Cancers (Basel). 2022 Apr 23;14(9):2105. doi: 10.3390/cancers14092105.

ABSTRACT

Colorectal cancer (CRC) is the third most common cancer in the world. Despite improvement in standardized screening methods and the development of promising therapies, the 5-year survival rates are as low as 10% in the metastatic setting. The increasing life expectancy of the general population, higher rates of obesity, poor diet, and comorbidities contribute to the increasing trends in incidence. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC with the advantage of treating underlying comorbidities and decreasing chemotherapy toxicity. This review elaborates on the current data that supports drug repurposing as a feasible option for patients with CRC with a focus on the evidence and mechanism of action promising repurposed candidates that are widely used, including but not limited to anti-malarial, anti-helminthic, anti-inflammatory, anti-hypertensive, anti-hyperlipidemic, and anti-diabetic agents.

PMID:35565237 | DOI:10.3390/cancers14092105

Cancers (Basel). 2022 Apr 21;14(9):2072. doi: 10.3390/cancers14092072.

ABSTRACT

Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments.

PMID:35565202 | DOI:10.3390/cancers14092072

Int J Mol Sci. 2022 May 8;23(9):5245. doi: 10.3390/ijms23095245.

ABSTRACT

PLATO (Polypharmacology pLATform predictiOn) is an easy-to-use drug discovery web platform, which has been designed with a two-fold objective: to fish putative protein drug targets and to compute bioactivity values of small molecules. Predictions are based on the similarity principle, through a reverse ligand-based screening, based on a collection of 632,119 compounds known to be experimentally active on 6004 protein targets. An efficient backend implementation allows to speed-up the process that returns results for query in less than 20 s. The graphical user interface is intuitive to give practitioners easy input and transparent output, which is available as a standard report in portable document format. PLATO has been validated on thousands of external data, with performances better than those of other parallel approaches. PLATO is available free of charge (http://plato.uniba.it/ accessed on 13 April 2022).

PMID:35563636 | DOI:10.3390/ijms23095245

Int J Mol Sci. 2022 May 4;23(9):5129. doi: 10.3390/ijms23095129.

ABSTRACT

The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can contribute to the resistance to targeted small molecules, cytotoxic chemotherapy, and αPD1 immunotherapy. As genetic PDL1 depletion is not currently clinically tractable, we screened FDA-approved drugs to identify those that significantly deplete tumor PDL1. Among the candidates, we identified the β-lactam cephalosporin antibiotic cefepime as a tumor PDL1-depleting drug (PDD) that increases tumor DNA damage and sensitivity to DNA-damaging agents in vitro in distinct aggressive mouse and human cancer lines, including glioblastoma multiforme, ovarian cancer, bladder cancer, and melanoma. Cefepime reduced tumor PDL1 post-translationally through ubiquitination, improved DNA-damaging-agent treatment efficacy in vivo in immune-deficient and -proficient mice, activated immunogenic tumor STING signals, and phenocopied specific genetic PDL1 depletion effects. The β-lactam ring and its antibiotic properties did not appear contributory to PDL1 depletion or to these treatment effects, and the related cephalosporin ceftazidime produced similar effects. Our findings highlight the rapidly translated potential for PDDs to inhibit tumor-intrinsic PDL1 signals and improve DNA-damaging agents and immunotherapy efficacy.

PMID:35563520 | DOI:10.3390/ijms23095129

Int J Mol Sci. 2022 May 4;23(9):5106. doi: 10.3390/ijms23095106.

ABSTRACT

Mutations in human VPS13A-D genes result in rare neurological diseases, including chorea-acanthocytosis. The pathogenesis of these diseases is poorly understood, and no effective treatment is available. As VPS13 genes are evolutionarily conserved, the effects of the pathogenic mutations could be studied in model organisms, including yeast, where one VPS13 gene is present. In this review, we summarize advancements obtained using yeast. In recent studies, vps13Δ and vps13-I2749 yeast mutants, which are models of chorea-acanthocytosis, were used to screen for multicopy and chemical suppressors. Two of the suppressors, a fragment of the MYO3 and RCN2 genes, act by downregulating calcineurin activity. In addition, vps13Δ suppression was achieved by using calcineurin inhibitors. The other group of multicopy suppressors were genes: FET4, encoding iron transporter, and CTR1, CTR3 and CCC2, encoding copper transporters. Mechanisms of their suppression rely on causing an increase in the intracellular iron content. Moreover, among the identified chemical suppressors were copper ionophores, which require a functional iron uptake system for activity, and flavonoids, which bind iron. These findings point at areas for further investigation in a higher eukaryotic model of VPS13-related diseases and to new therapeutic targets: calcium signalling and copper and iron homeostasis. Furthermore, the identified drugs are interesting candidates for drug repurposing for these diseases.

PMID:35563497 | DOI:10.3390/ijms23095106

Int J Mol Sci. 2022 May 4;23(9):5105. doi: 10.3390/ijms23095105.

ABSTRACT

Fabry disease is caused by a deficiency of lysosomal alpha galactosidase and has a very large genotypic and phenotypic spectrum. Some patients who carry hypomorphic mutations can benefit from oral therapy with a pharmacological chaperone. The drug requires a very precise regimen because it is a reversible inhibitor of alpha-galactosidase. We looked for molecules that can potentiate this pharmacological chaperone, among drugs that have already been approved for other diseases. We tested candidate molecules in fibroblasts derived from a patient carrying a large deletion in the gene GLA, which were stably transfected with a plasmid expressing hypomorphic mutants. In our cell model, three drugs were able to potentiate the action of the pharmacological chaperone. We focused our attention on one of them, acetylsalicylic acid. We expect that acetylsalicylic acid can be used in synergy with the Fabry disease pharmacological chaperone and prolong its stabilizing effect on alpha-galactosidase.

PMID:35563496 | DOI:10.3390/ijms23095105

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R6296.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a survival rate of 10%. It is projected to be the second leading cause of cancer related deaths in USA by 2030. The therapeutic development against PDAC has been slow and chemotherapeutic resistance for available treatment options is a significant problem. Over the past few years, drug repurposing has shown promise as a fast, economic and reliable strategy to develop novel treatment options for most of the diseases. The repurposing of Remdesivir for COVID-19 is a recent example. Based on literature review, we screened multiple drugs for their anti-cancer efficacy and discovered potent anti-cancer activity of an anti-parasitic drug, MBO. We identified the anti-cancer effects of MBO in human PDAC cell lines AsPC-1, MiaPaCa-2, BXPC3, Panc-1 and SUIT-2. We also confirmed the effect of MBO to suppress colony formation in PDAC cell lines AsPC-1, MiaPaCa-2 and BXPC3. MBO induced apoptotic cell death in PDAC cell lines which was confirmed by Annexin V/APC analysis using flow cytometry. Importantly, through western blot analysis we identified that MBO inhibits the DARPP-32/β-catenin axis, an unexplored cellular signaling axis in PDAC. This identification is crucial since DARPP-32 is a novel protein which was recently identified to play a role in metastasis of PDAC. Pre-clinical efficacy of MBO was evaluated in an in vivotumor model by subcutaneously injecting human PDAC cell line MiaPaCa-2 in the left flank of the mice. MBO significantly suppressed tumor growth by 80% at an oral dose of 5 mg/kg. To summarize, our results show MBO inhibits the growth of PDAC by inhibiting the novel DARPP-32/ β-catenin axis.

PMID:35556644 | DOI:10.1096/fasebj.2022.36.S1.R6296

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R3191.

ABSTRACT

Although the study of dopamine is most often associated with the regulation of reward and motor function, a growing body of research indicates that dopamine also acts as an immunomodulatory regulator. Our data show that dopamine can influence the secretion of inflammatory cytokines in myeloid cells such as macrophages and microglia. Specifically, we have shown that dopamine modulates inflammation in primary human monocyte-derived macrophages (hMDM) through activation of the transcription factor NF-κB and priming of the NLRP3 inflammasome, upregulating the expression of IL-1 family cytokines (IL-1β and IL-18). However, the effect of dopamine on other proteins in the NLR family, including NLRP1, NLRC4, NLRC5, and AIM2, has not been defined. Each NLR protein is associated with a different inflammasome complex that has distinct activating stimuli, yet all inflammasomes mediate the secretion of IL-1 family cytokines. We hypothesize that the effects of dopamine on different types of inflammasomes is distinct and may result in activation of discrete inflammatory pathways and/or differentially regulate cytokine secretion. To address this, we examined dopamine-mediated changes in NLR proteins in both hMDM and a human microglial cell line (C20 cells). Our data indicate that in hMDM, dopamine upregulates expression of NLRC5, NLRC4, and AIM2 transcripts, while not changing NLRP1 mRNA expression. However, in microglia there was no expression of NLRC4 or AIM2, and dopamine downregulates NLRP1, while not changing NLRC5 mRNA expression. Ongoing work is using high-content immunofluorescent imaging and Western blotting to analyze inflammasome protein expression in these myeloid cell models and determine how this correlates with NLR gene expression as well as dopamine receptor expression. Determining how dopamine affects NLR expression could improve our understanding of the role of dopamine and its receptors as drug targets in individuals with substance use disorders. Further, the activity of these inflammasomes is associated with a number of neuroimmunological diseases such as Parkinson's, Alzheimer's, multiple sclerosis and HIV that show disrupted dopamine signaling. Therefore, understanding the more specific immunologic actions of dopamine could initiate drug repurposing and the development of new therapeutic strategies based on manipulating dopamine's effects on the immune system.

PMID:35554038 | DOI:10.1096/fasebj.2022.36.S1.R3191

Cancer Treat Res. 2022;183:49-89. doi: 10.1007/978-3-030-96376-7_2.

ABSTRACT

Melanoma gave science a window into the role immune evasion plays in the development of malignancy. The entire spectrum of immune focused anti-cancer therapies has been subjected to clinical trials in this disease, with limited success until the immune checkpoint blockade era. That revolution launched first in melanoma, heralded a landscape change throughout cancer that continues to reverberate today.

PMID:35551656 | DOI:10.1007/978-3-030-96376-7_2

Bioorg Chem. 2022 Mar 22;124:105755. doi: 10.1016/j.bioorg.2022.105755. Online ahead of print.

ABSTRACT

Drug repositioning is one of the most effective approaches towards drug discovery and development. It involves the identification of new therapeutic indications of existing drugs. The present study evaluated several drugs for their ability to modulate activity of the p8 subunit of TFIIH complex. Negative modulation of p8 subunit activity disrupts protein-protein interactions (PPIs) among the subunits of TFIIH complex, and thereby the TFIIH-associated functions. TFIIH complex has key role in the transcription and nucleotide excision repair activity in cancerous cells. TFIIH complex has emerged as a privileged drug target in anticancer research. Out of 60 drugs, amlopipine (13), diltiazem (16), gemfibrozil (19), levocitrizine dihydrochloride (20), losartan potassium (22), clorthalidone (24), and escitalopram (28) showed interactions with subunit p8 in the ligand-protein binding and chemical shift perturbation studies. The Kd values were found to be between 0.25 and 1 mM. These drugs also caused thermal destabilization of the subunit p8 by negatively shifting the melting temperature by ≥ 2 °C. Molecular docking studies indicated the interaction of these drugs with important residues of p8-p52 complex, such as Glu48, Lys51, Glu496, and Glu455 via non-covalent interactions. This study has thereby identified 7 drugs that can be investigated further as potential anticancer drugs.

PMID:35551043 | DOI:10.1016/j.bioorg.2022.105755

Toxicol Appl Pharmacol. 2022 May 9:116055. doi: 10.1016/j.taap.2022.116055. Online ahead of print.

ABSTRACT

Peroxisome proliferator-activated receptor-gamma (PPARγ) has been shown to have therapeutic promise in the treatment of ischemic stroke and is supported by several studies. To identify possible PPARγ activators, the current study used an in silico technique in conjunction with molecular simulations and in vivo validation. FDA-approved drugs were evaluated using molecular docking to determine their affinity for PPARγ. The findings of molecular simulations support the repurposing of rabeprazole and ethambutol for the treatment of ischemic stroke. Adult Sprague Dawley rats were subjected to transient middle cerebral artery occlusion (t-MCAO). Five groups were made as a sham-operated, t-MCAO group, rabeprazole +t-MCAO, ethambutol +t-MCAO, and pioglitazone +t-MCAO. The neuroprotective effects of these drugs were evaluated using the neurological deficit score and the infarct area. The inflammatory mediators and signaling transduction proteins were quantified using Western blotting, ELISA, and immunohistochemistry. The repurposed drugs mitigated cerebral ischemic injury by PPARγ mediated downregulation of nods like receptor protein 3 inflammasomes (NLRP3), tumor necrosis factor-alpha (TNF-α), cyclooxygenase 2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-kB), and c-Jun N-terminal kinase (p-JNK). Our data demonstrated that rabeprazole and ethambutol have neuroprotective potential via modulating the cytoprotective stress response, increasing cellular survival, and balancing homeostatic processes, and so may be suitable for future research in stroke therapy.

PMID:35550883 | DOI:10.1016/j.taap.2022.116055

Biochim Biophys Acta Mol Basis Dis. 2022 May 9:166430. doi: 10.1016/j.bbadis.2022.166430. Online ahead of print.

ABSTRACT

Type I interferon (IFN-I) signalling represents a major target for modulation in a virus' bid for latency. IFN-I perturbations are also present in such as Alzheimer's disease (AD) and multiple sclerosis (MS), where viral infections are known to increase symptomatic burden. IFN-I modulation such as via IFNβ-1a, an established MS treatment, has been researched to a limited extent to both AD and COVID-19. In this mini review, we present emerging research on trained immunity as a pathogenetic basis for Alzheimer's disease and the emerging context for IFNβ-1a repositioning, via mechanisms shared with multiple sclerosis and induced by viral infections.

PMID:35550850 | DOI:10.1016/j.bbadis.2022.166430

Cytokine Growth Factor Rev. 2022 May 9:S1359-6101(22)00029-6. doi: 10.1016/j.cytogfr.2022.04.007. Online ahead of print.

ABSTRACT

Atopic dermatitis is a chronic recurring pruritic inflammatory skin disease manifested by increased pro-inflammatory mediators which lead to dry, thickened, cracked, scaly skin. The current treatment options for atopic dermatitis management comprise drawbacks and leave unmet effective clinical needs. So, the approach for repurposing existing drugs for atopic dermatitis management may potentially overcome these unmet needs. Diseases that share the common pathophysiological pathways with atopic dermatitis can serve as a foundation for the repurposing of drugs. Drugs used in the management of cancer, rheumatoid arthritis, and other immune-mediated diseases such as psoriasis are under investigation to know the potential in atopic dermatitis management by utilizing repurposing strategies for a novel therapeutic indication. This review mainly envisages the probable repurposing of drugs for the management of atopic dermatitis disease; the barriers and regulatory aspects involved in the repurposing of existing drugs.

PMID:35550114 | DOI:10.1016/j.cytogfr.2022.04.007

Int J Radiat Biol. 2022 May 13:1-29. doi: 10.1080/09553002.2022.2078001. Online ahead of print.

ABSTRACT

PURPOSE: As the "de novo" drug discovery faces a highly attrition rates, drug repositioning procures a heighten concern in identifying novel uses for existing medications. This study aimed to fabricate radioiodinated resveratrol as a potent microtubules interfering agent for cancer theragnosis.

METHODS: Resveratrol was radiolabeled with radioactive iodine where the radioiodination efficiency was enlightened and the computational approaches were employed to investigate the affinity and specificity with tubulins. Furthermore, the in-vivo distribution and pharmacokinetic studies in normal and tumor induced mice were investigated.

RESULTS: The maximum radioiodination yield (94.6 ± 1.66) was achieved at optimum preparation parameters stated as 100 μg/mL of oxidizing agent, 100 μg/ml of resveratrol, reaction time of 30 min and reaction pH 5. The in-silico studies showed that di-iodinated resveratrol (compound 6) exhibited the best binding score (-34.46) and interaction with the β-tubulin binding site. The in-vivo distribution in tumor models revealed a significant accumulation (4.02% ID/g) in tumor lesion at 60 min p.i. The rate of drug elimination demonstrated a mono-exponential decline of radioactivity versus time in the blood.

CONCLUSION: Radioiodinated resveratrol revealed good microtubules targeting which render it as a novel theranostic probe for cancer management.

PMID:35549606 | DOI:10.1080/09553002.2022.2078001

Biomol Ther (Seoul). 2022 May 13. doi: 10.4062/biomolther.2022.037. Online ahead of print.

ABSTRACT

The drug repurposing strategy has been applied to the development of emergency COVID-19 therapeutic medicines. Current drug repurposing approaches have been directed against RNA polymerases and viral proteases. Recently, we found that the inhibition of the interaction between the SARS-CoV-2 structural nucleocapsid (N) and spike (S) proteins decreased viral replication. In this study, drug repurposing candidates were screened by in silico molecular docking simulation with the SARS-CoV-2 structural N protein. In the ChEMBL database, 1994 FDA-approved drugs were selected for the in silico virtual screening against the N terminal domain (NTD) of the SARS-CoV-2 N protein. The tyrosine 109 residue in the NTD of the N protein was used as the center of the ligand binding grid for the docking simulation. In plaque forming assays performed with SARS-CoV-2 infected Vero E6 cells, atovaquone, abiraterone acetate, and digoxin exhibited a tendency to reduce the size of the viral plagues without affecting the plaque numbers. Abiraterone acetate significantly decreased the accumulation of viral particles in the cell culture supernatants in a concentration-dependent manner. In addition, abiraterone acetate significantly decreased the production of N protein and S protein in the SARS-CoV-2-infected Vero E6 cells. In conclusion, abiraterone acetate has therapeutic potential to inhibit the viral replication of SARS-CoV-2.

PMID:35548881 | DOI:10.4062/biomolther.2022.037

Front Cell Infect Microbiol. 2022 Apr 25;12:860442. doi: 10.3389/fcimb.2022.860442. eCollection 2022.

ABSTRACT

Parasitic infections caused by protozoans that infect the mucosal surfaces are widely neglected worldwide. Collectively, Entamoeba histolytica, Giardia lamblia, Cryptosporidium spp. and Trichomonas vaginalis infect more than a billion people in the world, being a public health problem mainly in developing countries. However, the exact incidence and prevalence data depend on the population examined. These parasites ultimately cause pathologies that culminate in liver abscesses, malabsorption syndrome, vaginitis, and urethritis, respectively. Despite this, the antimicrobial agents currently used to treat these diseases are limited and often associated with adverse side effects and refractory cases due to the development of resistant parasites. The paucity of drug treatments, absence of vaccines and increasing problems of drug resistance are major concerns for their control and eradication. Herein, potential candidates are reviewed with the overall aim of determining the knowledge gaps and suggest future perspectives for research. This review focuses on this public health problem and focuses on the progress of drug repositioning as a potential strategy for the treatment of mucosal parasites.

PMID:35548465 | PMC:PMC9084232 | DOI:10.3389/fcimb.2022.860442

Semergen. 2022 May 8:S1138-3593(22)00082-X. doi: 10.1016/j.semerg.2022.03.003. Online ahead of print.

NO ABSTRACT

PMID:35545490 | DOI:10.1016/j.semerg.2022.03.003

Lancet Microbe. 2022 May;3(5):e382-e391. doi: 10.1016/S2666-5247(21)00326-8. Epub 2022 Apr 1.

ABSTRACT

BACKGROUND: Mycobacterium chimaera is a slowly growing non-tuberculous mycobacterium associated with outbreaks of fatal infections in patients after cardiac surgery, and it is increasingly being detected in patients with chronic lung conditions. M chimaera can cause disseminated disease, osteomyelitis, and chronic skin or soft-tissue infections. We aimed to find new inhibitory compounds and drug repurposing opportunities for M chimaera, as current therapeutic options often result in poor outcomes.

METHODS: In an open drug discovery approach, we screened the Medicines for Malaria Venture (MMV) Pathogen Box to assess the in-vitro antimicrobial drug susceptibility of M chimaera compared with the antimicrobial drug susceptibility of the slowly growing, major human pathogen Mycobacterium tuberculosis, and the rapidly growing Mycobacterium abscessus reference strains. Compounds identified from an initial resazurin microtitre cell viability assay screen were further characterised by determining the minimum inhibitory concentration (MIC) of MMV Pathogen Box compounds against M chimaera; and the MICs of a panel of 20 drugs commonly used to treat mycobacterial infections against M tuberculosis, M abscessus, and M chimaera. We also assessed the time-kill kinetics of doxycycline, clarithromycin, ethambutol, and rifabutin against M chimaera.

FINDINGS: M chimaera was inhibited by 21 (5%) of 400 compounds in the Pathogen Box. Ten compounds were active against all three mycobacteria. MMV675968, with activity against slowly growing mycobacteria that probably targets folate metabolism, had a mean MIC of 2·22 μM (0·80 μg/mL) against M chimaera. Antimicrobial susceptibility testing showed that oxazolidinones such as linezolid (mean MIC 3·13 μg/mL) were active against M chimaera and that bedaquiline was the most potent compound (mean MIC 0·02 μg/mL). Doxycycline, a broad-spectrum antimicrobial drug with excellent tissue penetration properties, also inhibited M chimaera with a mean MIC of 6·25 μg/mL.

INTERPRETATION: Molecular diagnostics present an opportunity for more effective, targeted drug therapies-treating bacterial infections at the species level. Using an open drug discovery platform, we identified compounds that inhibit the newly recognised pathogen M chimaera. The existing evidence base is poor and the option for expensive drug discovery is improbable; therefore, we have also found options for drug repurposing. Future in-vivo efficacy studies will reveal whether these findings result in new, targeted treatment regimens for M chimaera.

FUNDING: Wellcome Trust, National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), and the University of Sussex Junior Research Associate scheme.

PMID:35544099 | DOI:10.1016/S2666-5247(21)00326-8

Int J Oncol. 2022 Jul;61(1):80. doi: 10.3892/ijo.2022.5370. Epub 2022 May 11.

ABSTRACT

Drug repositioning is a strategy for repurposing the approved or investigational drugs that are outside the scope of the original medical indication. Memantine is used as a non‑competitive N‑methyl‑D‑aspartate receptor antagonist to prevent glutamate‑mediated excitotoxicity in Alzheimer's disease, and is one of the promising agents which is utilized for the purpose of cancer therapy. However, the association between memantine and Golgi glycoprotein 1 (GLG1), an intracellular fibroblast growth factor receptor, in cancers has not yet been clarified. The present study analyzed the expression and location of GLG1 in tumor cells treated with memantine. Memantine was found to suppress the growth of malignant glioma and breast cancer cells in a concentration‑dependent manner. The mRNA expression of GLG1 was upregulated in a concentration‑dependent manner, and the splicing variant profiles were altered in all cell lines examined. The results of western blot analysis revealed an increase in the full‑length and truncated forms of GLG1. Moreover, GLG1 spread in the cytosol of memantine‑treated cells, whereas it localized in the Golgi apparatus in control cells. Since GLG1 functions as a decoy FGF receptor, the modulation of GLG1 may prove to be one of the mechanisms underlying the cancer‑suppressive effects of memantine.

PMID:35543162 | DOI:10.3892/ijo.2022.5370

Comb Chem High Throughput Screen. 2022 May 9. doi: 10.2174/1386207325666220509194428. Online ahead of print.

ABSTRACT

BACKGROUND: Currently, there are no effective differentiation-inducing agents for gliomas. Drug repositioning is a time-saving, low-risk, and low-cost drug development strategy. In this study, drugs that could induce the differentiation of glioma cells were searched for using a drug repositioning strategy.

METHOD: Data mining was used to screen for differentially expressed genes (DEGs). The STRING 11.0 database was used for enrichment analysis. The Connectivity Map database was used for drug screening. The ChEMBL and STITCH databases were used to search for drug targets. The SwissDock database was used for molecular docking.

RESULTS: A total of 45 DEGs were identified. The biological processes in which the DEGs were enriched mainly involved nervous system development and the regulation of biological processes. The enriched molecular functions mainly involved transcription-related molecular binding. The enriched cellular components mainly involved membrane-bound organelles and cellular protrusions. The enriched local network clusters mainly involved autophagy, the retinoic acid signalling pathway, and DNA methylation. The drug screening results showed that the drug with the highest score was acenocoumarol. A total of 12 acenocoumarol targets were obtained, among which histone deacetylase 1 (HDAC1) was the target with the highest degree value; the lowest ΔG value for acenocoumarol docked with HDAC1 was -7.52 kcal/mol, which was between those of the HDAC1 inhibitors romidepsin and vorinostat.

CONCLUSION: Acenocoumarol may be a potential differentiation-inducing agent for glioma cells.

PMID:35538833 | DOI:10.2174/1386207325666220509194428