Mol Divers. 2023 Apr 16. doi: 10.1007/s11030-023-10646-2. Online ahead of print.

ABSTRACT

Hepatitis C virus, a member of the Flaviviridae family and genus Hepacivirus, is an enveloped, positively single stranded RNA virus. Its surface consists of a heterodimer of E1 and E2 proteins which play a crucial role in receptor binding and membrane fusion. In this study we have used in silico virtual screening by utilizing ensemble docking on the approved drugs. These drugs can bind with high efficiency to the 36 prominent conformations of the CD81 binding site clustered from a total of 3 µs MD simulation data on the E2 protein. We started with 9213 compounds from the FDA list of drugs and progressively came down to 5 compounds which have been seen to bind with very high efficiency to not only all the conformations but also the two predicted druggable pockets that encompass the CD81 binding site. MM/PBSA binding energy calculations also point to the highly stable interaction of the compounds to the E2 protein. This study may in future broaden the arsenal of therapeutics for use against HCV infection and lead to more effective care against the virus.

PMID:37061608 | DOI:10.1007/s11030-023-10646-2

Adv Protein Chem Struct Biol. 2023;135:97-124. doi: 10.1016/bs.apcsb.2023.01.003. Epub 2023 Mar 11.

ABSTRACT

Cyclin-dependent kinase 6 (CDK6) is an essential kinase in cell cycle progression, which is a viable target for inhibitors in various malignancies, including breast cancer. This study aimed to virtually screen efficient compounds as new leads in treating breast cancer using a drug repurposing approach. Apoptosis regulatory compounds were taken from the seleckchem database. Molecular docking experiments were carried out in the presence of abemaciclib, a routinely used FDA drug. Compared to conventional drugs, the two compounds demonstrated a higher binding affinity for CDK6. Compounds (N-benzyl-6-[(4-hydroxyphenyl)methyl]-8-(naphthalen-1-ylmethyl)-4,7-dioxo-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide) and (1'-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4'-piperidine]) were discovered to have an inhibitory effect against CDK6 at -8.49 and -6.78kcal/mol, respectively, compared to -8.09kcal/mol of the control molecule, the interacting residues of these two new compounds were found to fall within the binding site of the CDK6 molecule. Both compounds exhibited equal ADME features compared with abemaciclib and would be well distributed and metabolized by the body with an appropriate druglikeness range. Lastly, molecular dynamics was initiated for 200ns for the selected potent inhibitors and abemaciclib as complexed with CDK6. The RMSD, RMSF, Rg, H-Bond interactions, SASA, PCA, FEL, and MM/PBSA analysis were performed for the complexes to assess the stability, fluctuations, radius of gyration, hydrogen bond interaction, solvent accessibility, essential dynamics, free energy landscape, and MM/PBSA. The selected two compounds are small molecules in the appropriate druglikeness range. The results observed in molecular docking and molecular dynamics simulations were most promising for two compounds, suggesting their potent inhibitory effect against CDK6. We propose that these candidate compounds can undergo in vitro validation and in vivo testing for their further use against cancer.

PMID:37061342 | DOI:10.1016/bs.apcsb.2023.01.003

J Mol Graph Model. 2023 Apr 14;122:108471. doi: 10.1016/j.jmgm.2023.108471. Online ahead of print.

ABSTRACT

An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer's disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives - Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.

PMID:37087882 | DOI:10.1016/j.jmgm.2023.108471

Biochem Biophys Res Commun. 2023 Apr 14;661:75-81. doi: 10.1016/j.bbrc.2023.04.008. Online ahead of print.

ABSTRACT

Cisplatin resistance is the main reason for uveal melanoma (UM) treatment failure. Thus, developing strategy that increasing cisplatin sensitivity is needed. In this study, we performed drug repositioning analysis with the Connectivity Map database using a panel of previously identified cisplatin sensitivity-associated genes and cisplatin resistance-associated genes as the signature and obtained the antiparasitic drug selamectin. We demonstrated that the selamectin and cisplatin combination showed a synergistic effect on inhibiting UM cell growth. Experiments in tumor-bearing nude mice further showed that selamectin and cisplatin have synergistic effects in reducing tumor growth. Previous studies have linked increased autophagy with tumor resistance to chemotherapy. We found that selamectin inhibited the expression of the autophagy-related gene ATG9B, thus reducing autophagy. The cisplatin resistance-associated genes PDGFRB, DUSP1, MAST1 and IL11 were significantly downregulated in UM cells treated with selamectin. In summary, our study shows that selamectin enhanced the sensitivity of UM to cisplatin, through the mechanism of inhibiting cisplatin resistance-associated gene expression and autophagy. These findings may provide a new strategy for the treatment of UM.

PMID:37087801 | DOI:10.1016/j.bbrc.2023.04.008

J Pharmacol Sci. 2023 May;152(1):1-21. doi: 10.1016/j.jphs.2023.02.004. Epub 2023 Feb 15.

ABSTRACT

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is caused when Spike-protein (S-protein) present on the surface of SARS-CoV-2 interacts with human cell surface receptor, Angiotensin-converting enzyme 2 (ACE2). This binding facilitates SARS-CoV-2 genome entry into the human cells, which in turn causes infection. Since the beginning of the pandemic, many different therapies have been developed to combat COVID-19, including treatment and prevention. This review is focused on the currently adapted and certain other potential therapies for COVID-19 treatment, which include drug repurposing, vaccines and drug-free therapies. The efficacy of various treatment options is constantly being tested through clinical trials and in vivo studies before they are made medically available to the public.

PMID:37059487 | DOI:10.1016/j.jphs.2023.02.004

Transl Res. 2023 Apr 12:S1931-5244(23)00057-9. doi: 10.1016/j.trsl.2023.04.001. Online ahead of print.

ABSTRACT

Focal segmental glomerulosclerosis (FSGS) is a glomerular lesion often associated with nephrotic syndrome. It is also associated with a high risk of progression to end-stage kidney disease. Current treatment of FSGS is limited to systemic corticosteroids or calcineurin inhibition, along with inhibitors of the renin-angiotensin-aldosterone system. FSGS is heterogeneous in etiology, and novel therapies targeting specific, dysregulated molecular pathways represent a major unmet medical need. We have generated a network-based molecular model of FSGS pathophysiology using previously established systems biology workflows to allow computational evaluation of compounds for their predicted interference with molecular processes contributing to FSGS. We identified the anti-platelet drug clopidogrel as a therapeutic option to counterbalance dysregulated FSGS pathways. This prediction of our computational screen was validated by testing clopidogrel in the adriamycin FSGS mouse model. Clopidogrel improved key FSGS outcome parameters and significantly reduced urinary albumin to creatinine ratio (p<0.01) and weight loss (p<0.01), and ameliorated histopathological damage (p<0.05). Clopidogrel is used to treat several cardiovascular diseases linked to chronic kidney disease. Clopidogrel's favorable safety profile and its efficacy in the adriamycin mouse FSGS model thus recommend it as an attractive drug repositioning candidate for clinical trial in FSGS.

PMID:37059330 | DOI:10.1016/j.trsl.2023.04.001

J Infect Public Health. 2023 Apr 13;16(6):928-937. doi: 10.1016/j.jiph.2023.04.011. Online ahead of print.

ABSTRACT

The unmet medical need for drug-resistant tuberculosis (DRTB) is a significant concern. Accordingly, identifying new drug targets for tuberculosis (TB) treatment and developing new therapies based on these drug targets is one of the strategies to tackle DRTB. QcrB is an innovative drug target to create treatments for DRTB. This article highlights QcrB inhibitors and their therapeutic compositions for treating TB. The literature for this article was gathered from PubMed and free patent databases utilizing different keywords related to QcrB inhibitor-based inventions. The data was collected from the conceptualization of telacebec (2010) QcrB to December 2022. A little interesting and encouraging research has been performed on QcrB inhibitors. Telacebec and TB47 are established QcrB inhibitors in the clinical trial. The inventive QcrB inhibitor-based drug combinations can potentially handle DRTB and reduce the TB therapy duration. The authors anticipate great opportunities in fostering QcrB inhibitor-based patentable pharmaceutical inventions against TB. Drug repurposing can be a promising strategy to get safe and effective QcrB inhibitors. However, developing drug resistance, drug tolerance, and selectivity of QcrB inhibitors for Mtb will be the main challenges in developing effective QcrB inhibitors. In conclusion, QcrB is a promising drug target for developing effective treatments for active, latent, and drug-resistant TB. Many inventive and patentable combinations and compositions of QcrB inhibitors with other anti-TB drugs are anticipated as future treatments for TB.

PMID:37086552 | DOI:10.1016/j.jiph.2023.04.011

Molecules. 2023 Mar 27;28(7):2989. doi: 10.3390/molecules28072989.

ABSTRACT

Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of -9.7, -9.6, and -9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection.

PMID:37049752 | DOI:10.3390/molecules28072989

Eur J Pharmacol. 2023 Apr 11:175718. doi: 10.1016/j.ejphar.2023.175718. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) stands as the second leading cause of cancer-related deaths worldwide with limited available medicines. While drug repurposing comes as a promising strategy for cancer treatment, we discovered that propranolol (Prop), a non-selective β1 and β2 adrenergic receptor blocker, significantly inhibited the development of subcutaneous CT26 CRC and AOM/DSS-induced CRC models. The RNA-seq analysis highlighted the activated immune pathways after Prop treatment, with GO analysis enriched in T-cell differentiation, leukocyte-mediated immunity, regulation of leukocyte-mediated cytotoxicity, and interferon-gamma production. Routine analyses of blood revealed a decrease in neutrophil to lymphocyte ratio, a biomarker of systemic inflammation, and a prognostic indicator in the Prop-treated groups in both CRC models. Analysis of the tumor-infiltrating immune cells exhibited that Prop regressed the exhaustion of CD4+ and CD8+ T cells in the CT26-derived graft models, which was further corroborated in the AOM/DSS-induced models. Furthermore, bioinformatic analysis fitted well with the experimental data, showing that β2 adrenergic receptor (ADRB2) was positively correlated with T-cell exhaustion signature in various tumors. The in vitro experiment showed no direct effect of Prop on CT26 cell viability, while T cells were activated with significantly-upregulated production of IFN-γ and Granzyme B. Consistently, Prop was unable to restrain CT26 tumor growth in nude mice. At last, the combination of Prop and the chemotherapeutic drug Irinotecan acted out the strongest inhibition in CT26 tumor progress. Collectively, we repurpose Prop as a promising and economical therapeutic drug for CRC treatment and highlight T-cell as its target.

PMID:37054937 | DOI:10.1016/j.ejphar.2023.175718

J Biomol Struct Dyn. 2023 Apr 13:1-27. doi: 10.1080/07391102.2023.2199866. Online ahead of print.

ABSTRACT

As breast cancer remains leading cause of cancer death globally, it is essential to develop an affordable breast cancer therapy in underdeveloped countries. Drug repurposing offers potential to address gaps in breast cancer treatment. Molecular networking studies were performed for drug repurposing approach by using heterogeneous data. The PPI networks were built to select the target genes from the EGFR overexpression signaling pathway and its associated family members. The selected genes EGFR, ErbB2, ErbB4 and ErbB3 were allowed to interact with 2637 drugs, leads to PDI network construction of 78, 61, 15 and 19 drugs, respectively. As drugs approved for treating non cancer-related diseases or disorders are clinically safe, effective, and affordable, these drugs were given considerable attention. Calcitriol had shown significant binding affinities with all four receptors than standard neratinib. The RMSD, RMSF, and H-bond analysis of protein-ligand complexes from molecular dynamics simulation (100 ns), confirmed the stable binding of calcitriol with ErbB2 and EGFR receptors. In addition, MMGBSA and MMP BSA also affirmed the docking results. These in-silico results were validated with in-vitro cytotoxicity studies in SK-BR-3 and Vero cells. The IC50 value of calcitriol (43.07 mg/ml) was found to be lower than neratinib (61.50 mg/ml) in SK-BR-3 cells. In Vero cells the IC50 value of calcitriol (431.05 mg/ml) was higher than neratinib (404.95 mg/ml). It demonstrates that calcitriol suggestively downregulated the SK-BR-3 cell viability in a dose-dependent manner. These implications revealed calcitriol has shown better cytotoxicity and decreased the proliferation rate of breast cancer cells than neratinib.Communicated by Ramaswamy H. Sarma.

PMID:37054526 | DOI:10.1080/07391102.2023.2199866

J Biomol Struct Dyn. 2023 Apr 13:1-12. doi: 10.1080/07391102.2023.2199868. Online ahead of print.

ABSTRACT

O-linked N-acetylglucosamine (O-GlcNAc) is a unique intracellular post-translational glycosylation at the hydroxyl group of serine or threonine residues in nuclear, cytoplasmic and mitochondrial proteins. The enzyme O-GlcNAc transferase (OGT) is responsible for adding GlcNAc, and anomalies in this process can lead to the development of diseases associated with metabolic imbalance, such as diabetes and cancer. Repurposing approved drugs can be an attractive tool to discover new targets reducing time and costs in the drug design. This work focuses on drug repurposing to OGT targets by virtual screening of FDA-approved drugs through consensus machine learning (ML) models from an imbalanced dataset. We developed a classification model using docking scores and ligand descriptors. The SMOTE approach to resampling the dataset showed excellent statistical values in five of the seven ML algorithms to create models from the training set, with sensitivity, specificity and accuracy over 90% and Matthew's correlation coefficient greater than 0.8. The pose analysis obtained by molecular docking showed only H-bond interaction with the OGT C-Cat domain. The molecular dynamics simulation showed the lack of H-bond interactions with the C- and N-catalytic domains allowed the drug to exit the binding site. Our results showed that the non-steroidal anti-inflammatory celecoxib could be a potentially OGT inhibitor.

PMID:37054524 | DOI:10.1080/07391102.2023.2199868

Eur J Epidemiol. 2023 Apr 13. doi: 10.1007/s10654-023-01000-9. Online ahead of print.

ABSTRACT

Despite increasing therapeutic options to treat rheumatoid arthritis (RA), many patients fail to reach treatment targets. The use of antidiabetic drugs like thiazolidinediones has been associated with lower RA risk. We aimed to explore the repurposing potential of antidiabetic drugs in RA prevention by assessing associations between genetic variation in antidiabetic drug target genes and RA using Mendelian randomization (MR). A two-sample MR design was used to estimate the association between the antidiabetic drug and RA risk using summary statistics from genome-wide association studies (GWAS). We selected independent genetic variants from the gene(s) that encode the target protein(s) of the investigated antidiabetic drug as instruments. We extracted the associations of instruments with blood glucose concentration and RA from the UK Biobank and a GWAS meta-analysis of clinically diagnosed RA, respectively. The effect of genetic variation in the drug target(s) on RA risk was estimated by the Wald ratio test or inverse-variance weighted method. Insulin and its analogues, thiazolidinediones, and sulfonylureas had valid genetic instruments (n = 1, 1, and 2, respectively). Genetic variation in thiazolidinedione target (gene: PPARG) was inversely associated with RA risk (odds ratio [OR] 0.38 per 0.1mmol/L glucose lowering, 95% confidence interval [CI] 0.20-0.73). Corresponding ORs (95%CIs) were 0.83 (0.44-1.55) for genetic variation in the targets of insulin and its analogues (gene: INSR), and 1.12 (0.83, 1.49) 1.25 (0.78-2.00) for genetic variation in the sulfonylurea targets (gene: ABCC8 and KCNJ11). In conclusion, genetic variation in the thiazolidinedione target is associated with a lower RA risk. The underlying mechanisms warrant further exploration.

PMID:37052755 | DOI:10.1007/s10654-023-01000-9

Molecules. 2023 Apr 6;28(7):3267. doi: 10.3390/molecules28073267.

ABSTRACT

Green alga Caulerpa racemosa is an underexploited species of macroalgae, even though it is characterized by a green color that indicates an abundance of bioactive pigments, such as chlorophyll and possibly xanthophyll. Unlike chlorophyll, which has been well explored, the composition of the carotenoids of C. racemosa and its biological activities have not been reported. Therefore, this study aims to look at the carotenoid profile and composition of C. racemose and determine their biological activities, which include antidiabetic, anti-obesity, anti-oxidative, anti-inflammatory, and cytotoxicity in vitro. The detected carotenoids were all xanthophylls, which included fucoxanthin, lutein, astaxanthin, canthaxanthin, zeaxanthin, β-carotene, and β-cryptoxanthin based on orbitrap-mass spectrometry (MS) and a rapid ultra-high performance liquid chromatography (UHPLC) diode array detector. Of the seven carotenoids observed, it should be highlighted that β-carotene and canthaxanthin were the two most dominant carotenoids present in C. racemosa. Interestingly, the carotenoid extract of C. racemosa has good biological activity in inhibiting α-glucosidase, α-amylase, DPPH and ABTS, and the TNF-α and mTOR, as well as upregulating the AMPK, which makes it a drug candidate or functional antidiabetic food, a very promising anti-obesity and anti-inflammatory. More interestingly, the cytotoxicity value of the carotenoid extract of C. racemosa shows a level of safety in normal cells, which makes it a potential for the further development of nutraceuticals and pharmaceuticals.

PMID:37050034 | DOI:10.3390/molecules28073267

Cells. 2023 Mar 30;12(7):1057. doi: 10.3390/cells12071057.

ABSTRACT

Transcriptional regulation is fundamental to most biological processes and reverse-engineering programs can be used to decipher the underlying programs. In this review, we describe how genomics is offering a systems biology-based perspective of the intricate and temporally coordinated transcriptional programs that control neuronal apoptosis and survival. In addition to providing a new standpoint in human pathology focused on the regulatory program, cracking the code of neuronal cell fate may offer innovative therapeutic approaches focused on downstream targets and regulatory networks. Similar to computers, where faults often arise from a software bug, neuronal fate may critically depend on its transcription program. Thus, cracking the code of neuronal life or death may help finding a patch for neurodegeneration and cancer.

PMID:37048129 | DOI:10.3390/cells12071057

Int J Mol Sci. 2023 Apr 4;24(7):6712. doi: 10.3390/ijms24076712.

ABSTRACT

Ethacrynic acid (ECA) is a diuretic that inhibits Na-K-2Cl cotransporter (NKCC2) present in the thick ascending loop of Henle and muculo dens and is clinically used for the treatment of edema caused by excessive body fluid. However, its clinical use is limited due to its low bioavailability and side effects, such as liver damage and hearing loss at high doses. Despite this, ECA has recently emerged as a potential anticancer agent through the approach of drug repositioning, with a novel mechanism of action. ECA has been shown to regulate cancer hallmark processes such as proliferation, apoptosis, migration and invasion, angiogenesis, inflammation, energy metabolism, and the increase of inhibitory growth factors through various mechanisms. Additionally, ECA has been used as a scaffold for synthesizing a new material, and various derivatives have been synthesized. This review explores the potential of ECA and its derivatives as anticancer agents, both alone and in combination with adjuvants, by examining their effects on ten hallmarks of cancer and neuronal contribution to cancer. Furthermore, we investigated the trend of synthesis research of a series of ECA derivatives to improve the bioavailability of ECA. This review highlights the importance of ECA research and its potential to provide a cost-effective alternative to new drug discovery and development for cancer treatment.

PMID:37047688 | DOI:10.3390/ijms24076712

Int J Mol Sci. 2023 Mar 31;24(7):6577. doi: 10.3390/ijms24076577.

ABSTRACT

There are several studies on the deregulated gene expression profiles in kidney cancer, with varying results depending on the tumor histology and other parameters. None of these, however, have identified the networks that the co-deregulated genes (co-DEGs), across different studies, create. Here, we reanalyzed 10 Gene Expression Omnibus (GEO) studies to detect and annotate co-deregulated signatures across different subtypes of kidney cancer or in single-gene perturbation experiments in kidney cancer cells and/or tissue. Using a systems biology approach, we aimed to decipher the networks they form along with their upstream regulators. Differential expression and upstream regulators, including transcription factors [MYC proto-oncogene (MYC), CCAAT enhancer binding protein delta (CEBPD), RELA proto-oncogene, NF-kB subunit (RELA), zinc finger MIZ-type containing 1 (ZMIZ1), negative elongation factor complex member E (NELFE) and Kruppel-like factor 4 (KLF4)] and protein kinases [Casein kinase 2 alpha 1 (CSNK2A1), mitogen-activated protein kinases 1 (MAPK1) and 14 (MAPK14), Sirtuin 1 (SIRT1), Cyclin dependent kinases 1 (CDK1) and 4 (CDK4), Homeodomain interacting protein kinase 2 (HIPK2) and Extracellular signal-regulated kinases 1 and 2 (ERK1/2)], were computed using the Characteristic Direction, as well as GEO2Enrichr and X2K, respectively, and further subjected to GO and KEGG pathways enrichment analyses. Furthermore, using CMap, DrugMatrix and the LINCS L1000 chemical perturbation databases, we highlight putative repurposing drugs, including Etoposide, Haloperidol, BW-B70C, Triamterene, Chlorphenesin, BRD-K79459005 and β-Estradiol 3-benzoate, among others, that may reverse the expression of the identified co-DEGs in kidney cancers. Of these, the cytotoxic effects of Etoposide, Catecholamine, Cyclosporin A, BW-B70C and Lasalocid sodium were validated in vitro. Overall, we identified critical co-DEGs across different subtypes in kidney cancer, and our results provide an innovative framework for their potential use in the future.

PMID:37047552 | DOI:10.3390/ijms24076577

Int J Mol Sci. 2023 Mar 29;24(7):6446. doi: 10.3390/ijms24076446.

ABSTRACT

Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional therapies in oncology and immunotherapeutic drugs, such as immune checkpoint inhibitors and immunogenic cell death inducers, and has substantially progressed the treatment of several malignancies and improved the clinical management of advanced disease. Unfortunately, because of tumor-intrinsic and/or -extrinsic mechanisms for escaping immune surveillance, only a fraction of patients clinically respond to and benefit from cancer immunotherapy. Accumulating evidence derived from studies of drug repositioning, that is, the strategy to identify new uses for approved or investigational drugs that are outside the scope of the original medical indication, has suggested that some anthelmintic drugs, in addition to their antineoplastic effects, exert important immunomodulatory actions on specific subsets of immune cell and related pathways. In this review, we report and discuss current knowledge on the impact of anthelmintic drugs on host immunity and their potential implication in cancer immunotherapy.

PMID:37047419 | DOI:10.3390/ijms24076446

Cancers (Basel). 2023 Mar 28;15(7):2020. doi: 10.3390/cancers15072020.

ABSTRACT

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

PMID:37046681 | DOI:10.3390/cancers15072020

FASEB J. 2023 May;37(5):e22914. doi: 10.1096/fj.202201952R.

ABSTRACT

Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC50 in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian cancer, where the rate of rise of CA-125 was significantly reduced following treatment with zafirlukast, while no severe adverse events were reported. Thiol isomerase inhibition with zafirlukast represents a novel, well-tolerated therapeutic in the treatment of ovarian cancer.

PMID:37043381 | DOI:10.1096/fj.202201952R

J Biomol Struct Dyn. 2023 Apr 12:1-12. doi: 10.1080/07391102.2023.2199874. Online ahead of print.

ABSTRACT

Several generations of anti-epileptic drugs (AEDs) are available but have several associated side effects apart from a limited success rate. Drug repositioning strategies have gained importance in the last two decades owing to lower failure rates and economic burden. Drugs with similar side effect profiles may share a common mechanism of action and thus can be linked to other disease treatments. The present study was carried out to identify the newly approved drug candidate(s) as AEDs using clinical side-effects drug repositioning strategy. The clinical side effect similarity of drugs available in the SIDER v4.1 database was estimated against common side effects of 5 major marketed AEDs, using the 'dplyr' package library in the R. Further drugs were filtered based on Blood Brain Barrier permeability prediction and FDA-approval status. Molecular docking studies were performed for selected 26 hits (drugs) against previously identified epilepsy target receptors: Voltage-gated sodium channel α2 (Nav1.2), GABA receptor α1-β1 (GABAr α1-β1), and Voltage-gated calcium channel α-1 G (Cav3.1). Only 2 drugs (Ziprasidone and Paroxetine) showed better binding affinities against studied epilepsy receptors Nav1.2, GABAr α1-β1, and Cav3.1, than their corresponding standard AEDs, i.e. Carbamazepine, Clonazepam, and Pregabalin, respectively. Ziprasidone reportedly showed seizure-like symptoms in ∼3% of patients and was hence omitted from further study. The MDS study of docked complexes of Paroxetine with selected epilepsy target receptors showed stable RMSD values and better interaction energies. The study reveals Paroxetine as a potential candidate to be repurposed for 1st line epileptic seizure medication.Communicated by Ramaswamy H. Sarma.

PMID:37042987 | DOI:10.1080/07391102.2023.2199874