Sci Transl Med. 2022 Sep 7;14(661):eabo5987. doi: 10.1126/scitranslmed.abo5987. Epub 2022 Sep 7.

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is a common and frequently lethal cancer with few therapeutic options. In particular, there are few effective targeted therapies. Development of highly effective therapeutic strategies tailored to patients with HNSCC remains a pressing challenge. To address this, we present a pharmacogenomic study to facilitate precision treatments for patients with HNSCC. We established a large collection of 56 HNSCC patient-derived cells (PDCs), which recapitulated the molecular features of the original tumors. Pharmacological assessment of HNSCCs was conducted using a three-tiered high-throughput drug screening using 2248 compounds across these PDC models and an additional 18 immortalized cell lines. We integrated genomic, transcriptomic, and pharmacological analysis to predict biomarkers, gene-drug associations, and validated biomarkers. These results supported drug repurposing for multiple HNSCC subtypes, including the JAK2 inhibitor fedratinib, for low KRT18-expressing HNSCC cases, and the topoisomerase inhibitor mitoxantrone, for IL6R-activated HNSCC cases. Our results demonstrated concordance between susceptibility predictions from the PDCs and the matched patients' responses to standard clinical medication. Moreover, we identified and experimentally confirmed that high expression of ITGB1 elicited therapeutic resistance to docetaxel and high SOD1 expression conferred resistance to afatinib. We further validated ITGB1 as a predictive biomarker for the efficacy of docetaxel therapy in a phase 2 clinical trial. In summary, our study shows that this HNSCC cell resource, as well as the resulting pharmacogenomic profiles, is effective for biomarker discovery and for guiding precision oncology therapies in HNSCCs.

PMID:36070368 | DOI:10.1126/scitranslmed.abo5987

Biomed Pharmacother. 2022 May;149:112922. doi: 10.1016/j.biopha.2022.112922. Epub 2022 Apr 5.

ABSTRACT

The overexpression of ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein) or ABCG2 (BCRP/MXR/ABCP) in cancer cells is frequently associated with the development of multidrug resistance (MDR) in cancer patients, which remains a major obstacle to effective cancer treatment. By utilizing energy derived from ATP hydrolysis, both transporters have been shown to reduce the chemosensitivity of cancer cells by actively effluxing cytotoxic anticancer drugs out of cancer cells. Knowing that there are presently no approved drugs or other therapeutics for the treatment of multidrug-resistant cancers, in recent years, studies have investigated the repurposing of tyrosine kinase inhibitors (TKIs) to act as agents against MDR mediated by ABCB1 and/or ABCG2. SKLB610 is a multi-targeted TKI with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor 2 (FGFR2). In this study, we investigate the interaction of SKLB610 with ABCB1 and ABCG2. We discovered that neither ABCB1 nor ABCG2 confers resistance to SKLB610, but SKLB610 selectively sensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer agents in a concentration-dependent manner. Our data indicate that SKLB610 reverses ABCG2-mediated MDR by attenuating the drug-efflux function of ABCG2 without affecting its total cell expression. These findings are further supported by results of SKLB610-stimulated ABCG2 ATPase activity and in silico docking of SKLB610 in the drug-binding pocket of ABCG2. In summary, we reveal the potential of SKLB610 to overcome resistance to cytotoxic anticancer drugs, which offers an additional treatment option for patients with multidrug-resistant cancers and warrants further investigation.

PMID:36068781 | DOI:10.1016/j.biopha.2022.112922

Biomed Pharmacother. 2022 May;149:112911. doi: 10.1016/j.biopha.2022.112911. Epub 2022 Apr 4.

ABSTRACT

This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson's disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness.

PMID:36068774 | DOI:10.1016/j.biopha.2022.112911

Methods Mol Biol. 2022;2547:187-199. doi: 10.1007/978-1-0716-2573-6_8.

ABSTRACT

The SARS-CoV-2 virus has been the subject of intense pharmacological research. Various pharmacotherapeutic approaches including antiviral and immunotherapy are being explored. A pandemic, however, cannot depend on the development of new drugs; the time required for conventional drug discovery and development is far too lengthy. As such, repurposing drugs is being used as a viable approach for identifying pharmacological agents for COVID-19 infections. Evaluation of repurposed drug candidates with pharmacogenomic analysis is being used to identify near-term pharmacological remedies for COVID-19.

PMID:36068465 | DOI:10.1007/978-1-0716-2573-6_8

J Adv Res. 2022 Sep 3:S2090-1232(22)00199-0. doi: 10.1016/j.jare.2022.08.018. Online ahead of print.

ABSTRACT

BACKGROUND: Repurposing antifungal drugs in cancer therapy has attracted unprecedented attention in both preclinical and clinical research due to specific advantages, such as safety, high-cost effectiveness and time savings compared with cancer drug discovery. The surprising and encouraging efficacy of antifungal drugs in cancer therapy, mechanistically, is attributed to the overlapping targets or molecular pathways between fungal and cancer pathogenesis. Advancements in omics, informatics and analytical technology have led to the discovery of increasing "off-site" targets from antifungal drugs involved in cancerogenesis, such as smoothened (D477G) inhibition from itraconazole in basal cell carcinoma.

AIM OF REVIEW: This review illustrates several antifungal drugs repurposed for cancer therapy and reveals the underlying mechanism based on their original target and "off-site" target. Furthermore, the challenges and perspectives for the future development and clinical applications of antifungal drugs for cancer therapy are also discussed, providing a refresh understanding of drug repurposing. Key Scientific Concepts of Review: This review may provide a basic understanding of repurposed antifungal drugs for clinical cancer management, thereby helping antifungal drugs broaden new indications and promote clinical translation.

PMID:36067975 | DOI:10.1016/j.jare.2022.08.018

Comput Biol Med. 2022 Aug 30;149:106029. doi: 10.1016/j.compbiomed.2022.106029. Online ahead of print.

ABSTRACT

BACKGROUND: To understand the transcriptomic response to SARS-CoV-2 infection, is of the utmost importance to design diagnostic tools predicting the severity of the infection.

METHODS: We have performed a deep sampling analysis of the viral transcriptomic data oriented towards drug repositioning. Using different samplers, the basic principle of this methodology the biological invariance, which means that the pathways altered by the disease, should be independent on the algorithm used to unravel them.

RESULTS: The transcriptomic analysis of the altered pathways, reveals a distinctive inflammatory response and potential side effects of infection. The virus replication causes, in some cases, acute respiratory distress syndrome in the lungs, and affects other organs such as heart, brain, and kidneys. Therefore, the repositioned drugs to fight COVID-19 should, not only target the interferon signalling pathway and the control of the inflammation, but also the altered genetic pathways related to the side effects of infection. We also show via Principal Component Analysis that the transcriptome signatures are different from influenza and RSV. The gene COL1A1, which controls collagen production, seems to play a key/vital role in the regulation of the immune system. Additionally, other small-scale signature genes appear to be involved in the development of other COVID-19 comorbidities.

CONCLUSIONS: Transcriptome-based drug repositioning offers possible fast-track antiviral therapy for COVID-19 patients. It calls for additional clinical studies using FDA approved drugs for patients with increased susceptibility to infection and with serious medical complications.

PMID:36067633 | DOI:10.1016/j.compbiomed.2022.106029

Bioinformatics. 2022 Sep 6:btac611. doi: 10.1093/bioinformatics/btac611. Online ahead of print.

ABSTRACT

SUMMARY: Drug repurposing is an approach used to discover new indications for existing drugs. Recently, several computational approaches have been developed for drug repurposing in cancer. Nevertheless, no approaches have reported a systematic analysis of pathway crosstalk. Pathway crosstalk, which refers to the phenomenon of interaction or cooperation between pathways, is a critical aspect of tumor pathways that allows cancer cells to survive and acquire resistance to drug therapy. Here, we innovatively developed a system biology R-based software package, DRviaSPCN, to repurpose drugs for cancer via a subpathway (SP) crosstalk network. This package provides a novel approach to prioritize cancer candidate drugs by considering drug-induced SPs and their crosstalk effects. The operation modes mainly include construction of the SP network and calculation of the centrality scores of SPs to reflect the influence of SP crosstalk, calculation of enrichment scores of drug- and disease-induced dysfunctional SPs and weighted them by the centrality scores of SPs, evaluation of the drug-disease reverse association at the weighted SP level, identification of cancer candidate drugs, and visualization of the results. Its capabilities enable DRviaSPCN to find cancer candidate drugs, which will complement the recent tools which did not consider crosstalk among pathways/SPs. DRviaSPCN may help to facilitate the development of drug discovery.

AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and available under GPL-2 license from the CRAN website (https://CRAN.R-project.org/package=DRviaSPCN).

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36066432 | DOI:10.1093/bioinformatics/btac611

J Mol Model. 2022 Sep 5;28(10):295. doi: 10.1007/s00894-022-05301-w.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic human pathogen. It synthesizes the poison called Hydrogen Cyanide (HCN). The synthesis of HCN is mediated by the enzyme HCN synthase which is obtained from the hcnABC operon and the transcription of the hcnABC operon is mediated by three proteins LasR, RhlR, and ANR. In our previous works, we analyzed the activation process of RhlR and LasR proteins by their cognate auto-inducer ligands (N-butanoyl-L-homoserine lactone and N-(3-oxododecanoyl)-homoserine lactone respectively). In this work, we attempted to identify some multi-targeting ligands which would be able to destroy the structural integrity of both the RhlR and LasR proteins using steered MD simulations. We used the virtual screening of ligand libraries, and for that purpose, we used the NCI drug database. We selected the top 4 ligands from our virtual screening experiments. We then tried to check their relative binding affinities with the LasR and RhlR proteins in comparison to their native auto-inducer ligands. Through this work, we were able to identify 4 such ligands which were capable of binding to both the RhlR and LasR proteins in a better way than their native auto-inducer ligands. The efficacies of these ligands to actually perturb the structural integrity of RhlR and LasR proteins could be tested in wet lab. The work is the first work in the field of structure-based drug design to come up with possible multi-targeting drug-like structures against the RhlR and LasR proteins from Pseudomonas aeruginosa.

PMID:36064977 | DOI:10.1007/s00894-022-05301-w

J Biomed Sci. 2022 Sep 6;29(1):65. doi: 10.1186/s12929-022-00847-6.

ABSTRACT

Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from numerous teams have led to the generation of a voluminous library composed of chemically and mechanistically diverse small molecules as anti-COVID19 scaffolds. This review article presents an overview of medicinal chemistry campaigns and drug repurposing programs that culminated in the identification of a plethora of small molecule-based anti-COVID19 drugs mediating their antiviral effects through inhibition of proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin and other targets. In light of the evidence ascertaining the potential of small molecule drugs to approach conserved proteins required for the viral replication of all coronaviruses, accelerated FDA approvals are anticipated for small molecules for the treatment of COVID19 shortly. Though the recent attempts invested in this direction in pursuit of enrichment of the anti-COVID-19 armoury (chemical tools) are praiseworthy, some strategies need to be implemented to extract conclusive benefits of the recently reported small molecule viz. (i) detailed preclinical investigation of the generated anti-COVID19 scaffolds (ii) in-vitro profiling of the inhibitors against the emerging SARS-CoV-2 variants (iii) development of assays enabling rapid screening of the libraries of anti-COVID19 scaffold (iv) leveraging the applications of machine learning based predictive models to expedite the anti-COVID19 drug discovery campaign (v) design of antibody-drug conjugates.

PMID:36064696 | DOI:10.1186/s12929-022-00847-6

Exp Brain Res. 2022 Sep 5. doi: 10.1007/s00221-022-06448-x. Online ahead of print.

ABSTRACT

Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental disorders that have become a primary clinical and social concern, with a prevalence of 2-3% in the population. Neuronal function and behaviour undergo significant malleability during the critical period of development that is found to be impaired in ID/ASD. Human genome sequencing studies have revealed many genetic variations associated with ASD/ID that are further verified by many approaches, including many mouse and other models. These models have facilitated the identification of fundamental mechanisms underlying the pathogenesis of ASD/ID, and several studies have proposed converging molecular pathways in ASD/ID. However, linking the mechanisms of the pathogenic genes and their molecular characteristics that lead to ID/ASD has progressed slowly, hampering the development of potential therapeutic strategies. This review discusses the possibility of recognising the common molecular causes for most ASD/ID based on studies from the available models that may enable a better therapeutic strategy to treat ID/ASD. We also reviewed the potential biomarkers to detect ASD/ID at early stages that may aid in diagnosis and initiating medical treatment, the concerns with drug failure in clinical trials, and developing therapeutic strategies that can be applied beyond a particular mutation associated with ASD/ID.

PMID:36063192 | DOI:10.1007/s00221-022-06448-x

Pharm Dev Technol. 2022 Sep 5:1-55. doi: 10.1080/10837450.2022.2121840. Online ahead of print.

ABSTRACT

Ivermectin (IVM) is a drug widely used in veterinary and human medicine for the management of parasitic diseases. Its repositioning potential has been recently considered for the treatment of different diseases, such as cancer and viral infections. However, IVM faces some limitations to its formulations due to its low water solubility and bioavailability, along with reports of drug resistance. In this sense, novel technological approaches have been explored to optimize its formulations and/or to develop innovative medicines. Therefore, this review discusses the strategies proposed in the last decade to improve the safety and efficacy of IVM and to explore its novel therapeutic applications. Among these technologies, the use of micro/nano-drug delivery systems is the most used approach, followed by long-acting formulations. In general, the development of these novel formulations seems to run side by side in veterinary and human health, showing a shared interface between the two areas. Although the technologies proposed indicate a promising future in the development of innovative dosage forms containing IVM, its safety and therapeutic targets must be further evaluated. Overall, these approaches comprise tailoring drug delivery profiles, decreasing the risks of developing drug resistance, and supporting the application of IVM for reaching different therapeutic targets.

PMID:36062978 | DOI:10.1080/10837450.2022.2121840

Front Physiol. 2022 Aug 19;13:872421. doi: 10.3389/fphys.2022.872421. eCollection 2022.

ABSTRACT

Sphingomyelin (SM) belongs to a class of lipids termed sphingolipids. The disruption in the sphingomyelin signaling pathway is associated with various neurodegenerative disorders. TNF-α, a potent pro-inflammatory cytokine generated in response to various neurological disorders like Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple Sclerosis (MS), is an eminent regulator of the sphingomyelin metabolic pathway. The immune-triggered regulation of the sphingomyelin metabolic pathway via TNF-α constitutes the sphingomyelin signaling pathway. In this pathway, sphingomyelin and its downstream sphingolipids activate various signaling cascades like PI3K/AKT and MAPK/ERK pathways, thus, controlling diverse processes coupled with neuronal viability, survival, and death. The holistic analysis of the immune-triggered sphingomyelin signaling pathway is imperative to make necessary predictions about its pivotal components and for the formulation of disease-related therapeutics. The current work offers a comprehensive in silico systems analysis of TNF-α mediated sphingomyelin and downstream signaling cascades via a model-based quantitative approach. We incorporated the intensity values of genes from the microarray data of control individuals from the AD study in the input entities of the pathway model. Computational modeling and simulation of the inflammatory pathway enabled the comprehensive study of the system dynamics. Network and sensitivity analysis of the model unveiled essential interaction parameters and entities during neuroinflammation. Scanning of the key entities and parameters allowed us to determine their ultimate impact on neuronal apoptosis and survival. Moreover, the efficacy and potency of the FDA-approved drugs, namely Etanercept, Nivocasan, and Scyphostatin allowed us to study the model's response towards inhibition of the respective proteins/enzymes. The network analysis revealed the pivotal model entities with high betweenness and closeness centrality values including recruit FADD, TNFR_TRADD, act CASP2, actCASP8, actCASP3 and 9, cytochrome C, and RIP_RAIDD which profoundly impacted the neuronal apoptosis. Whereas some of the entities with high betweenness and closeness centrality values like Gi-coupled receptor, actS1PR, Sphingosine, S1P, actAKT, and actERK produced a high influence on neuronal survival. However, the current study inferred the dual role of ceramide, both on neuronal survival and apoptosis. Moreover, the drug Nivocasan effectively reduces neuronal apoptosis via its inhibitory mechanism on the caspases.

PMID:36060699 | PMC:PMC9437628 | DOI:10.3389/fphys.2022.872421

Front Oncol. 2022 Aug 18;12:893951. doi: 10.3389/fonc.2022.893951. eCollection 2022.

ABSTRACT

BACKGROUND: Colchicine is a traditional medication that is currently approved to treat gout and familial Mediterranean fever (FMF). However, colchicine has a wide range of anti-inflammatory activities, and several studies have indicated that it may be useful in a variety of other conditions, such as rheumatic disease, cardiac disease, and cancer. Osteosarcoma, the most common type of bone sarcoma, is derived from primitive bone-forming mesenchymal cells. In this study, we investigated whether colchicine could be used to treat osteosarcoma through the regulation of cell cycle signaling.

METHODS: Two human osteosarcoma cell lines, U2OS and Saos-2, were used. A clonogenic assay was used to determine the antiproliferative effects of colchicine on osteosarcoma cells. Reactive oxygen species (ROS) production and apoptosis were measured by flow cytometry. Migration and invasion assays were performed to investigate the inhibitory effects of colchicine. The signaling pathways related to colchicine treatment were verified by GO biological process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.

RESULTS: Colchicine was selected as the lead compound based on the results of initial screening and cell viability assays conducted in Saos-2 and U2Os cells. Colchicine reduced the viability of Saos-2 and U2OS cells in a concentration-dependent manner. It also significantly inhibited colony-forming ability and induced ROS production and apoptosis. It also inhibited the migration and invasion of both Saos-2 and U2OS cells. GOBP and KEGG enrichment analyses indicated the involvement of microtubule-based processes and cancer-related pathways.

CONCLUSIONS: These findings suggest that colchicine has therapeutic potential in osteosarcoma.

PMID:36059694 | PMC:PMC9433722 | DOI:10.3389/fonc.2022.893951

Front Immunol. 2022 Aug 17;13:922531. doi: 10.3389/fimmu.2022.922531. eCollection 2022.

ABSTRACT

Ankylosing spondylitis (AS) is a chronic inflammatory disease that causes spinal inflammation and fusion. Although the cause of AS is unknown, genetic factors (e.g., HLA-B27) and environmental factors (e.g., sex, age, and infection) increase the risk of AS. Current treatments for AS are to improve symptoms and suppress disease progression. There is no way to completely cure it. High blood cholesterol and lipid levels aggravate the symptoms of autoimmune diseases. We applied hyperlipidemia drugs ezetimibe and rosuvastatin to AS mice and to PBMCs from AS patients. Ezetimibe and rosuvastatin was administered for 11 weeks to AS model mice on the SKG background. Then, the tissues and cells of mice were performed using flow cytometry, computed tomography, immunohistochemistry, and immunofluorescence. Also, the normal mouse splenocytes were cultured in Th17 differentiation conditions for in vitro analysis such as flow cytometry, ELISA and RNA sequencing. The 10 AS patients' PBMCs were treated with ezetimibe and rosuvastatin. The patients' PBMC were analyzed by flow cytometry and ELISA for investigation of immune cell type modification. Ezetimibe caused substantial inhibition for AS. The present study showed that ezetimibe inhibits Th17 cell function, thereby slowing the progression of AS. It is well known that statins are more effective in reducing blood lipid concentrations than ezetimibe, however, our results that ezetimibe had a better anti-inflammatory effect than rosuvastatin in AS. This data suggests that ezetimibe has an independent anti-inflammatory effect independent of blood lipid reduction. To investigate whether ezetimibe has its anti-inflammatory effect through which signaling pathway, various in vitro experiments and RNA sequencing have proceeded. Here, this study suggests that ezetimibe can be an effective treatment for AS patients by inhibiting Th17 differentiation-related genes such as IL-23R and IL-1R. Thus, this study suggests that ezetimibe has therapeutic potential for AS through inhibition of Th17 differentiation and the production of pro-inflammatory cytokines.

PMID:36059546 | PMC:PMC9428320 | DOI:10.3389/fimmu.2022.922531

Am J Hum Genet. 2022 Sep 1;109(9):1620-1637. doi: 10.1016/j.ajhg.2022.07.011.

ABSTRACT

Genetically informed drug development and repurposing is an attractive prospect for improving patient outcomes in psychiatry; however, the effectiveness of these endeavors is confounded by heterogeneity. We propose an approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritize individual "directional anchor" genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, which we call a pharmagenic enrichment score (PES), identify individuals with a higher burden of genetic risk, localized in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

PMID:36055211 | DOI:10.1016/j.ajhg.2022.07.011

Biomed Pharmacother. 2022 Aug 30;154:113616. doi: 10.1016/j.biopha.2022.113616. Online ahead of print.

ABSTRACT

Understanding cancer biology and the development of novel agents for cancer treatment has always been the goal of cancer researchers. However, the research and development of new drugs is hindered by its long development time, exorbitant cost, high regulatory hurdles, and staggering failure rates. Given the challenges involved drug development for cancer therapies, alternative strategies, in particular the repurposing of 'old' drugs that have been approved for other indications, are attractive. Itraconazole is an FDA-approved anti-fungal drug of the triazole class, and has been used clinically for more than 30 years. Recent drug repurposing screens revealed itraconazole exerts anti-cancer activity via inhibiting angiogenesis and multiple oncogenic signaling pathways. To explore the potential utilization of itraconazole in different types of malignancies, we retrieved the published literature relating to itraconazole in cancer and reviewed the mechanisms of itraconazole in preclinical and clinical cancer studies. Current research predicts the hedgehog signaling pathway as the main target by which itraconazole inhibits a variety of solid and hematological cancers. As clinical trial results become available, itraconazole could emerge as a new antitumor drug that can be used in combination with first-line antitumor drugs.

PMID:36055112 | DOI:10.1016/j.biopha.2022.113616

Mov Disord. 2022 Aug 29. doi: 10.1002/mds.29205. Online ahead of print.

ABSTRACT

BACKGROUND: Available treatments for Parkinson's disease (PD) are only partially or transiently effective. Identifying existing molecules that may present a therapeutic or preventive benefit for PD (drug repositioning) is thus of utmost interest.

OBJECTIVE: We aimed at detecting potentially protective associations between marketed drugs and PD through a large-scale automated screening strategy.

METHODS: We implemented a machine learning (ML) algorithm combining subsampling and lasso logistic regression in a case-control study nested in the French national health data system. Our study population comprised 40,760 incident PD patients identified by a validated algorithm during 2016 to 2018 and 176,395 controls of similar age, sex, and region of residence, all followed since 2006. Drug exposure was defined at the chemical subgroup level, then at the substance level of the Anatomical Therapeutic Chemical (ATC) classification considering the frequency of prescriptions over a 2-year period starting 10 years before the index date to limit reverse causation bias. Sensitivity analyses were conducted using a more specific definition of PD status.

RESULTS: Six drug subgroups were detected by our algorithm among the 374 screened. Sulfonamide diuretics (ATC-C03CA), in particular furosemide (C03CA01), showed the most robust signal. Other signals included adrenergics in combination with anticholinergics (R03AL) and insulins and analogues (A10AD).

CONCLUSIONS: We identified several signals that deserve to be confirmed in large studies with appropriate consideration of the potential for reverse causation. Our results illustrate the value of ML-based signal detection algorithms for identifying drugs inversely associated with PD risk in health-care databases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PMID:36054665 | DOI:10.1002/mds.29205

CNS Neurosci Ther. 2022 Sep 2. doi: 10.1111/cns.13961. Online ahead of print.

ABSTRACT

AIMS: Stroke has a high incidence and is a disabling condition that can lead to severe cognitive, motor, and sensory dysfunction. In this study, we employed a drug repurposing strategy to investigate the neuroprotective effect of lomitapide on focal ischemic brain injury and explore its potential mechanism of action.

METHODS: Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male C57BL/6 mice and simulated by oxygen-glucose deprivation in N2a-BV2 cells in co-cultivation.

RESULTS: Lomitapide significantly increased the survival rate, reduced the neuronal tissue loss, and improved the neurological function after MCAO. Furthermore, lomitapide could increase the expression of LC3-II, reduce the expression of P62 and LAMP2, promote autophagic flux, and inhibit apoptosis by increasing and inhibiting the expression of the apoptosis-associated proteins Bcl-2 and Bax, respectively. In addition, lomitapide inhibited the migration of pro-inflammatory microglia.

CONCLUSION: Lomitapide is a lipid-lowering drug, and this is the first study to explore its protective effect on ischemic nerve injury in vitro and in vivo. Our results suggest that lomitapide can be repositioned as a potential therapeutic drug for the treatment of stroke.

PMID:36052650 | DOI:10.1111/cns.13961

Front Pharmacol. 2022 Aug 17;13:952192. doi: 10.3389/fphar.2022.952192. eCollection 2022.

ABSTRACT

The coronavirus disease 2019 pandemic accelerated drug/vaccine development processes, integrating scientists all over the globe to create therapeutic alternatives against this virus. In this work, we have collected information regarding proteins from SARS-CoV-2 and humans and how these proteins interact. We have also collected information from public databases on protein-drug interactions. We represent this data as networks that allow us to gain insights into protein-protein interactions between both organisms. With the collected data, we have obtained statistical metrics of the networks. This data analysis has allowed us to find relevant information on which proteins and drugs are the most relevant from the network pharmacology perspective. This method not only allows us to focus on viral proteins as the main targets for COVID-19 but also reveals that some human proteins could be also important in drug repurposing campaigns. As a result of the analysis of the SARS-CoV-2-human interactome, we have identified some old drugs, such as disulfiram, auranofin, gefitinib, suloctidil, and bromhexine as potential therapies for the treatment of COVID-19 deciphering their potential complex mechanism of action.

PMID:36052135 | PMC:PMC9424758 | DOI:10.3389/fphar.2022.952192

Nihon Yakurigaku Zasshi. 2022;157(5):286-292. doi: 10.1254/fpj.22021.

ABSTRACT

Recent advance of medications and devices brings more effective treatment intervention to the patients with asthma. As far as obeying guidelines, approximately 90% of patients with asthma acquire good control. However, there are still small number of patients with asthma who resist conventional treatment. Most of them are corticosteroid-insensitive. It would be thought that there are two ways to deal with this problem. The first one is biologics. However, these are very expensive. The second way is a treatment intervention focusing on cancellation of corticosteroid-resistance. In early 2010s, a new-intracellular signaling pathway (phosphatydilinositol-3-kinese: PI3K pathway) is proven to be closely associated with corticosteroid-resistance. PI3K-inhibitor should be one of the promising candidates to attenuate corticosteroid-resistance. But PI3K-inhibitor also has a toxicity when given systemically. Drug-repositioning (DR) is a good option to deal with it. To find out PI3K-inhibitor from numerous medicines gives an answer how to inhibit PI3K pathway. The presenter has found both low-dose theophylline and long-acting beta-2 agonist have a potential to antagonize PI3K. These medicines have been prescribed for decades and their safety has already been proved. It is possible for clinicians to inhibit PI3K activation in patients with asthma associated with corticosteroid-resistance using these medicines without waiting for development of bran-new PI3K inhibitors. DR revealed that nortriptyline acts as a steroid-enhancer via its anti-PI3K activity. Calcium-channel blocker saves lung function in patients with asthma in long-term observation. DR promises us to find cheap and safe options to treat difficult asthma by inhibiting specific intracellular signaling pathways.

PMID:36047137 | DOI:10.1254/fpj.22021