Front Pharmacol. 2023 Mar 3;14:1057301. doi: 10.3389/fphar.2023.1057301. eCollection 2023.

ABSTRACT

Background: Polypharmacy is common in patients with dysphagia. Routinely used drugs may influence swallowing function either improving or worsening it. We aimed to explore the potential effects of three commonly used drug classes on dysphagia and aspiration pneumonia through a systematic review and a real-world data analysis to probe the possibility of drug repurposing for dysphagia treatment. Material and Methods: Five electronic databases were searched. Studies on adults at risk for dysphagia, treated with Dipeptidyl-Peptidase IV Inhibitors (DPP-4i), Adrenergic Beta-Antagonists (beta-blockers), or Angiotensin-Converting Enzyme Inhibitors (ACEi), and reporting outcomes on dysphagia or aspiration pneumonia were included. A nested case/non-case study was performed on adverse events recorded in the FDA Adverse Event Reporting System (FAERS) on patients >64 years. Cases (dysphagia or aspiration pneumonia) were compared between patients only treated with Levodopa and patients who were concomitantly treated with the drugs of interest. Results: Twenty studies were included in the review (17 on ACEi, 2 on beta-blockers, and 1 on DPP-4i). Contrasting findings on the effects of ACEi were found, with a protective effect mainly reported in Asian studies on neurological patients. Beta-blockers were associated with a reduced dysphagia rate. The study on DPP-4i suggested no effect on dysphagia and an increased risk of aspiration pneumonia. The FAERS analysis showed a reduction of the risk for dysphagia/aspiration pneumonia with ACEi, beta-blockers, and DPP-4i. Conclusion: Our study explores the potential drug repurposing of ACEi, beta-blockers and DPP-4i in neurological patients with dysphagia to improve swallowing function and reduce aspiration pneumonia risk. Future randomized controlled studies should confirm these results and clarify the underlying mechanisms of action.

PMID:36937893 | PMC:PMC10022593 | DOI:10.3389/fphar.2023.1057301

Front Pharmacol. 2023 Mar 2;14:1143981. doi: 10.3389/fphar.2023.1143981. eCollection 2023.

NO ABSTRACT

PMID:36937872 | PMC:PMC10018132 | DOI:10.3389/fphar.2023.1143981

Front Pharmacol. 2023 Mar 1;14:1130828. doi: 10.3389/fphar.2023.1130828. eCollection 2023.

ABSTRACT

Several efforts to repurpose drugs for COVID-19 treatment have largely either failed to identify a suitable agent or agents identified did not translate to clinical use. Reasons that have been suggested to explain the failures include use of inappropriate doses, that are not clinically achievable, in the screening experiments, and the use of inappropriate pre-clinical laboratory surrogates to predict efficacy. In this study, we used an innovative algorithm, that incorporates dissemination and implementation considerations, to identify potential drugs for COVID-19 using iterative computational and wet laboratory methods. The drugs were screened at doses that are known to be achievable in humans. Furthermore, inhibition of viral induced cytopathic effect (CPE) was used as the laboratory surrogate to predict efficacy. Erythromycin, pyridoxine, folic acid and retapamulin were found to inhibit SARS-CoV-2 induced CPE in Vero cells at concentrations that are clinically achievable. Additional studies may be required to further characterize the inhibitions of CPE and the possible mechanisms.

PMID:36937851 | PMC:PMC10014809 | DOI:10.3389/fphar.2023.1130828

Chem Sci. 2023 Feb 21;14(11):3030-3047. doi: 10.1039/d2sc05534a. eCollection 2023 Mar 15.

ABSTRACT

Small soluble oligomers of the protein α-synuclein (αSO) have been linked to disruptions in neuronal homeostasis, contributing to the development of Parkinson's Disease (PD). While this makes αSO an obvious drug target, the development of effective therapeutics against αSO is challenged by its low abundance and structural and morphological complexity. Here, we employ two different approaches to neutralize toxic interactions made by αSOs with different cellular components. First, we use available data to identify four neuronal proteins as likely candidates for αSO interactions, namely Cfl1, Uchl1, Sirt2 and SerRS. However, despite promising results when immobilized, all 4 proteins only bind weakly to αSO in solution in microfluidic assays, making them inappropriate for screening. In contrast, the formation of stable contacts formed between αSO and vesicles consisting of anionic lipids not only mimics a likely biological role of αSO but also provided a platform to screen two small molecule libraries for disruptors of these contacts. Of the 7 best leads obtained in this way, 2 significantly impaired αSO contacts with other proteins in a sandwich ELISA assay using αSO-binding monoclonal antibodies and nanobodies. In addition, 5 of these leads suppressed α-synuclein amyloid formation. Thus, a repurposing screening that directly targets a key culprit in PD pathogenesis shows therapeutic potential.

PMID:36937574 | PMC:PMC10016340 | DOI:10.1039/d2sc05534a

Comput Struct Biotechnol J. 2023 Feb 24;21:1907-1920. doi: 10.1016/j.csbj.2023.02.041. eCollection 2023.

ABSTRACT

Despite the massive investment in Alzheimer's disease (AD), there are still no disease-modifying treatments (DMTs) for AD. One major reason is attributed to the limitation of clinical "one-size-fits-all" approach, since the same AD treatment solely based on clinical diagnosis was unlikely to achieve good clinical efficacy. In recent years, computational approaches based on multiomics data have provided an unprecedented opportunity for drug discovery since they can substantially lower the costs and boost the efficiency. In this study, we intended to identify potential drug candidates for different pathological stages of AD by computationally repurposing Food and Drug Administration (FDA) approved drugs. First, we assembled gene expression data from three different AD pathological stages, which include mild cognitive impairment (MCI) and early and late stages of AD (EAD, LAD). We next quantified the network distances between drug target networks and AD modules by utilizing a network proximity approach, and identified 193 candidates that possessed significant associations with AD. After searching for previous literature evidence, 63 out of 193 (32.6%) predicted drugs were demonstrated to exert therapeutic effects on AD. We further explored the novel mechanism of action (MOA) for these drug candidates by determining the specific brain cells they might function on based on AD patient single cell transcriptomic data. Additionally, we selected several promising candidates that could cross the blood brain barrier together with confirmed neuroprotective effects, and subsequently determined the antioxidative activity of these compounds. Experimental results showed that azathioprine decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels and improved the superoxide dismutase (SOD) activity in APP-SH-SY5Y cells. Finally, we deciphered the potential MOA of azathioprine against AD via network analysis and validated several apoptosis-related proteins (Caspase 3, Cleaved Caspase 3, Bax, Bcl2) through western blotting. In summary, this study presented an effective computational strategy utilizing omics data for AD drug repurposing, which provides a new perspective for drug discovery and development.

PMID:36936813 | PMC:PMC10015208 | DOI:10.1016/j.csbj.2023.02.041

Cell Rep Methods. 2023 Feb 21;3(2):100413. doi: 10.1016/j.crmeth.2023.100413. eCollection 2023 Feb 27.

ABSTRACT

In recent years, there has been a surge of interest in using machine learning algorithms (MLAs) in oncology, particularly for biomedical applications such as drug discovery, drug repurposing, diagnostics, clinical trial design, and pharmaceutical production. MLAs have the potential to provide valuable insights and predictions in these areas by representing both the disease state and the therapeutic agents used to treat it. To fully utilize the capabilities of MLAs in oncology, it is important to understand the fundamental concepts underlying these algorithms and how they can be applied to assess the efficacy and toxicity of therapeutics. In this perspective, we lay out approaches to represent both the disease state and the therapeutic agents used by MLAs to derive novel insights and make relevant predictions.

PMID:36936080 | PMC:PMC10014302 | DOI:10.1016/j.crmeth.2023.100413

Infect Genet Evol. 2023 Mar 17:105426. doi: 10.1016/j.meegid.2023.105426. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of the disease range from an asymptomatic condition to life-threatening events and death, with more severe courses being associated with age, male sex, and comorbidities. Besides these risk factors, intrinsic characteristics of the virus as well as genetic factors of the host are expected to account for COVID-19 clinical heterogeneity. Genetic studies have long been recognized as fundamental to identify biological mechanisms underlying congenital diseases, to pinpoint genes/proteins responsible for the susceptibility to different inherited conditions, to highlight targets of therapeutic relevance, to suggest drug repurposing, and even to clarify causal relationships that make modifiable some environmental risk factors. Though these studies usually take long time to be concluded and, above all, to translate their discoveries to patients' bedside, the scientific community moved really fast to deliver genetic signals underlying different COVID-19 phenotypes. In this Review, besides a concise description of COVID-19 symptomatology and of SARS-CoV-2 mechanism of infection, we aimed to recapitulate the current literature in terms of host genetic factors that specifically associate with an increased severity of the disease.

PMID:36934789 | DOI:10.1016/j.meegid.2023.105426

Colloids Surf B Biointerfaces. 2023 Mar 7;225:113253. doi: 10.1016/j.colsurfb.2023.113253. Online ahead of print.

ABSTRACT

Disulfiram (DSF), a drug for alcohol withdrawal, has attracted extensive scientific attention due to its potential to treat cancer. The metabolite of DSF, diethyl dithiocarbamate (DDTC), forms a Cu-DDTC complex in vivo with copper ions, which has been shown to be a proteasome inhibitor with high antitumor activity. However, the in vivo stability of Cu-DDTC complexes remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with high antitumor activity was prepared by using the nanoscale metal-organic framework (MOF) Cu-BTC as a carrier and loading diethyldithiocarbamate (DDTC) through coordination interaction. The results showed that Cu-BTC@DDTC had high drug loading and adequate stability, and exhibited DDTC-Cu(I) chemical valence characteristics and polycrystalline structure features. In vitro cytocompatibility investigation and animal xenograft tumor model evaluation demonstrated the anti-cancer potential of Cu-BTC@DDTC, especially the combination of Cu-BTC@DDTC with low-dose cisplatin showed significant antitumor effect and biosafety. This study provides a feasible protocol for developing antitumor drugs based on the drug repurposing strategy.

PMID:36934611 | DOI:10.1016/j.colsurfb.2023.113253

Life Sci. 2023 Mar 16:121575. doi: 10.1016/j.lfs.2023.121575. Online ahead of print.

ABSTRACT

Heart disease and cancer are two major causes of morbidity and mortality in the industrialized countries, and their increasingly recognized connections are shifting the focus from single disease studies to an interdisciplinary approach. Fibroblast-mediated intercellular crosstalk is critically involved in the evolution of both pathologies. In healthy myocardium and in non-cancerous conditions, resident fibroblasts are the main cell source for synthesis of the extracellular matrix (ECM) and important sentinels of tissue integrity. In the setting of myocardial disease or cancer, quiescent fibroblasts activate, respectively, into myofibroblasts (myoFbs) and cancer-associated fibroblasts (CAFs), characterized by increased production of contractile proteins, and by a highly proliferative and secretory phenotype. Although the initial activation of myoFbs/CAFs is an adaptive process to repair the damaged tissue, massive deposition of ECM proteins leads to maladaptive cardiac or cancer fibrosis, a recognized marker of adverse outcome. A better understanding of the key mechanisms orchestrating fibroblast hyperactivity may help developing innovative therapeutic options to restrain myocardial or tumor stiffness and improve patient prognosis. Albeit still unappreciated, the dynamic transition of myocardial and tumor fibroblasts into myoFbs and CAFs shares several common triggers and signaling pathways relevant to TGF-β dependent cascade, metabolic reprogramming, mechanotransduction, secretory properties, and epigenetic regulation, which might lay the foundation for future antifibrotic intervention. Therefore, the aim of this review is to highlight emerging analogies in the molecular signature underlying myoFbs and CAFs activation with the purpose of identifying novel prognostic/diagnostic biomarkers, and to elucidate the potential of drug repositioning strategies to mitigate cardiac/cancer fibrosis.

PMID:36933828 | DOI:10.1016/j.lfs.2023.121575

Pharmacol Ther. 2023 Mar 16:108383. doi: 10.1016/j.pharmthera.2023.108383. Online ahead of print.

ABSTRACT

Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.

PMID:36933702 | DOI:10.1016/j.pharmthera.2023.108383

Clin Immunol. 2023 Mar 16:109295. doi: 10.1016/j.clim.2023.109295. Online ahead of print.

ABSTRACT

Previous studies found cDC1s to be protective in early stage anti-GBM disease through Tregs, but pathogenic in late stage Adriamycin nephropathy through CD8+ T cells. Flt3 ligand is a growth factor essential for cDC1 development and Flt3 inhibitors are currently used for cancer treatment. We conducted this study to clarify the role and mechanisms of effects of cDC1s at different time points in anti-GBM disease. In addition, we aimed to utilize drug repurposing of Flt3 inhibitors to target cDC1s as a treatment of anti-GBM disease. We found that in human anti-GBM disease, the number of cDC1s increased significantly, proportionally more than cDC2s. The number of CD8+ T cells also increased significantly and their number correlated with cDC1 number. In XCR1-DTR mice, late (day 12-21) but not early (day 3-12) depletion of cDC1s attenuated kidney injury in mice with anti-GBM disease. cDC1s separated from kidneys of anti-GBM disease mice were found to have a pro-inflammatory phenotype (i.e. express high level of IL-6 and IL-12) in late but not early stage. In the late depletion model, the number of CD8+ T cells was also reduced, but not Tregs. CD8+ T cells separated from kidneys of anti-GBM disease mice expressed high levels of cytotoxic molecules (granzyme B and perforin) and inflammatory cytokines (TNF-α and IFN-γ), and their expression reduced significantly after cDC1 depletion with diphtheria toxin. These findings were reproduced using a Flt3 inhibitor in wild type mice. Therefore, cDC1s are pathogenic in anti-GBM disease through activation of CD8+ T cells. Flt3 inhibition successfully attenuated kidney injury through depletion of cDC1s. Repurposing Flt3 inhibitors has potential as a novel therapeutic strategy for anti-GBM disease.

PMID:36933629 | DOI:10.1016/j.clim.2023.109295

Chin Med. 2023 Mar 17;18(1):30. doi: 10.1186/s13020-023-00729-5.

ABSTRACT

BACKGROUND: Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms.

METHODS: A drug repositioning strategy was used to screen an FDA-approved drug library with approximately 3000 compounds in an in vitro hepatocyte model of lipid accumulation, with honokiol identified as an effective anti-NAFLD candidate. We systematically examined the therapeutic effect of honokiol in NAFLD and metabolic syndrome in multiple in vitro and in vivo models. Transcriptomic examination and biotin-streptavidin binding assays were used to explore the underlying molecular mechanisms, confirmed by rescue experiments.

RESULTS: Honokiol significantly inhibited metabolic syndrome and NAFLD progression as evidenced by improved hepatic steatosis, liver fibrosis, adipose inflammation, and insulin resistance. Mechanistically, the beneficial effects of honokiol were largely through AMPK activation. Rather than acting on the classical upstream regulators of AMPK, honokiol directly bound to the AMPKγ1 subunit to robustly activate AMPK signaling. Mutation of honokiol-binding sites of AMPKγ1 largely abolished the protective capacity of honokiol against NAFLD.

CONCLUSION: These findings clearly demonstrate the beneficial effects of honokiol in multiple models and reveal a previously unappreciated signaling mechanism of honokiol in NAFLD and metabolic syndrome. This study also provides new insights into metabolic disease treatment by targeting AMPKγ1 subunit-mediated signaling activation.

PMID:36932412 | DOI:10.1186/s13020-023-00729-5

Comput Biol Med. 2023 Mar 11;157:106781. doi: 10.1016/j.compbiomed.2023.106781. Online ahead of print.

ABSTRACT

RNA-sequencing has been proposed as a valuable technique to develop individualized therapy concepts for cancer patients based on their tumor-specific mutational profiles. Here, we aimed to identify drugs and inhibitors in an individualized therapy-based drug repurposing approach focusing on missense mutations for 35 biopsies of cancer patients. The missense mutations belonged to 9 categories (ABC transporter, apoptosis, angiogenesis, cell cycle, DNA damage, kinase, protease, transcription factor, tumor suppressor). The highest percentages of missense mutations were observed in transcription factor genes. The mutational profiles of all 35 tumors were subjected to hierarchical heatmap clustering. All 7 leukemia biopsies clustered together and were separated from solid tumors. Based on these individual mutation profiles, two strategies for the identification of possible drug candidates were applied: Firstly, virtual screening of FDA-approved drugs based on the protein structures carrying particular missense mutations. Secondly, we mined the Drug Gene Interaction (DGI) database (https://www.dgidb.org/) to identify approved or experimental inhibitors for missense mutated proteins in our dataset of 35 tumors. In conclusion, our approach based on virtual drug screening of FDA-approved drugs and DGI-based inhibitor selection may provide new, individual treatment options for patients with otherwise refractory tumors that do not respond anymore to standard chemotherapy.

PMID:36931205 | DOI:10.1016/j.compbiomed.2023.106781

PLoS One. 2023 Mar 16;18(3):e0266572. doi: 10.1371/journal.pone.0266572. eCollection 2023.

ABSTRACT

The active global SARS-CoV-2 pandemic caused more than 426 million cases and 5.8 million deaths worldwide. The development of completely new drugs for such a novel disease is a challenging, time intensive process. Despite researchers around the world working on this task, no effective treatments have been developed yet. This emphasizes the importance of drug repurposing, where treatments are found among existing drugs that are meant for different diseases. A common approach to this is based on knowledge graphs, that condense relationships between entities like drugs, diseases and genes. Graph neural networks (GNNs) can then be used for the task at hand by predicting links in such knowledge graphs. Expanding on state-of-the-art GNN research, Doshi et al. recently developed the Dr-COVID model. We further extend their work using additional output interpretation strategies. The best aggregation strategy derives a top-100 ranking of 8,070 candidate drugs, 32 of which are currently being tested in COVID-19-related clinical trials. Moreover, we present an alternative application for the model, the generation of additional candidates based on a given pre-selection of drug candidates using collaborative filtering. In addition, we improved the implementation of the Dr-COVID model by significantly shortening the inference and pre-processing time by exploiting data-parallelism. As drug repurposing is a task that requires high computation and memory resources, we further accelerate the post-processing phase using a new emerging hardware-we propose a new approach to leverage the use of high-capacity Non-Volatile Memory for aggregate drug ranking.

PMID:36928101 | DOI:10.1371/journal.pone.0266572

OMICS. 2023 Mar;27(3):93-108. doi: 10.1089/omi.2023.0005.

ABSTRACT

Epstein-Barr virus (EBV) is associated with several tumors, and has substantial relevance for public health. Therapeutics innovation for EBV-related disorders is much needed. In this context, miRNAs are noncoding RNA molecules that play vital roles in EBV infection. miRNA-Seq and RNA-Seq data for EBV-associated clinical samples and cell lines have been generated, but their detailed integrative analyses, and exploitation for drug repurposing against EBV are lacking. Hence, we identified and analyzed the differentially expressed miRNAs (DEmiRs) in EBV-infected cell lines (28) and infected (28) and uninfected human tissue (20) samples using an in-house pipeline. We found significantly enriched host miRNAs like hsa-mir-3651, hsa-mir-1248, and hsa-mir-29c-3p in EBV-infected samples from EBV-associated nasopharyngeal carcinoma and Hodgkin's lymphoma, among others. Furthermore, we also identified significantly enriched novel miRNAs such as hsa-mir-29c-3p, hsa-mir-3651, and hsa-mir-98-3p, which were not previously reported in EBV-related tumors. Differentially expressed mRNAs (DEMs) were identified in EBV-infected cell lines (21) and uninfected human tissue (14) samples. We predicted and selected 1572 DEMs (upregulated) that are targeted by 547 DEmiRs (downregulated). These were further classified into essential (870) and nonessential (702) genes. Moreover, a miRNA-mRNA network was developed for the hub miRNAs. Importantly, we used the DEMs during EBV latent infection types I, II, and III to identify the candidate drugs for repurposing: Glyburide, Levodopa, Nateglinide, and Stiripentol, among others. To the best of our knowledge, this is the first integrative analyses that identified DEmiRs and DEMs as potential therapeutic targets and predicted drugs as potential candidates for repurposing against EBV-related tumors.

PMID:36927073 | DOI:10.1089/omi.2023.0005

Cancer Res Commun. 2022 Aug 17;2(8):814-826. doi: 10.1158/2767-9764.CRC-22-0128. eCollection 2022 Aug.

ABSTRACT

PURPOSE: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma.

EXPERIMENTAL DESIGN: A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed.

RESULTS: The overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87-21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67-86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8+, showed the greatest increase in infiltration.

CONCLUSIONS: Priming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma.

SIGNIFICANCE: There are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma.

PMID:36923309 | PMC:PMC10010343 | DOI:10.1158/2767-9764.CRC-22-0128

Expert Opin Drug Deliv. 2023 Mar 15. doi: 10.1080/17425247.2023.2190581. Online ahead of print.

ABSTRACT

INTRODUCTION: Glioblastoma (GB) is one of the most challenging central nervous system (CNS) tumors in treatment options and response, urging the development of novel management strategies. The anti-alcoholism drug, disulfiram (DS), has a potential anticancer activity, and its complex mechanism of action is assumed to be well exploited against the heterogeneous GB.

AREA COVERED: Through a systematic literature review about repositioning DS to GB treatment, an evaluation of the clinical, pharmacological, and formulation strategies is provided to specify the challenges of drug delivery and thus to advance its clinical translation. From 6 databases, 35 articles were selected, including case report (1); clinical trials (3); original articles mainly representing in vitro and preclinical pharmacological data, and 10 dealing with technological approaches.

EXPERT OPINION: The repositioning of DS in GB treatment is facing drug and tumor-associated limitations due to the oral drug's low bioavailability, unwanted metabolism, and inefficient delivery to brain-tumor tissue. Development strategies using molecular encapsulation of DS and the parenteral dosage forms improve the anticancer pharmacology of the drug. The development of optimized drug delivery systems (DDS) shows promise for the clinical translation of DS into GB adjuvant therapy.

PMID:36922013 | DOI:10.1080/17425247.2023.2190581

J Med Chem. 2023 Mar 15. doi: 10.1021/acs.jmedchem.2c01408. Online ahead of print.

ABSTRACT

Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53-MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.

PMID:36921275 | DOI:10.1021/acs.jmedchem.2c01408

Mol Biol Rep. 2023 Mar 14. doi: 10.1007/s11033-023-08346-z. Online ahead of print.

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of mortality and morbidity in children under the age of five. Despite this, there is still a lack of safe and effective vaccines and antiviral agents for clinical use. Andrographolide exerts antiviral functions against a variety of viruses, but whether (and how) it exerts antiviral effects on RSV remains unclear.

METHODS AND RESULTS: In vitro RSV infection models using A549 and 16HBE cell lines were established, and the effects of andrographolide on RSV were analyzed via RSV N gene load and proinflammatory cytokine levels. The RNA transcriptome was sequenced, and data were analyzed by R software. Andrographolide-related target genes were extracted via network pharmacology using online databases. Lentiviral transfection was applied to knockdown the heme oxygenase-1 gene (Hmox1, HO-1). Results showed that andrographolide suppressed RSV replication and attenuated subsequent inflammation. Network pharmacology and RNA sequencing analysis indicated that the hub gene HO-1 may play a pivotal role in the anti-RSV effects of andrographolide. Furthermore, andrographolide exerted antiviral effects against RSV partially by inducing HO-1 but did not activate the antiviral interferon response.

CONCLUSION: Our findings demonstrated that andrographolide exerted anti-RSV activity by up-regulating HO-1 expression in human airway epithelial cells, providing novel insights into potential therapeutic targets and drug repurposing in RSV infection.

PMID:36918433 | DOI:10.1007/s11033-023-08346-z

Toxicol Appl Pharmacol. 2023 Mar 12:116469. doi: 10.1016/j.taap.2023.116469. Online ahead of print.

ABSTRACT

Promiscuity of therapeutics has important implications in treatment and toxicity. So far, a comprehensive understanding of promiscuity related to kinase inhibitors is lacking and such an analysis may offer potential opportunities for drug repurposing. In the present study, profiling of inhibitor-specific kinases based on the available biochemical IC50s was performed, fold-change of IC50 values for additional targets were calculated by taking the primary target as the reference kinase, and finally the promiscuity degree (PD) for FDA-approved kinase inhibitors was calculated. Surprisingly, class II inhibitors showed more PD than that of the class I inhibitors. We further identified cancer types and sub-types in which additional kinase targets or off-targets of inhibitors were overexpressed for potential drug repurposing. In addition, the expression of these kinases in normal human tissues were also profiled to predict toxicity following drug repositioning. Taken together, the study offers opportunities for cancer treatment in a kinase-specific manner.

PMID:36918129 | DOI:10.1016/j.taap.2023.116469