geronikaki A, Kartsev V, Petrou A, Akrivou MG, Vizirianakis IS, Chatzopoulou FM, Lichitsky B, Sirakanyan S, Kostic M, Smiljkovic M, Soković M, Druzhilovskiy D, Poroikov V

Abstract
Griseofulvin is a well-known antifungal drug launched in 1962 by Merck & Co. for treatment of dermatophyte infections. However, according to the predictions using Way2Drug computational drug repurposing platform, it may have antibacterial activity. Since no faultless confirmation of this prediction was found in the published literature, we estimated in silico antibacterial activity for 42 griseofulvin derivatives synthesized earlier. Antibacterial activity was predicted for 33 from 42 molecules, which lead to the conclusion that this activity might be considered as typical for the appropriate chemical series. Therefore, the experimental testing of antibacterial activity was performed on a panel of gram-positive and gram-negative microorganisms. The antibacterial activity was evaluated using the microdilution method detecting the minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations. The tested compounds exhibited the potent antibacterial activity against all the studied bacteria, with MIC and MBC ranging from 0.0037-0.04 mg/ml and 0.01-0.16 mg/ml, respectively. Their activity exceeded 2.5 to 12 times those of the ampicillin and 2 to 8 times those of the streptomycin, which were used as the reference drugs. Similarity analysis for all 42 compounds with the about 470 thousand drug-like compounds indexed by Clarivate Analytics Integrity database confirmed the significant novelty of the antibacterial activity for the compounds from this chemical class. Therefore, our study demonstrated that by computer-aided prediction of biological activity spectra for a particular chemical series it is possible to identify typical biological activities, which may be used for discovery of new applications for those molecules, e.g., drug repurposing.

PMID: 31931149 [PubMed - as supplied by publisher]

Ropinirole, a New ALS Drug Candidate Developed Using iPSCs.

Trends Pharmacol Sci. 2020 Jan 08;:

Authors: Okano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S

Abstract
Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugs - ropinirole (ROPI), retigabine, and bosutinib - have been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.

PMID: 31926602 [PubMed - as supplied by publisher]

Metabolomics-Driven Exploration of the Chemical Drug Space to Predict Combination Antimicrobial Therapies.

Mol Cell. 2019 06 20;74(6):1291-1303.e6

Authors: Campos AI, Zampieri M

Abstract
Alternative to the conventional search for single-target, single-compound treatments, combination therapies can open entirely new opportunities to fight antibiotic resistance. However, combinatorial complexity prohibits experimental testing of drug combinations on a large scale, and methods to rationally design combination therapies are lagging behind. Here, we developed a combined experimental-computational approach to predict drug-drug interactions using high-throughput metabolomics. The approach was tested on 1,279 pharmacologically diverse drugs applied to the gram-negative bacterium Escherichia coli. Combining our metabolic profiling of drug response with previously generated metabolic and chemogenomic profiles of 3,807 single-gene deletion strains revealed an unexpectedly large space of inhibited gene functions and enabled rational design of drug combinations. This approach is applicable to other therapeutic areas and can unveil unprecedented insights into drug tolerance, side effects, and repurposing. The compendium of drug-associated metabolome profiles is available at https://zampierigroup.shinyapps.io/EcoPrestMet, providing a valuable resource for the microbiological and pharmacological communities.

PMID: 31047795 [PubMed - indexed for MEDLINE]

Construction of asthma related competing endogenous RNA network revealed novel long non-coding RNAs and potential new drugs.

Respir Res. 2020 Jan 10;21(1):14

Authors: Liao Y, Li P, Wang Y, Chen H, Ning S, Su D

Abstract
BACKGROUND: Asthma is a heterogeneous disease characterized by chronic airway inflammation. Long non-coding RNA can act as competing endogenous RNA to mRNA, and play significant role in many diseases. However, there is little known about the profiles of long non-coding RNA and the long non-coding RNA related competing endogenous RNA network in asthma. In current study, we aimed to explore the long non-coding RNA-microRNA-mRNA competing endogenous RNA network in asthma and their potential implications for therapy and prognosis.
METHODS: Asthma-related gene expression profiles were downloaded from the Gene Expression Omnibus database, re-annotated with these genes and identified for asthma-associated differentially expressed mRNAs and long non-coding RNAs. The long non-coding RNA-miRNA interaction data and mRNA-miRNA interaction data were downloaded using the starBase database to construct a long non-coding RNA-miRNA-mRNA global competing endogenous RNA network and extract asthma-related differentially expressed competing endogenous RNA network. Finally, functional enrichment analysis and drug repositioning of asthma-associated differentially expressed competing endogenous RNA networks were performed to further identify key long non-coding RNAs and potential therapeutics associated with asthma.
RESULTS: This study constructed an asthma-associated competing endogenous RNA network, determined 5 key long non-coding RNAs (MALAT1, MIR17HG, CASC2, MAGI2-AS3, DAPK1-IT1) and identified 8 potential new drugs (Tamoxifen, Ruxolitinib, Tretinoin, Quercetin, Dasatinib, Levocarnitine, Niflumic Acid, Glyburide).
CONCLUSIONS: The results suggested that long non-coding RNA played an important role in asthma, and these novel long non-coding RNAs could be potential therapeutic target and prognostic biomarkers. At the same time, potential new drugs for asthma treatment have been discovered through drug repositioning techniques, providing a new direction for the treatment of asthma.

PMID: 31924195 [PubMed - in process]

Editorial: Innovative Therapeutic and Vaccine Approaches Against Respiratory Pathogens.

Front Immunol. 2019;10:2960

Authors: Calzas C, Descamps D, Chignard M, Chevalier C

PMID: 31921201 [PubMed - in process]