Viruses. 2025 May 18;17(5):722. doi: 10.3390/v17050722.

ABSTRACT

The COVID-19 pandemic has had a significant impact and continues to alarm the entire world due to the rapid emergence of new variants, even after mass vaccinations. There is still an urgent need for new antivirals or strategies to combat the SARS-CoV-2 infections; however, we have success stories with nirmatrelvir. Drug repurposing and drug discovery may lead to a successful SARS-CoV-2 antiviral; however, rapid drug use may cause unexpected mutations and antiviral drug resistance. Conversely, novel variants of the SARS-CoV-2 can diminish the neutralizing efficacy of vaccines, thereby enhancing viral fitness and increasing the likelihood of drug resistance emergence. Additionally, the disposal of antivirals in wastewater also contributes to drug resistance. Overall, the present review summarizes the strategies and mechanisms involved in the development of drug resistance in SARS-CoV-2. Understanding the mechanism of antiviral resistance is crucial to mitigate the significant healthcare threat and to develop effective therapeutics against drug resistance.

PMID:40431733 | DOI:10.3390/v17050722

Pharmaceutics. 2025 May 9;17(5):631. doi: 10.3390/pharmaceutics17050631.

ABSTRACT

Background/Objectives: Nanocarrier particle design for treating chronic pulmonary diseases presents several challenges, including anatomical and physiological barriers. Drug-repurposing technology using monodispersed spherical silica is one of the innovative ways to deliver drugs. In the present study, the anticancer potential of combinational cisplatin/ribavirin was explored for targeted lung cancer therapeutics. Methods: Monodispersed spherical silica (80 nm) capable of diffusing into the tracheal mucus region was chosen and doped with 10 wt% superparamagnetic iron oxide nanoparticles (SPIONs). Subsequently, it was wrapped with chitosan (Chi, 0.6 wt/vol%), functionalized with 5% wt/wt cisplatin (Cp)/ribavarin (Rib) and angiotensin-converting enzyme 2 (ACE-2) (1.0 μL/mL). Formulations are based on monodispersed spherical silica or halloysite and are termed as (S/MSSiO2/Chi/Cp/Rib) or (S/Hal/Chi/Cp/Rib), respectively. Results: X-ray diffraction (XRD) and diffuse reflectance UV-visible spectroscopy (DRS-UV-vis) analysis of S/MSSiO2/Chi/Cp/Rib confirmed the presence of SPION nanoclusters on the silica surface (45% coverage). The wrapping of chitosan on the silica was confirmed with a Fourier transformed infrared (FTIR) stretching band at 670 cm-1 and ascribed to the amide group of the polymer. The surface charge by zetasizer and saturation magnetization by vibrating sample magnetometer (VSM) were found to be -15.3 mV and 8.4 emu/g. The dialysis membrane technique was used to study the Cp and Rib release between the tumor microenvironment and normal pH ranges from 5.5 to 7.4. S/MSSiO2/Chi formulation demonstrated pH-responsive Cp and Rib at acidic pH (5.6) and normal pH (7.4). Cp and Rib showed release of ~27% and ~17% at pH 5.6, which decreases to ~14% and ~3.2% at pH 7.4, respectively. To assess the compatibility and cytotoxic effect of our nanocomposites, the cell viability assay (MTT) was conducted on cancer lung cells A549 and normal HEK293 cells. Conclusions: The study shows that the designed nanoformulations with multifunctional capabilities are able to diffuse into the lung cells bound with dual drugs and the ACE-2 receptor.

PMID:40430922 | DOI:10.3390/pharmaceutics17050631

Pharmaceutics. 2025 Apr 24;17(5):558. doi: 10.3390/pharmaceutics17050558.

ABSTRACT

Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of death among women worldwide. The cancer-related characteristics of cell proliferation, invasion, migration, and apoptosis are all targeted by metformin. Among breast cancer patients, triple-negative breast cancer (TNBC) is linked to an increased risk of early recurrence and metastases and has poor prognosis. In addition, TNBC has fewer treatment options compared to other breast cancer subtypes because it lacks hormone receptors and human epidermal growth factor receptor 2 (HER2), and it often develops resistance to available treatment options. The current review highlights the recent updates on the mechanistic insights and the efficacy of metformin and metformin-based approaches for the treatment of TNBC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring metformin's effects on metabolic pathways, and then its combination with other therapeutic agents, targeting cell signaling pathways, and approaches to enhance metformin's effects. We also present clinical studies that underscore the beneficial outcomes of metformin or its combination with other agents in TNBC patients.

PMID:40430851 | DOI:10.3390/pharmaceutics17050558

Pharmaceuticals (Basel). 2025 May 9;18(5):700. doi: 10.3390/ph18050700.

ABSTRACT

Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease, due to their multifaced and complicated nature, remain uncurable and impose substantial financial and human burdens on society. Therefore, developing new innovative therapeutic strategies is vital. In this context, drug repurposing has emerged as a promising avenue to expedite the development of treatments for these challenging conditions. One particularly compelling target in this regard is the chaperone protein sigma-1 receptor (S1R), which has garnered significant attention for its neuroprotective properties. Interestingly, several medications, including fluvoxamine (an antidepressant), dextromethorphan (a cough suppressant), and amantadine (an antiviral), which were initially developed for unrelated indications, have shown encouraging results in neurodegenerative therapy through S1R activation. These findings suggest that existing drugs in pharmacopeias can play an essential role in alleviating neurodegenerative symptoms by modulating S1R, thereby offering a faster route and cost-effective path to clinical applications compared to the de novo development of entirely new compounds. Furthermore, as a synergistic benefit, combining S1R-targeting drugs with other therapeutic agents may also improve treatment efficacy. In this review, we highlight key repurposed drugs targeting S1R and explore their mechanisms of action, shedding light on their emerging therapeutic potential in the fight against neurodegeneration.

PMID:40430519 | DOI:10.3390/ph18050700

Pharmaceuticals (Basel). 2025 May 1;18(5):669. doi: 10.3390/ph18050669.

ABSTRACT

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme's active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC50) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC50 values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with KI = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease.

PMID:40430488 | DOI:10.3390/ph18050669

Pharmaceuticals (Basel). 2025 Apr 23;18(5):613. doi: 10.3390/ph18050613.

ABSTRACT

Background: Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (Culicoides paraensis), OROV has no specific antiviral treatment or vaccine. This study aims to identify host-targeted therapeutics against OROV using computational approaches, offering a potential strategy for sustainable antiviral drug discovery. Methods: Virus-associated host targets were identified using the OMIM and GeneCards databases. The Enrichr and DSigDB platforms were used for drug prediction, filtering compounds based on Lipinski's rule for drug likeness. A protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape 3.10.3 software. Four key host targets-IL10, FASLG, PTPRC, and FCGR3A-were prioritized based on their roles in immune modulation and OROV pathogenesis. Molecular docking simulations were performed using the PyRx software to evaluate the binding affinities of selected small-molecule inhibitors-Acetohexamide, Deptropine, Methotrexate, Retinoic Acid, and 3-Azido-3-deoxythymidine-against the identified targets. Results: The PPI network analysis highlighted immune-mediated pathways such as Fc-gamma receptor signaling, cytokine control, and T-cell receptor signaling as critical intervention points. Molecular docking revealed strong binding affinities between the selected compounds and the prioritized targets, suggesting their potential efficacy as host-targeting antiviral candidates. Acetohexamide and Deptropine showed strong binding to multiple targets, indicating broad-spectrum antiviral potential. Further in vitro and in vivo validations are needed to confirm these findings and translate them into clinically relevant treatments. Conclusions: This study highlights the potential of using computational approaches to identify host-targeted therapeutics for Oropouche virus (OROV). By targeting key host proteins involved in immune modulation-IL10, FASLG, PTPRC, and FCGR3A-the selected compounds, Acetohexamide and Deptropine, demonstrate strong binding affinities, suggesting their potential as broad-spectrum antiviral candidates. Further experimental validation is needed to confirm their efficacy and potential for clinical application, offering a promising strategy for sustainable antiviral drug discovery.

PMID:40430433 | DOI:10.3390/ph18050613

Int J Mol Sci. 2025 May 14;26(10):4701. doi: 10.3390/ijms26104701.

ABSTRACT

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review examines recent advances in combating P-gp-mediated resistance, including the development of novel P-gp inhibitors, innovative drug delivery systems (e.g., nanoparticle-based delivery), and strategies to modulate P-gp expression or activity. These modulation strategies encompass targeting relevant signaling pathways (e.g., NF-κB, PI3K/Akt) and exploring drug repurposing. While progress has been made, overcoming P-gp-mediated resistance remains crucial for improving patient outcomes. Future research directions should prioritize the development of potent, selective, and safe P-gp inhibitors with minimal off-target effects, alongside exploring synergistic combination therapies with existing chemotherapeutics or novel agents to effectively circumvent multidrug resistance in hematological malignancies.

PMID:40429842 | DOI:10.3390/ijms26104701

Int J Mol Sci. 2025 May 9;26(10):4546. doi: 10.3390/ijms26104546.

ABSTRACT

Lung cancer is among the most common malignancies globally, is frequently associated with a poor prognosis, and is the second leading cause of cancer-related mortality in both genders. Resistance to treatment, heterogeneity, and invasiveness make lung cancer one of the most challenging tumors to combat. Drug repurposing is considered an advantageous strategy for expediting and economizing drug discovery, as it involves rebranding an existing drug for a new therapeutic use. Since depression is a prevalent psychiatric illness among individuals diagnosed with lung cancer, various selective serotonin reuptake inhibitors (SSRIs) used for the treatment of depression were examined for their possible use in lung cancer treatment as repurposed drugs. Herein, we evaluated the efficacy of SSRIs, both alone and in combination with various anticancer agents, in the treatment of lung cancer along with their mechanisms of action. The innovative approach of repurposing SSRIs offers hope by simplifying the drug discovery process and potentially revealing new therapeutic options for lung cancer. Exploring SSRIs' effects on lung cancer treatment may unlock unexpected avenues for combating this aggressive disease.

PMID:40429689 | DOI:10.3390/ijms26104546

Int J Mol Sci. 2025 May 8;26(10):4497. doi: 10.3390/ijms26104497.

ABSTRACT

Programmed death-ligand 1 (PD-L1) is a crucial immune checkpoint protein that tumors often exploit to evade immune surveillance. This study systematically screened a library of 1031 FDA-approved drugs using a high-throughput molecular dynamics approach to identify potential inhibitors targeting PD-L1. From this screening, five promising compounds-vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine-showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These candidates were further evaluated through extended molecular dynamics simulations lasting up to 150 ns to assess their structural stability, residue fluctuations, and binding free energy. Among the identified compounds, pivmecillinam demonstrated the most favorable results, exhibiting stable binding interactions and a binding free energy of -18.01 kcal/mol, comparable to that of the known PD-L1 inhibitor BMS-1. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents.

PMID:40429641 | DOI:10.3390/ijms26104497

Sci Rep. 2025 May 27;15(1):18533. doi: 10.1038/s41598-025-02999-5.

ABSTRACT

Red radish microgreens (RRM) have gained considerable attention for their promising therapeutic potential. However, the molecular mechanisms underlying their bioactivity remain inadequately characterized. This study explores the anti-inflammatory, antioxidant, and anticancer properties of RRM extract using in silico and in vivo Drosophila model analyses. The metabolite profile of the RRM extract was characterized using comprehensive metabolomics techniques, including Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography High-Resolution Mass Spectrometry (LC-HRMS). Furthermore, in silico analysis utilizing network pharmacology identified target proteins of RRM compounds associated with cancer, inflammation, and oxidative stress. Concurrently, in vivo experiments with Drosophila melanogaster PGRP-LBΔ (Dm PGRP-LBΔ) larvae was conducted to assess the extract's impact on immune and oxidative stress pathways. In silico analysis revealed that RRM compounds interacted with key proteins (AKT1, ESR1, MAPK1, SRC, TP53), modulating pathways related to cancer, inflammation, and oxidative stress. Molecular dynamics simulations reinforced the docking results by confirming robust binding of kaempferitrin to AKT1. In vivo studies showed that RRM extract suppressed immune-related genes (dptA, totA) through the NFκB and JAK-STAT pathways, reduced ROS levels, and selectively regulated antioxidant gene expression by enhancing sod1 while decreasing sod2 and cat. These results suggest RRM extract as a functional food for managing oxidative stress, inflammation, and cancer. Further research in higher organisms and clinical settings is needed.

PMID:40425671 | DOI:10.1038/s41598-025-02999-5

Curr Opin Oncol. 2025 Apr 22. doi: 10.1097/CCO.0000000000001148. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Maintenance therapy (MT), particularly antiangiogenic approaches such metronomic chemotherapy (MC), correspond to the continuous administration of low-dose anticancer agents in a context of minimal residual disease. While widely used in pediatric acute lymphoblastic leukemia for decades, MT has recently shown promise in solid tumors. Additionally, antivascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) are increasingly explored in pediatric sarcomas.

RECENT FINDINGS: This review summarize current evidence on MT efficacy in pediatric sarcomas, focusing on MC and TKIs. It examines their impact on the tumor microenvironment and cancer progression, as well as potential future applications, including standalone use or combination with targeted therapies, immunotherapies and/or drug repurposing.

SUMMARY: MT has been demonstrated to improve outcomes in specific sarcomas, especially high-risk localized rhabdomyosarcoma, and has therefore become a standard of care. Its role in other sarcomas, such as Ewing sarcoma and osteosarcoma, is under investigation. However, critical challenges remain, including optimizing drug selection, treatment duration, and patient stratification to maximize benefits.

PMID:40421977 | DOI:10.1097/CCO.0000000000001148

Phytother Res. 2025 May 26. doi: 10.1002/ptr.8490. Online ahead of print.

ABSTRACT

Growing rates of overweight and obesity worldwide call for novel approaches to treatment, and plant-derived natural products present a promising therapeutic option. Evaluate the efficacy of plant-derived natural products as dietary interventions for overweight and obesity through a systematic review and network meta-analysis. We conduct a systematic review and network meta-analysis following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. We searched from five databases and registries up to March 2024, selecting randomized controlled trials examining dietary interventions with plant-derived natural products for adults with obesity or overweight. The frequentist approach was used for the network meta-analysis, assessing 13 metabolic and obesity-related outcomes. Our review included 39 studies with 2513 participants with PROSPERO registration ID CRD42024520305. African Mango emerged as the most effective intervention, reducing body weight (MD: -10.00 kg, 95% CI: -16.74 to -3.26), waist circumference (MD: -11.70 cm, 95% CI: -17.15 to -6.25), total cholesterol (MD: -44.01 mg/dL, 95% CI: -58.95 to -29.08), triglycerides (MD: -42.65 mg/dL, 95% CI: -79.70 to -5.60), and random blood glucose (MD: -14.95 mg/dL, 95% CI: -18.60 to -11.30). Green coffee led to the largest reduction in body fat percentage (MD: -2.90%, 95% CI: -4.88 to -0.92) and BMI (MD: -3.08 kg/m2, 95% CI: -6.35 to 0.19). Ephedra was most effective in reducing fasting blood glucose (MD: -4.60 mg/dL, 95% CI: -5.49 to -3.71) and HOMA-IR (MD: -16.20, 95% CI: -18.66 to -13.74). There were too few direct comparisons between various metabolites; thus, most of the comparisons were indirect comparisons through placebo. Plant-derived natural products significantly impact obesity management, notably in body weight, waist circumference, and lipid profile reduction; however, further high-quality and rigorous studies were needed to establish the clinical efficacy of the plant-derived natural products.

PMID:40420357 | DOI:10.1002/ptr.8490

Microb Pathog. 2025 May 24:107724. doi: 10.1016/j.micpath.2025.107724. Online ahead of print.

ABSTRACT

The pandemic of COVID-19 has ignited a global race to locate effective therapies with drug repositioning emerging as a leading strategy due to its cost-effectiveness and established safety profiles. Remdesivir, Favipiravir, Hydroxychloroquine, and Chloroquine have been the focus of rigorous clinical trials to determine their therapeutic potential against SARS-CoV-2. This article delves into the innovative synthetic strategies behind these drugs, providing a blueprint for researchers navigating the complex landscape of antiviral development. Beyond synthesis, we explore the fascinating mechanisms of action: hydroxychloroquine and chloroquine elevate lysosomal pH to impede autophagy and viral replication; favipiravir, a nucleoside analogue, induces lethal mutagenesis or RNA chain termination and remdesivir disrupts viral RNA synthesis through delayed chain termination. By merging synthetic methodologies with mechanistic insights, this article offers a comprehensive resource aimed at accelerating the development of potent COVID-19 therapies and underscores the crucial part that chemistry in addressing global health emergencies. It also underscores the vital function of chemistry in addressing global health emergencies and highlights how innovative drug design and repurposing can provide rapid responses to emerging infectious diseases. This fusion of chemistry and virology not only advances our understanding of drug action but also paves the way for the discovery of new therapeutic agents crucial in future pandemics.

PMID:40419200 | DOI:10.1016/j.micpath.2025.107724

Mol Divers. 2025 May 26. doi: 10.1007/s11030-025-11214-6. Online ahead of print.

ABSTRACT

Tumor cell survival depends on the presence of oxygen and nutrients provided by existing blood vessels, particularly when cancer is in its early stage. Along with tumor growth in the vicinity of blood vessels, malignant cells require more nutrients; hence, capillary sprouting occurs from parental vessels, a process known as angiogenesis. Although multiple cellular pathways have been identified, controlling them with one single biomolecule as a multi-target inhibitor could be an attractive strategy for reducing medication side effects. Three critical pathways in angiogenesis have been identified, which are activated by the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR). This study aimed to develop a methodology to discover multi-target inhibitors among over 2000 FDA-approved drugs. Hence, a novel ensemble approach was employed, comprising classification and regression models. First, three different deep autoencoder classifications were generated for each target individually. The top 100 trained models were selected for the high-throughput virtual screening step. After that, all identified molecules with a probability of more than 0.9 in more than 70% of the models were removed to ensure accurate consideration in the regression step. Since the ultimate aim of virtual screening is to discover molecules with the highest success rate in the pharmaceutical industry, various aspects of the molecules in different assays were considered by integrating ten different regression models. In conclusion, this paper contributes to pharmaceutical sciences by introducing eleven diverse scaffolds and eight approved drugs that can potentially be used as inhibitors of angiogenesis receptors, including VEGFR, FGFR, and EGFR. Considering three target receptors simultaneously is another central concept and contribution used. This concept could increase the chance of success, while reducing the possibility of resistance to these agents.

PMID:40418485 | DOI:10.1007/s11030-025-11214-6

Arch Pharm (Weinheim). 2025 May;358(5):e70017. doi: 10.1002/ardp.70017.

ABSTRACT

Drug repurposing, which involves applying existing pharmaceuticals to new therapeutic areas, offers several advantages, including increased efficiency, reduced costs, and lower risks. The research aimed to investigate the molecular mechanisms underlying the new application of the antipsychotic drug aripiprazole (APZ) in the treatment of endometrial cancer (EC), as well as its synergistic efficacy when used in combination with progestin. The cell viability assay and proliferation assay demonstrated that APZ exerted a significant inhibitory effect on the proliferation of ISK and KLE cells. Moreover, APZ was found to induce cell apoptosis prominently by flow cytometry. Network pharmacology analysis indicated that the anti-EC effects of APZ were mediated via the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which was subsequently confirmed by Western blot analysis. Furthermore, APZ significantly enhanced the proliferation inhibitory effect of medroxyprogesterone acetate (MPA) against progestin-resistant KLE cells, displaying remarkable synergistic activity. These findings position APZ as a promising therapeutic candidate for EC, with potential utility both as a monotherapy and in combination with MPA, offering new avenues for EC treatment strategies.

PMID:40415233 | DOI:10.1002/ardp.70017

Australas J Dermatol. 2025 May 24. doi: 10.1111/ajd.14530. Online ahead of print.

NO ABSTRACT

PMID:40411268 | DOI:10.1111/ajd.14530

IEEE J Biomed Health Inform. 2025 May 23;PP. doi: 10.1109/JBHI.2025.3573158. Online ahead of print.

ABSTRACT

Predicting drug-disease associations is a crucial step in drug repositioning, especially with computational methods that quickly locate potential drug-disease pairs. Heterogenous network is a common tool for introducing multiple type relation information about drugs and diseases. However, the diversity of relations is ignored in most of existing methods, which makes them difficult to explore type semantic information with structure properties. Therefore, we propose a relation-centric GNN framework to encode critical association patterns. Firstly, we utilize a relation-centric graph, line graph, to represent the context of a drug-disease pair identified as the center node. The prediction problem is modeled to learn the embedding vector of the center node. Secondly, a multi-grained line graph neural network (MGLGNN) is designed to excavate fine-grained features that encapsulate local graph structures. We theoretically define a handful of typical nodes that can be regarded as high-order abstractions of relations in each type. Then, MGLGNN distills the local information and passes it to typical nodes from a global perspective. With learned multi-grained features, the center node automatically captures heterogenous relation semantics and structure patterns. Thirdly, a hierarchical contrastive learning (HCL) mechanism is proposed to ensure the quality of multi-grained features in an unsupervised way. Extensive experiments show the great potential of our model in mining drug-disease associations.

PMID:40408216 | DOI:10.1109/JBHI.2025.3573158

Med Sci (Basel). 2025 Apr 23;13(2):47. doi: 10.3390/medsci13020047.

ABSTRACT

Cancer is the second leading cause of mortality worldwide. Despite the available treatment options, a majority of cancer patients develop drug resistance, indicating the need for alternative approaches. Repurposed drugs, such as antiglycolytic and anti-microbial agents, have gained substantial attention as potential alternative strategies against different disease pathophysiologies, including lung cancer. To that end, multiple studies have suggested that the antiglycolytic dichloroacetate (DCA) and the antibiotic salinomycin (SAL) possess promising anticarcinogenic activity, attributed to their abilities to target the key metabolic enzymes, ion transport, and oncogenic signaling pathways involved in regulating cancer cell behavior, including cell survival and proliferation. We used the following searches and selection criteria. (1) Biosis and PubMed were used with the search terms dichloroacetate; salinomycin; dichloroacetate as an anticancer agent; salinomycin as an anticancer agent; dichloroacetate side effects; salinomycin side effects; salinomycin combination therapy; dichloroacetate combination therapy; and dichloroacetate or salinomycin in combination with other agents, including chemotherapy and tyrosine kinase inhibitors. (2) The exclusion criteria included not being related to the mechanisms of DCA and SAL or not focusing on their anticancer properties. (3) All the literature was sourced from peer-reviewed journals within a timeframe of 1989 to 2024. Importantly, experimental studies have demonstrated that both DCA and SAL exert promising anticarcinogenic properties, as well as having synergistic effects in combination with other therapeutic agents, against multiple cancer models. The goal of this review is to highlight the mechanistic workings and efficacy of DCA and SAL as monotherapies, and their combination with other therapeutic agents in various cancer models, with a major emphasis on non-small-cell lung cancer (NSCLC) treatment.

PMID:40407542 | DOI:10.3390/medsci13020047

Methods Protoc. 2025 May 6;8(3):48. doi: 10.3390/mps8030048.

ABSTRACT

BACKGROUND: Lafora disease (LD) is an ultra-rare and fatal neurodegenerative disorder with limited therapeutic options. Current treatments primarily address symptoms, with modest efficacy in halting disease progression, thus highlighting the urgent need for novel therapeutic approaches. Gene therapy, antisense oligonucleotides, and recombinant enzymes have recently been, and still are, under investigation. Drug repurposing may offer a promising approach to identify new, possibly effective, therapies.

METHODS: This study aims to investigate the conditions for repurposing empagliflozin, an SGLT2 (sodium/glucose cotransporter-2) inhibitor, as a potential treatment for LD and to establish a clinical protocol. Clinical phase: This 12-month prospective observational study will assess the safety and clinical efficacy of empagliflozin in two patients with early to intermediate LD stage. The primary endpoints will include changes in the severity of epilepsy and cognitive function, while the secondary endpoints will assess motor function, global function, and autonomy. Multiple clinical and instrumental evaluations (including MRI and PET with 18F-fluorodeoxyglucose) will be performed before and during treatment. Safety monitoring will include regular clinical assessments and reports of adverse events. Preclinical phase: In silico studies (using both molecular docking calculations and reverse ligand-based screening) and in vitro cell-based assays will allow us to investigate the effects of empagliflozin (and other gliflozins) on some key targets likely implicated in LD pathogenesis, such as GLUT1, GLUT3, glycogen synthase (hGYS), and glycogen phosphorylase (GP), as suggested in the literature and digital platforms for in silico target fishing.

RESULTS: The expected outcome of this study is twofold, i.e., (i) assessing the safety and tolerability of empagliflozin in LD patients and (ii) gathering preliminary data on its potential efficacy in improving clinical and neurologic features. Additionally, the in silico and in vitro studies may provide new insights into the mechanisms through which empagliflozin may exert its therapeutic effects in LD.

CONCLUSION: The findings of this study are expected to provide evidence in support of the repurposing of empagliflozin for the treatment of LD.

PMID:40407475 | DOI:10.3390/mps8030048

Br J Dermatol. 2025 May 23:ljaf195. doi: 10.1093/bjd/ljaf195. Online ahead of print.

ABSTRACT

BACKGROUND: Epidermolysis bullosa simplex (EBS) is a hereditary skin fragility disorder caused by missense pathogenic variants in KRT5 or KRT14. These variants trigger the collapse of the cytoskeleton into cytoplasmic protein aggregates, which renders the epidermis highly susceptible to mechanical stress and leads to intraepidermal blistering and loss of intercellular cohesion. Currently, no molecular therapies for EBS exist.

OBJECTIVES: Characterization of K5 or K14 mutant keratinocytes, from patients with EBS, in response to PKC412 treatment in monolayer culture and in epidermal equivalents. This clarifies the potential of PKC412 as a drug repurposing therapy approach in EBS.

METHODS: We conducted a comprehensive characterization of K5 and K14 mutant keratinocytes in response to PKC412, examining its effects on proliferation, wound closure, and apoptosis. Additionally, we evaluated the improvement of intercellular cohesion through stretch assays, epithelial sheet assays, and assessment of desmosomal organization. Finally, we investigated the efficacy of PKC412 application in both skin explants and EBS-derived epidermal equivalent cultures.

RESULTS: We demonstrated that PKC412 is effective in various keratinocytes carrying pathogenic variants associated with localized, generalized, or intermediate forms of EBS. PKC412 enhanced intercellular adhesion in both immortalized normal and EBS keratinocytes, as well as normal primary keratinocytes, and under stretch conditions. Immunoblot analyses revealed a concentration-dependent reduction in desmoplakin phosphorylation, which remained stable over the course of three days at the sites investigated. Additionally, application of PKC412 in epidermal equivalent cultures restored desmoplakin distribution in the epidermal basal layer.

CONCLUSIONS: PKC412 markedly enhanced intercellular cohesion and stress resilience in patient-derived EBS keratinocytes, both in monolayer and 3D culture systems. These findings highlight PKC412 as a promising therapeutic candidate for the treatment of EBS.

PMID:40406951 | DOI:10.1093/bjd/ljaf195