Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer.

Front Genet. 2019;10:420

Authors: Turanli B, Karagoz K, Bidkhori G, Sinha R, Gatza ML, Uhlen M, Mardinoglu A, Arga KY

Abstract
Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype, is the 5th leading cause of cancer deaths for women in the United States. The overall prognosis for TNBC patients remains poor given that few treatment options exist; including targeted therapies (not FDA approved), and multi-agent chemotherapy as standard-of-care treatment. TNBC like other complex diseases is governed by the perturbations of the complex interaction networks thereby elucidating the underlying molecular mechanisms of this disease in the context of network principles, which have the potential to identify targets for drug development. Here, we present an integrated "omics" approach based on the use of transcriptome and interactome data to identify dynamic/active protein-protein interaction networks (PPINs) in TNBC patients. We have identified three highly connected modules, EED, DHX9, and AURKA, which are extremely activated in TNBC tumors compared to both normal tissues and other breast cancer subtypes. Based on the functional analyses, we propose that these modules are potential drivers of proliferation and, as such, should be considered candidate molecular targets for drug development or drug repositioning in TNBC. Consistent with this argument, we repurposed steroids, anti-inflammatory agents, anti-infective agents, cardiovascular agents for patients with basal-like breast cancer. Finally, we have performed essential metabolite analysis on personalized genome-scale metabolic models and found that metabolites such as sphingosine-1-phosphate and cholesterol-sulfate have utmost importance in TNBC tumor growth.

PMID: 31134131 [PubMed]

IP1867B suppresses the insulin-like growth factor 1 receptor (IGF1R) ablating epidermal growth factor receptor inhibitor resistance in adult high grade gliomas.

Cancer Lett. 2019 May 23;:

Authors: Mihajluk K, Simms C, Reay M, Madureira P, Howarth A, Murray P, Nasser S, Duckworth CA, Pritchard DM, Pilkington GJ, Hill R

Abstract
High grade gliomas (HGGs) are aggressive primary brain tumours with local invasive growth and poor clinical prognosis. Clinical outcome is compounded by resistance to standard and novel therapeutics. We have evaluated reformulated aspirin (IP1867B) alone and in combination with conventional and novel anti-aHGG agents. We show that recent biopsy-derived aHGG models were highly resistant to conventional therapeutics although show sensitivity to IP1867B, a reformulated "liquid" aspirin. IP1867B treatment mediated a potent suppression of the IL6/STAT3 and NF-κB pathways and observed a significant reduction in EGFR transcription and protein expression. We observed the loss of the insulin-like growth factor 1 and insulin-like growth factor 1 receptor expression at both the transcript and protein level post IP1867B treatment. This increased sensitivity to EGFR inhibitors. In vivo, IP1867B was very well tolerated, had little-to-no gastric lesions versus aspirin and, directed a significant reduction of tumour burden with suppression of EGFR, IGF1 and IGFR1. With EGFR inhibitors, we noted a potent synergistic response in aHGG cells. These data provide a rationale for further investigation of IP1867B with a number of anti-EGFR agents currently being evaluated in the clinic.

PMID: 31129148 [PubMed - as supplied by publisher]

Systematic analysis of genes and diseases using PheWAS-Associated networks.

Comput Biol Med. 2019 May 01;109:311-321

Authors: Khosravi A, Kouhsar M, Goliaei B, Jayaram B, Masoudi-Nejad A

Abstract
Several scientific sources have reported different causes of various diseases. One of these factors is genetic variation. Natural selection, molecular evolution and susceptibility to external conditions are the main causes of genetic variations. Phenome-Wide Association Studies (PheWAS) can emphasize the associations of genetic variations and diseases. The systematic analysis of these associations can highlight various important aspects of gene correlations and disease relationships. In this study, we have investigated a systematic approach to analyze associated networks of genes and diseases to explore novel scientific information. We have constructed the Associated Gene Network (AGN, n = 1769) and the Associated Disease Network (ADN, n = 503) based on common diseases and genes, respectively. We have evaluated these networks based on topological measures and compared them with a randomized null network. The comparative modular analysis based on size and quantity is a clear indication of the significance of these networks. We have found numerous novel associations of genes involved in different diseases. We have also found different diseases related to one another, which can correlate scientific evidence. We have verified our analysis through GO and KEGG enrichment for different case studies and concluded that AGN and ADN can be used as reference biological networks for various purposes such as drug design and drug repurposing.

PMID: 31128465 [PubMed - as supplied by publisher]

Identifying and targeting cancer-specific metabolism with network-based drug target prediction.

EBioMedicine. 2019 May 21;:

Authors: Pacheco MP, Bintener T, Ternes D, Kulms D, Haan S, Letellier E, Sauter T

Abstract
BACKGROUND: Metabolic rewiring allows cancer cells to sustain high proliferation rates. Thus, targeting only the cancer-specific cellular metabolism will safeguard healthy tissues.
METHODS: We developed the very efficient FASTCORMICS RNA-seq workflow (rFASTCORMICS) to build 10,005 high-resolution metabolic models from the TCGA dataset to capture metabolic rewiring strategies in cancer cells. Colorectal cancer (CRC) was used as a test case for a repurposing workflow based on rFASTCORMICS.
FINDINGS: Alternative pathways that are not required for proliferation or survival tend to be shut down and, therefore, tumours display cancer-specific essential genes that are significantly enriched for known drug targets. We identified naftifine, ketoconazole, and mimosine as new potential CRC drugs, which were experimentally validated.
INTERPRETATION: The here presented rFASTCORMICS workflow successfully reconstructs a metabolic model based on RNA-seq data and successfully predicted drug targets and drugs not yet indicted for colorectal cancer. FUND: This study was supported by the University of Luxembourg (IRP grant scheme; R-AGR-0755-12), the Luxembourg National Research Fund (FNR PRIDE PRIDE15/10675146/CANBIO), the Fondation Cancer (Luxembourg), the European Union's Horizon2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No 642295 (MEL-PLEX), and the German Federal Ministry of Education and Research (BMBF) within the project MelanomSensitivity (BMBF/BM/7643621).

PMID: 31126892 [PubMed - as supplied by publisher]

Updates to Binding MOAD (Mother of All Databases): Polypharmacology Tools and Their Utility in Drug Repurposing.

J Mol Biol. 2019 May 21;:

Authors: Smith RD, Clark JJ, Ahmed A, Orban ZJ, Dunbar JB, Carlson HA

Abstract
The goal of Binding MOAD is to provide users with a dataset focused on high-quality X-ray crystal structures that have been solved with biologically relevant ligands bound. Where available, experimental binding affinities (Ka, Kd, Ki, IC50) are provided from the primary literature of the crystal structure. The database has been updated regularly since 2005, and this most recent update has added nearly 7000 new structures (growth of 21%). MOAD currently contains 32,747 structures, composed of 9117 protein families and 16,044 unique ligands. The data is freely available on www.BindingMOAD.org. This paper outlines updates to the data in Binding MOAD as well as improvements made to both the website and its contents. The NGL viewer has been added to improve visualization of the ligands and protein structures. MarvinJS has been implemented, over the outdated MarvinView, to work with JChem for small molecule searching in the database. To add tools for predicting polypharmacology, we have added information about sequence, binding-site, and ligand similarity between entries in the database. A main premise behind polypharmacology is that similar binding sites will bind similar ligands. The large amount of protein-ligand information available in Binding MOAD allows us to compute pairwise ligand and binding-site similarities. Lists of similar ligands and similar binding sites have been added to allow users to identify potential polypharmacology pairs. To show the utility of the polypharmacology data, we detail a few examples from Binding MOAD of drug repurposing targets with their respective similarities.

PMID: 31125569 [PubMed - as supplied by publisher]

Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study.

Amyloid. 2019 May 23;:1-11

Authors: Gamez J, Salvadó M, Reig N, Suñé P, Casasnovas C, Rojas-Garcia R, Insa R

Abstract
Objective: To assess the transthyretin (TTR) stabilization activity of tolcapone (SOM0226) in patients with hereditary ATTR amyloidosis, asymptomatic carriers and healthy volunteers. Methods: A phase IIa proof-of-concept trial included two phases separated by a 6-week washout period. Phase A: single 200 mg dose of tolcapone; phase B: three 100 mg doses taken at 4 h intervals. The primary efficacy variable was TTR stabilization. Results: Seventeen subjects were included (wild type, n = 6; mutation TTR Val30Met, n = 11). TTR stabilization was observed in all participants. Two hours after dosing, 82% of participants in phase A and 93% of those in phase B reached a TTR stabilization value of at least 20%. In phase A, there was an increase of 52% in TTR stabilization vs baseline values 2 h after dosing, which decreased to 22.9% at 8 h. In phase B, there was a significant increase of 38.8% in TTR stabilization 2 h after the first 100 mg dose. This difference was maintained after 10 h and decreased after 24 h. No serious adverse events were observed. Conclusions: The ability of tolcapone for stabilizing TTR supports further development and repositioning of the drug for the treatment of ATTR amyloidosis. EudraCT trial number: 2014-001586-27 ClinicalTrials.gov Identifier: NCT02191826.

PMID: 31119947 [PubMed - as supplied by publisher]

Avapritinib, a selective inhibitor of KIT and PDGFRα reverses ABCB1 and ABCG2-mediated multidrug resistance in cancer cell lines.

Mol Pharm. 2019 May 22;:

Authors: Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV

Abstract
The frequent occurrence of multidrug resistance (MDR) conferred by the overexpression of ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 in cancer cells remains a therapeutic obstacle for scientists and clinicians. Consequently, developing or identifying modulators of ABCB1 and ABCG2 that are suitable for clinical practice is of great importance. Therefore, we have explored the drug repositioning approach to identify candidate modulators of ABCB1 and ABCG2 from tyrosine kinase inhibitors with known pharmacological properties and anticancer activities. In this study, we discovered that avapritinib (BLU-285), a potent, selective and orally bioavailable tyrosine kinase inhibitor against mutant forms of KIT and platelet-derived growth factor receptor alpha (PDGFRA), attenuates the transport function of both ABCB1 and ABCG2. Moreover, avapritinib restores the chemosensitivity of ABCB1- and ABCG2-overexpressing MDR cancer cells at non-toxic concentrations. These findings were further supported by results of apoptosis induction assays, ATP hydrolysis assays and docking of avapritinib in the drug-binding pockets of ABCB1 and ABCG2. In summary, our study revealed an additional action of avapritinib on ABC drug transporters and combination of avapritinib with conventional chemotherapy should be further investigated in patients with MDR tumors.

PMID: 31117741 [PubMed - as supplied by publisher]

Integrating the drug, disulfiram into the vitamin E-TPGS-modified PEGylated nanostructured lipid carriers to synergize its repurposing for anti-cancer therapy of solid tumors.

Int J Pharm. 2019 Feb 25;557:374-389

Authors: Banerjee P, Geng T, Mahanty A, Li T, Zong L, Wang B

Abstract
The 'repurposed drug,' disulfiram (DSF), is an inexpensive FDA-approved anti-alcoholism drug with multi-target anti-cancer effect. However, the use of DSF in clinical settings remains limited due to its high instability in blood. In the present study, we created nanostructured lipid carriers (NLC) encapsulated DSF modified with d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E-TPGS). A spherical shape, superior drug encapsulation (80.7%), and decreased crystallinity of DSF were confirmed with results obtained from TEM, XRD, and DSC analysis. Addition of TPGS considerably improved the physicochemical stability profile of NLC-encapsulated DSF under the different conditions tested here. Furthermore, TPGS-DSF-NLCs outperformed unmodified DSF-NLCs and the free DSF solution by having significantly higher cytotoxicity, lower IC50 value (4T1: 263.2 nM and MCF-7: 279.9 nM), and an enhanced cellular uptake in MCF7 and 4T1 cell lines. In vivo anti-tumor analysis in 4T1 murine xenograft model mice revealed a significant (p-value < 0.05) decrease in tumor volume and higher tumor growth inhibition rate (48.24%) with TPGS-DSF-NLC treatment as compared to both the free DSF solution (8.49%) and DSF-NLC formulations (29.2%). Histopathology analysis of tumor tissues further confirmed a noticeably higher anti-tumor activity of TPGS-DSF-NLC through augmented cell necrosis in solid tumors. Hence, the present study established that addition of TPGS can synergize the anti-cancer activity of NLC-encapsulated DSF formulations, and thus, offer a promising anti-cancer delivery system for DSF.

PMID: 30610896 [PubMed - indexed for MEDLINE]

deepDR: A network-based deep learning approach to in silico drug repositioning.

Bioinformatics. 2019 May 22;:

Authors: Zeng X, Zhu S, Liu X, Zhou Y, Nussinov R, Cheng F

Abstract
MOTIVATION: Traditional drug discovery and development are often time-consuming and high-risk. Repurposing/repositioning of approved drugs offers a relatively low-cost and high-efficiency approach towards rapid development of efficacious treatments. The emergence of large-scale, heterogeneous biological networks has offered unprecedented opportunities for developing in silico drug repositioning approaches. However, capturing highly non-linear, heterogenous network structures by most existing approaches for drug repositioning has been challenging.
RESULTS: In this study, we developed a network-based deep-learning approach, termed deepDR, for in silico drug repurposing by integrating 10 networks: one drug-disease, one drug-side-effect, one drug-target, and 7 drug-drug networks. Specifically, deepDR learns high-level features of drugs from the heterogeneous networks by a multimodal deep autoencoder. Then the learned low-dimensional representation of drugs together with clinically reported drug-disease pairs are encoded and decoded collectively via a variational autoencoder to infer candidates for approved drugs for which they were not originally approved. We found that deepDR revealed high performance (the area under receiver operating characteristic curve [AUROC] = 0.908), outperforming conventional network-based or machine learning-based approaches. Importantly, deepDR-predicted drug-disease associations were validated by the ClinicalTrials.gov database (AUROC = 0.826) and we showcased several novel deepDR-predicted approved drugs for Alzheimer's disease (e.g., risperidone and aripiprazole) and Parkinson's disease (e.g., methylphenidate and pergolide).
AVAILABILITY: Source code and data can be downloaded from https://github.com/ChengF-Lab/deepDR.
SUPPLEMENTARY INFORMATION: Supplementary data are available online at Bioinformatics.

PMID: 31116390 [PubMed - as supplied by publisher]

[The time has come of a therapeutic (re)positioning of the ultra-rare diseases].

Med Sci (Paris). 2018 12;34(12):1019-1021

Authors: Martinat C, Peschanski M

PMID: 30623755 [PubMed - indexed for MEDLINE]

Repurposing of FDA-Approved NSAIDs for DPP-4 Inhibition as an Alternative for Diabetes Mellitus Treatment: Computational and in Vitro Study.

Pharmaceutics. 2019 May 17;11(5):

Authors: Chittepu VCSR, Kalhotra P, Osorio-Gallardo T, Gallardo-Velázquez T, Osorio-Revilla G

Abstract
A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein-ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus.

PMID: 31108878 [PubMed]

Target identification and intervention strategies against amebiasis.

Drug Resist Updat. 2019 May 03;44:1-14

Authors: Ankri S, Nagaraja S

Abstract
Entamoeba histolytica is the etiological agent of amebiasis, which is an endemic parasitic disease in developing countries and is the cause of approximately 70,000 deaths annually. E. histolytica trophozoites usually reside in the colon as a non-pathogenic commensal in most infected individuals (90% of infected individuals are asymptomatic). For unknown reasons, these trophozoites can become virulent and invasive, cause amebic dysentery, and migrate to the liver where they cause hepatocellular damage. Amebiasis is usually treated either by amebicides which are classified as (a) luminal and are active against the luminal forms of the parasite, (b) tissue and are effective against those parasites that have invaded tissues, and (c) mixed and are effective against the luminal forms of the parasite and those forms which invaded the host's tissues. Of the amebicides, the luminal amebicide, metronidazole (MTZ), is the most widely used drug to treat amebiasis. Although well tolerated, concerns about its adverse effects and the possible emergence of MTZ-resistant strains of E. histolytica have led to the development of new therapeutic strategies against amebiasis. These strategies include improving the potency of existing amebicides, discovering new uses for approved drugs (repurposing of existing drugs), drug rediscovery, vaccination, drug targeting of essential E. histolytica components, and the use of probiotics and bioactive natural products. This review examines each of these strategies in the light of the current knowledge on the gut microbiota of patients with amebiasis.

PMID: 31112766 [PubMed - as supplied by publisher]

Miconazole triggers various forms of cell death in human breast cancer MDA-MB-231 cells.

Pharmazie. 2019 May 01;74(5):290-294

Authors: Chengzhu WU, Gao M, Shen L, Bohan LI, Bai X, Gui J, Hongmei LI, Huo Q, Tao MA

Abstract
In recent years, "drug repurposing" has become an important approach and focus of studies on anti-tumor drug research and development (R&D). As one of the first-generation broad-spectrum imidazole anti-fungal drugs, miconazole (MCZ) exhibits anti-tumor effects in addition to its anti-fungal effect. However, no report has focused on examining the effect of MCZ on the proliferation and cell-death of human breast cancer MDA-MB-231 cells. MCZ significantly inhibited the proliferation of MDA-MB-231 cells in a concentration- and time-dependent manner. We also observed that MCZ induced both apoptosis and necroptosis in MDA-MB-231 cells. Transmission electron microscopy showed submicroscopic structures in these cells, which correspond to necrotic features, in addition to the characteristic features of apoptosis. Pretreatment of cells with z-VAD-fmk, an apoptosis inhibitor or Nec-1, a necroptosis inhibitor, significantly increased their viability compared with MCZ treatment. The initial mechanism of MCZ-mediated cell death in human breast cancer MDA-MB-231 cells involves an increase in the Bax/Bcl-2 ratio, downregulation of apoptosis induced by Akt and p-Akt-473, a simultaneous upregulation of the receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) protein expression, and ROS production to induce necroptosis. Our results suggest that MCZ may be a potential lead compound for the development of anti-breast cancer drugs.

PMID: 31109399 [PubMed - in process]

Drug ReposER: a web server for predicting similar amino acid arrangements to known drug binding interfaces for potential drug repositioning.

Nucleic Acids Res. 2019 May 20;:

Authors: Ab Ghani NS, Ramlan EI, Firdaus-Raih M

Abstract
A common drug repositioning strategy is the re-application of an existing drug to address alternative targets. A crucial aspect to enable such repurposing is that the drug's binding site on the original target is similar to that on the alternative target. Based on the assumption that proteins with similar binding sites may bind to similar drugs, the 3D substructure similarity data can be used to identify similar sites in other proteins that are not known targets. The Drug ReposER (DRug REPOSitioning Exploration Resource) web server is designed to identify potential targets for drug repurposing based on sub-structural similarity to the binding interfaces of known drug binding sites. The application has pre-computed amino acid arrangements from protein structures in the Protein Data Bank that are similar to the 3D arrangements of known drug binding sites thus allowing users to explore them as alternative targets. Users can annotate new structures for sites that are similarly arranged to the residues found in known drug binding interfaces. The search results are presented as mappings of matched sidechain superpositions. The results of the searches can be visualized using an integrated NGL viewer. The Drug ReposER server has no access restrictions and is available at http://mfrlab.org/drugreposer/.

PMID: 31106379 [PubMed - as supplied by publisher]

A pooled analysis of two phase II trials evaluating metformin plus platinum-based chemotherapy in advanced non-small cell lung cancer.

Cancer Treat Res Commun. 2019 May 10;20:100150

Authors: Parikh AB, Marrone KA, Becker DJ, Brahmer JR, Ettinger DS, Levy BP

Abstract
BACKGROUND: Despite a wealth of preclinical and observational data, prospective data regarding the use of metformin in lung cancer is extremely limited.
METHODS: We pooled individualized data from two prospective trials evaluating metformin plus platinum-based chemotherapy, with or without bevacizumab, in non-diabetic patients with untreated advanced NSCLC. In addition to reporting on clinical efficacy and safety endpoints, we also explored metformin's activity in key molecular cohorts.
RESULTS: 33 patients were included in the pooled analysis, of whom 70% were current or previous smokers. 82% had standard tissue molecular testing results available. KRAS, EGFR, and LKB1 mutation prevalence was 48%, 26%, and 8.3%, respectively. Composite median PFS was 6 months for all patients (95% CI: [1.36, 7.96]), 7.2 months for KRAS mutants (95% CI: [1.18, 9.21]), and 6.6 months for EGFR mutants (95% CI: [1.18, 15.29]). Composite median OS was 14.8 months for all patients (95% CI: [8.25, 19.99]), 17.5 months for KRAS mutants (95% CI: [8.86, 26.96]), and 13.3 months for EGFR mutants (95% CI: [2.60, 25.86]). Lymphopenia was the most common grade 3 AE (12%), followed by leukopenia, nausea, vomiting, and hypertension (9% each). There were 2 grade 4 AEs, neutropenia (21%) and sepsis (3%), and 1 grade 5 AE (colonic perforation) attributed to bevacizumab.
CONCLUSION: Our results confirm the previously shown efficacy and tolerability of metformin in combination with chemotherapy and highlight encouraging activity in key molecular cohorts. Future efforts should build on this work by prospectively studying metformin in these molecular subgroups.

PMID: 31102920 [PubMed - as supplied by publisher]

Serendipitous drug repurposing through social media.

Drug Discov Today. 2019 May 15;:

Authors: Kelly DP, Blatt J

PMID: 31102729 [PubMed - as supplied by publisher]

Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells.

PLoS One. 2019;14(5):e0216358

Authors: Inada M, Shindo M, Kobayashi K, Sato A, Yamamoto Y, Akasaki Y, Ichimura K, Tanuma SI

Abstract
The interaction between high-mobility group box 1 protein (HMGB1) and receptor for advanced glycation end products (RAGE) is important for tumor cell growth. We investigated the tumor biological effects of HMGB1 and RAGE interaction. Previously, we identified an inhibitor of HMGB1/RAGE interaction, papaverine (a non-narcotic opium alkaloid), using a unique drug design system and drug repositioning approach. In the present study, we examined the anticancer effects of papaverine in human glioblastoma (GBM) temozolomide (TMZ; as a first-line anticancer medicine)-sensitive U87MG and TMZ-resistant T98G cells. HMGB1 supplementation in the culture medium promoted tumor cell growth in T98G cells, and this effect was canceled by papaverine. In addition, papaverine in T98G cells suppressed cancer cell migration. As an HMGB1/RAGE inhibitor, papaverine also significantly inhibited cell proliferation in U87MG and T98G cells. The effects of papaverine were evaluated in vivo in a U87MG xenograft mouse model by determining tumor growth delay. The results indicate that papaverine, a smooth muscle relaxant, is a potential anticancer drug that may be useful in GBM chemotherapy.

PMID: 31100066 [PubMed - in process]

Metformin as a protective agent against natural or chemical toxicities: a comprehensive review on drug repositioning.

J Endocrinol Invest. 2019 May 16;:

Authors: Meshkani SE, Mahdian D, Abbaszadeh-Goudarzi K, Abroudi M, Dadashizadeh G, Lalau JD, De Broe ME, Hosseinzadeh H

Abstract
BACKGROUND: Metformin is the first prescribed drug for hyperglycemia in type 2 diabetes mellitus. Mainly by activating AMPK pathway, this drug exerts various functions that among them protective effects are of the interest.
PURPOSE: Herein, we aimed to gather data about the protective impacts of metformin against various natural or chemical toxicities.
RESULTS: An extensive search among PubMed, Scopus, and Google Scholar was conducted by keywords related to protection, toxicity, natural and chemical toxins and, metformin. Our literature review showed metformin alongside its anti-hyperglycemic effect has a wide range of anti-toxic effects against anti-tumour and routine drugs, natural and chemical toxins, herbicides and, heavy metals.
CONCLUSION: It is evident that metformin is a potent drug against the toxicity of a broad spectrum of natural, chemical toxic agents which is proved by a vast number of studies. Metformin mainly through AMPK axis can protect different organs against toxicities. Moreover, metformin preserves DNA integrity and can be an option for adjuvant therapy to ameliorate side effect of other therapeutics.

PMID: 31098946 [PubMed - as supplied by publisher]

Potential Applications of NRF2 Inhibitors in Cancer Therapy.

Oxid Med Cell Longev. 2019;2019:8592348

Authors: Panieri E, Saso L

Abstract
The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.

PMID: 31097977 [PubMed - in process]

Spironolactone inhibits the growth of cancer stem cells by impairing DNA damage response.

Oncogene. 2019 04;38(17):3103-3118

Authors: Gold A, Eini L, Nissim-Rafinia M, Viner R, Ezer S, Erez K, Aqaqe N, Hanania R, Milyavsky M, Meshorer E, Goldberg M

Abstract
The cancer stem cell (CSC) model suggests that a subpopulation of cells within the tumor, the CSCs, is responsible for cancer relapse and metastasis formation. CSCs hold unique characteristics, such as self-renewal, differentiation abilities, and resistance to chemotherapy, raising the need for discovering drugs that target CSCs. Previously we have found that the antihypertensive drug spironolactone impairs DNA damage response in cancer cells. Here we show that spironolactone, apart from inhibiting cancerous cell growth, is also highly toxic to CSCs. Notably, we demonstrate that CSCs have high basal levels of DNA double-strand breaks (DSBs). Mechanistically, we reveal that spironolactone does not damage the DNA but impairs DSB repair and induces apoptosis in cancer cells and CSCs while sparing healthy cells. In vivo, spironolactone treatment reduced the size and CSC content of tumors. Overall, we suggest spironolactone as an anticancer reagent, toxic to both cancer cells and, particularly to, CSCs.

PMID: 30622338 [PubMed - indexed for MEDLINE]