Epilepsy Behav. 2024 Oct 27;161:110109. doi: 10.1016/j.yebeh.2024.110109. Online ahead of print.

ABSTRACT

The treatment of status epilepticus (SE) has changed little in the last 20 years, largely because of the high risks and costs of new drug development for SE. Moreover, SE poses specific challenges to drug development, such as patient diversity, logistical hurdles, and the need for acute treatment strategies that differ from chronic seizure prevention. This has reduced the appetite of industry to develop new drugs in this area. Drug repurposing is an attractive approach to address this unmet need. It offers significant advantages, including reduced development time, lower costs, and higher success rates, compared to novel drug development. Here I demonstrate how novel methods integrating biological knowledge and computational methods can be applied to drug repurposing in status epilepticus. Biological approaches focus on addressing mechanisms underlying drug resistance in SE (using for example ketamine, tacrolimus and safinamide) and longer-term consequences (using for example omaveloxolone, celecoxib and losartan). Additionally, artificial intelligence platforms, such as ChatGPT, can rapidly generate promising drug lists, while in silico methods can analyze gene expression changes to predict molecular targets. Combining AI and in silico approaches has identified several candidate drugs, including metformin, sirolimus and riluzole, for SE treatment. Despite the promise of repurposing, challenges remain, such as intellectual property issues and regulatory barriers. Nonetheless, drug repurposing presents a viable solution to the high costs and slow progress of traditional drug development for SE. This paper is based on a presentation made at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, in April 2024.

PMID:39467455 | DOI:10.1016/j.yebeh.2024.110109

Microbiol Immunol. 2024 Oct 28. doi: 10.1111/1348-0421.13178. Online ahead of print.

ABSTRACT

Bovine papillomavirus type 1 (BPV1) is an oncogenic virus that causes lesions and cancer in infected cattle. Despite being one of the most studied genotypes in the family and occurring in herds worldwide, there are currently no vaccines or drugs for its control. The viral E6 oncoprotein plays a crucial role in infection by this virus, making it a promising target for the development of new therapies. In this regard, we integrated structure-based virtual screening approaches, drug repositioning, and molecular dynamics to identify approved drugs with the potential to inhibit BPV1 E6. Our results reveal that Lumacaftor and MK-3207 are promising candidates for controlling BPV1 infection. The findings of this study may contribute to the development of E6 oncoprotein blockers in an accelerated and cost-effective manner.

PMID:39467039 | DOI:10.1111/1348-0421.13178

IEEE J Biomed Health Inform. 2024 Oct 28;PP. doi: 10.1109/JBHI.2024.3486730. Online ahead of print.

ABSTRACT

Computational drug repositioning which accelerates the process of drug development is able to reduce the cost in terms of time and money dramatically which brings promising and broad perspectives for the treatment of complex diseases. Heterogeneous networks fusion has been proposed to improve the performance of drug repositioning. Due to the difference and the specificity including the network structure and the biological function among different biological networks, it poses serious challenge on how to represent drug features and construct drug-disease associations in drug repositioning. Therefore, we proposed a novel drug repositioning method (ATDR) that employed attention transfer across different networks constructed by the deeply represented features integrated from biological networks to implement the disease-drug association prediction. Specifically, we first implemented the drug feature characterization with the graph representation of random surfing for different biological networks, respectively. Then, the drug network of deep feature representation was constructed with the aggregated drug informative features acquired by the multi-modal deep autoencoder on heterogeneous networks. Subsequently, we accomplished the drug-disease association prediction by transferring attention from the drug network to the drug-disease interaction network. We performed comprehensive experiments on different datasets and the results illustrated the outperformance of ATDR compared with other baseline methods and the predicted potential drug-disease interactions could aid in the drug development for disease treatments.

PMID:39466876 | DOI:10.1109/JBHI.2024.3486730

PLoS Genet. 2024 Oct 28;20(10):e1011458. doi: 10.1371/journal.pgen.1011458. Online ahead of print.

ABSTRACT

DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.

PMID:39466823 | DOI:10.1371/journal.pgen.1011458

AIDS Rev. 2024;26(3):93-101. doi: 10.24875/AIDSRev.24000010.

ABSTRACT

HIV epidemics still exist as a major global public health burden, especially in middle- and low-income countries. Given the lack of approved vaccines, antiretroviral therapy (ART) remains the primary approach to reduce the mortality and morbidity linked to this disease. Effective treatment for HIV-1 requires the simultaneous administration of multiple drugs. However, the virus can show resistance to antiretroviral drugs, resulting in treatment failure. Therefore, this study focused on assessing the prevalence of mutations within the Indian HIV-positive population. After assessing the data, we intended to identify the most effective highly active ART (HAART) regimens for individuals with drug-resistant variants. Furthermore, our analysis revealed a spectrum of HIV mutations, with varying effects on protein stability. The significance of this analysis lies in its potential to optimize HAART selection for HIV-positive individuals by accounting for both prevalence and stability-altering mutations. By considering mutation effects on protein stability, we can modify treatment regimens, increasing the likelihood of therapy success and diminishing the risk of resistance. Moreover, this study contributes to the broader field of drug repurposing, offering insights into the rational design of antiretroviral therapies.

PMID:39466703 | DOI:10.24875/AIDSRev.24000010

Infect Drug Resist. 2024 Oct 21;17:4539-4556. doi: 10.2147/IDR.S490998. eCollection 2024.

ABSTRACT

The development of antibiotic resistance complicates the treatment of infectious diseases and is a global public health threat. However, drug repurposing can address this resistance issue and reduce research and development costs. Niclosamide is a salicylanilide compound approved by the Food and Drug Administration (FDA), and it has been used clinically for treating parasitic infections for many years. Recent studies have shown that niclosamide can inhibit bacterial and fungus activity by affecting the quorum sensing system, biofilm formation, cell membrane potential, and other mechanisms. Here, we discuss recent advances in the antimicrobial applications of niclosamide and its derivatives to provide new perspectives in treating infectious diseases.

PMID:39464831 | PMC:PMC11505561 | DOI:10.2147/IDR.S490998

Drug Discov Ther. 2024 Oct 27. doi: 10.5582/ddt.2024.01063. Online ahead of print.

ABSTRACT

A pandemic known as anti-microbial resistance (AMR) poses a challenge to contemporary medicine. To stop AMR's rise and quick worldwide spread, urgent multisectoral intervention is needed. This review will provide insight on new and developing treatment approaches for AMR. Future therapy options may be made possible by the development of novel drugs that make use of developments in "omics" technology, artificial intelligence, and machine learning. Vaccines, immunoconjugates, antimicrobial peptides, monoclonal antibodies, and nanoparticles may also be intriguing options for treating AMR in the future. Combination therapy may potentially prove to be a successful strategy for combating AMR. To lessen the impact of AMR, ideas like drug repurposing, antibiotic stewardship, and the one health approach may be helpful.

PMID:39462601 | DOI:10.5582/ddt.2024.01063

BMJ Open. 2024 Oct 26;14(10):e082142. doi: 10.1136/bmjopen-2023-082142.

ABSTRACT

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients.

METHODS AND ANALYSIS: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research.

ETHICS AND DISSEMINATION: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences.

TRIAL REGISTRATION NUMBER: jRCT2051220002; Pre-results, NCT04744532; Pre-results.

PMID:39461864 | DOI:10.1136/bmjopen-2023-082142

Comput Biol Chem. 2024 Oct 24;113:108255. doi: 10.1016/j.compbiolchem.2024.108255. Online ahead of print.

ABSTRACT

Breast cancer has been one of the supreme causes of cancer-related deaths among women worldwide. To make the case even more compounded, due to innate or acquired causes, cancer cells often develop resistance against the available chemotherapy or monotargeted treatments. This resistance is concomitant with increased activation of the MAPK (mitogen-activated protein kinase) signaling pathway. This study simultaneously targets three imperative intermediates in this pathway using molecular docking and real-time simulation. Docking was performed via the integrated AutoDock Vina 1.1.2 & 1.2.5 of the PyRx software, while the Discovery Studio (BIOVIA) v24.1.0.23298 was utilized to conduct the simulation. The aim is to investigate the therapeutic prospects of known potential inhibitors of the targeted intermediates and repurposable drugs to comprehend the effectiveness of targeting these trinodes simultaneously. The target points were deemed to be PDPK1 (3-phosphoinositide-dependent protein kinase 1), ERK1/2 (extracellular signal-related protein kinases 1/2), and mTOR (mammalian target of Rapamycin). Our study reveals that out of the candidate inhibitors chosen for each node, MP7 exhibited the most superior binding affinities for all three: -10.918 kcal/mol for PDPK1, -10.224 kcal/mol for ERK1, -10.134 kcal/mol for ERK2, and -9.2 kcal/mol for mTOR (via AutoDock Vina 1, .2.5). Some scores with MP7 were often higher than the available single-targeted drugs for different nodes in the MAPK pathway. Additionally, a total of 1867 repurposed analgesic, antibiotic, and antiparasitic drugs, including Zavegepant (-13.399 kcal/mol for PDPK1), Adozelesin (-11.74 kcal/mol for mTOR) and Modoflaner (-11.29 kcal/mol for PDPK1), showed promising binding energetics while targeting our triad points than other compounds used. This approach prompts for mitigating not only breast cancer but other elusive diseases as well, with state-of-the-art multitargeted therapies coupled with bioinformatic strategies.

PMID:39461163 | DOI:10.1016/j.compbiolchem.2024.108255

Curr Microbiol. 2024 Oct 26;81(12):427. doi: 10.1007/s00284-024-03948-7.

ABSTRACT

Drug repurposing, also known as drug repositioning, is a currently tested approach by which new uses are being assigned for already tested drugs. In this case there are antibiotics that are used to combat bacterial infections. However, antibiotics are among the drugs that have been studied for possible antiviral activities. Therefore, the aim of this work is to carry out a review of the studies of antibiotics that could be repositioned for the treatment of viral infections. Among the main antibiotics that have demonstrated antiviral activity are macrolides and glycopeptides. In addition, several antibiotics from the group of tetracyclines, fluoroquinolones, cephalosporins and aminoglycosides have also been studied for their antiviral activity. These antibiotics have demonstrated antiviral activity against both RNA and DNA viruses, including the recent pandemic virus SARS-CoV-2. Some of these antibiotics were selected in addition to its antiviral activity for their immunomodulatory and anti-inflammatory properties. Of the antibiotics that present antiviral activity, in many cases the mechanisms of action are not exactly known. The use of these antibiotics to combat viral infections remains controversial and is not generally accepted, since clinical trials are required to prove its effectiveness. Therefore, there is currently no antibiotic approved as antiviral therapy. Hence is necessary to present the studies carried out on antibiotics that can be repositioned in the future as antiviral drugs.

PMID:39460768 | DOI:10.1007/s00284-024-03948-7

Pharmaceuticals (Basel). 2024 Oct 18;17(10):1394. doi: 10.3390/ph17101394.

ABSTRACT

Background/Objectives: Anaplastic thyroid cancer (ATC) is an aggressive and rare cancer with a poor prognosis, and traditional therapies have limited efficacy. This study investigates drug repositioning, focusing on auranofin, a gold-based drug originally used for rheumatoid arthritis, as a potential treatment for ATC. Methods: Auranofin was identified from an FDA-approved drug library and tested on two thyroid cancer cell lines, 8505C and FRO. Antitumor efficacy was evaluated through gene and protein expression analysis using Western blot, FACS, and mRNA sequencing. In vivo experiments were conducted using subcutaneous injections in nude mice to confirm the anticancer effects of auranofin. Results: Auranofin induced reactive oxygen species (ROS) production and apoptosis, leading to a dose-dependent reduction in cell viability, G1/S phase cell cycle arrest, and altered expression of regulatory proteins. It also inhibited cancer stem cell activity and suppressed epithelial-mesenchymal transition. mRNA sequencing revealed significant changes in the extracellular matrix-receptor interaction pathway, supported by Western blot results. In vivo xenograft models demonstrated strong antitumor activity. Conclusions: Auranofin shows promise as a repurposed therapeutic agent for ATC, effectively inhibiting cell proliferation, reducing metastasis, and promoting apoptosis. These findings suggest that auranofin could play a key role in future ATC treatment strategies.

PMID:39459033 | DOI:10.3390/ph17101394

Pharmaceuticals (Basel). 2024 Oct 9;17(10):1350. doi: 10.3390/ph17101350.

ABSTRACT

Background: Dysregulation of receptor tyrosine kinase c-MET is known to promote tumor development by stimulating oncogenic signaling pathways in different cancers, including pediatric neuroblastoma (NB). NB is an extracranial solid pediatric cancer that accounts for almost 15% of all pediatric cancer-related deaths, with less than a 50% long-term survival rate. Results: In this study, we analyzed a large cohort of primary NB patient data and revealed that high MET expression strongly correlates with poor overall survival, disease progression, relapse, and high MYCN levels in NB patients. To determine the effects of c-MET in NB, we repurposed a small molecule inhibitor, tivantinib, and found that c-MET inhibition significantly inhibits NB cellular growth. Tivantinib significantly blocks NB cell proliferation and 3D spheroid tumor formation and growth in different MYCN-amplified and MYCN-non-amplified NB cell lines. Furthermore, tivantinib blocks the cell cycle at the G2/M phase transition and induces apoptosis in different NB cell lines. As expected, c-MET inhibition by tivantinib inhibits the expression of multiple genes in PI3K, STAT, and Ras cell signaling pathways. Conclusions: Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers.

PMID:39458991 | DOI:10.3390/ph17101350

Pharmaceuticals (Basel). 2024 Sep 27;17(10):1286. doi: 10.3390/ph17101286.

ABSTRACT

BACKGROUND: Cu/Zn Superoxide Dismutase 1 (SOD1) is a 32 kDa cytosolic dimeric metalloenzyme that neutralizes superoxide anions into oxygen and hydrogen peroxide. Mutations in SOD1 are associated with ALS, a disease causing motor neuron atrophy and subsequent mortality. These mutations exert their harmful effects through a gain of function mechanism, rather than a loss of function. Despite extensive research, the mechanism causing selective motor neuron death still remains unclear. A defining feature of ALS pathogenesis is protein misfolding and aggregation, evidenced by ubiquitinated protein inclusions containing SOD1 in affected motor neurons. This work aims to identify compounds countering SOD1(A4V) misfolding and aggregation, which could potentially aid in ALS treatment.

METHODS: The approach employed was in vitro screening of a library comprising 1280 pharmacologically active compounds (LOPAC®) in the context of drug repurposing. Using differential scanning fluorimetry (DSF), these compounds were tested for their impact on SOD1(A4V) thermal stability.

RESULTS AND CONCLUSIONS: Dimer stability was the parameter chosen as the criterion for screening, since the dissociation of the native SOD1 dimer is the step prior to its in vitro aggregation. The screening revealed one compound raising protein-ligand Tm by 6 °C, eleven inducing a higher second Tm, suggesting a stabilization effect, and fourteen reducing Tm from 10 up to 26 °C, suggesting possible interactions or non-specific binding.

PMID:39458929 | DOI:10.3390/ph17101286

Biomedicines. 2024 Oct 9;12(10):2290. doi: 10.3390/biomedicines12102290.

ABSTRACT

Drug repositioning is an efficient strategy to search for new treatment alternatives that is especially valuable for neglected parasitic diseases such as leishmaniasis. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs) that have shown antileishmanial activity. Clomiphene is a SERM structurally similar to tamoxifen, whose antileishmanial potential is unknown. That is why the objective of the present work was to evaluate its antileishmanial activity in vitro and in vivo in comparison with tamoxifen. The inhibitory effect against promastigotes of L. amazonensis, L. major, and L. mexicana was evaluated for both compounds, as well as the cytotoxicity against mouse peritoneal macrophages, the growth inhibitory activity in intracellular amastigotes of L. mexicana, and the in vivo activity in mice experimentally infected with L. mexicana. Clomiphene was about twice as active as tamoxifen against both promastigotes and intracellular amastigotes, with IC50 values of 1.7-3.3 µM for clomiphene and 2.9-6.4 µM for tamoxifen against all three species of promastigotes and 2.8 ± 0.2 µM and 3.7 ± 0.3 µM, respectively, against L. mexicana amastigotes. Clomiphene structurally affected several parasite organelles in a concentration-dependent fashion, leading to the death of both promastigotes and intracellular amastigotes. Interestingly, the macrophage host cell did not appear damaged by any of the clomiphene concentrations tested. With oral administration at 20 mg/kg for 14 days, both compounds showed similar effects in terms of reducing the growth of the lesions, as well as the weight of the lesions and the parasite load at the end of the follow-up period. The results showed the potential of SERMs as antileishmanial drugs and support further testing of clomiphene and other compounds of this pharmacological group.

PMID:39457604 | DOI:10.3390/biomedicines12102290

Genes (Basel). 2024 Sep 25;15(10):1248. doi: 10.3390/genes15101248.

ABSTRACT

Non-small cell lung cancer (NSCLC), representing 85% of lung cancer cases, is characterized by its heterogeneity and progression through distinct stages. This study applied Weighted Gene Co-expression Network Analysis (WGCNA) to explore the molecular mechanisms of NSCLC and identify potential therapeutic targets. Gene expression data from the GEO database were analyzed across four NSCLC stages (NSCLC1, NSCLC2, NSCLC3, and NSCLC4), with the NSCLC2 dataset selected as the reference for module preservation analysis. WGCNA identified eight highly preserved modules-Cyan, Yellow, Red, Dark Turquoise, Turquoise, White, Purple, and Royal Blue-across datasets, which were enriched in key pathways such as "Cell cycle" and "Pathways in cancer", involving processes like cell division and inflammatory responses. Hub genes, including PLK1, CDK1, and EGFR, emerged as critical regulators of tumor proliferation and immune responses. Estrogen receptor ESR1 was also highlighted, correlating with improved survival outcomes, suggesting its potential as a prognostic marker. Signature-based drug repurposing analysis identified promising therapeutic candidates, including GW-5074, which inhibits RAF and disrupts the EGFR-RAS-RAF-MEK-ERK signaling cascade, and olomoucine, a CDK1 inhibitor. Additional candidates like pinocembrin, which reduces NSCLC cell invasion by modulating epithelial-mesenchymal transition, and citalopram, an SSRI with anti-carcinogenic properties, were also identified. These findings provide valuable insights into the molecular underpinnings of NSCLC and suggest new directions for therapeutic strategies through drug repurposing.

PMID:39457373 | DOI:10.3390/genes15101248

Int J Mol Sci. 2024 Oct 16;25(20):11106. doi: 10.3390/ijms252011106.

ABSTRACT

Despite recent advances in chronic obstructive pulmonary disease (COPD) research, few studies have identified the potential therapeutic targets systematically by integrating multiple-omics datasets. This project aimed to develop a systems biology pipeline to identify biologically relevant genes and potential therapeutic targets that could be exploited to discover novel COPD treatments via drug repurposing or de novo drug discovery. A computational method was implemented by integrating multi-omics COPD data from unpaired human samples of more than half a million subjects. The outcomes from genome, transcriptome, proteome, and metabolome COPD studies were included, followed by an in silico interactome and drug-target information analysis. The potential candidate genes were ranked by a distance-based network computational model. Ninety-two genes were identified as COPD signature genes based on their overall proximity to signature genes on all omics levels. They are genes encoding proteins involved in extracellular matrix structural constituent, collagen binding, protease binding, actin-binding proteins, and other functions. Among them, 70 signature genes were determined to be druggable targets. The in silico validation identified that the knockout or over-expression of SPP1, APOA1, CTSD, TIMP1, RXFP1, and SMAD3 genes may drive the cell transcriptomics to a status similar to or contrasting with COPD. While some genes identified in our pipeline have been previously associated with COPD pathology, others represent possible new targets for COPD therapy development. In conclusion, we have identified promising therapeutic targets for COPD. This hypothesis-generating pipeline was supported by unbiased information from available omics datasets and took into consideration disease relevance and development feasibility.

PMID:39456887 | DOI:10.3390/ijms252011106

Cancers (Basel). 2024 Oct 12;16(20):3454. doi: 10.3390/cancers16203454.

ABSTRACT

Drug repurposing is a strategy to discover new therapeutic uses for existing drugs, which have well-established toxicity profiles and are often more affordable. This approach has gained significant attention in recent years due to the high costs and low success rates associated with traditional drug development. Drug repositioning offers a more time- and cost-effective path for identifying new treatments. Several FDA-approved non-chemotherapy drugs have been investigated for their anticancer potential. Among these, anthelmintic benzimidazoles (such as albendazole, mebendazole, and flubendazole) have garnered interest due to their effects on microtubules and oncogenic signaling pathways. Blood cancers, which frequently develop resistance and have high mortality rates, present a critical need for effective therapies. This review highlights the recent advances in repurposing benzimidazoles for blood malignancies. These compounds induce cell cycle arrest, differentiation, tubulin depolymerization, loss of heterozygosity, proteasomal degradation, and inhibit oncogenic signaling to exert their anticancer effects. We also discuss current limitations and strategies to overcome them, emphasizing the potential of combining benzimidazoles with standard therapies for improved treatment of hematological cancers.

PMID:39456548 | DOI:10.3390/cancers16203454

Antioxidants (Basel). 2024 Oct 3;13(10):1201. doi: 10.3390/antiox13101201.

ABSTRACT

Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene TP53, wild-type (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with a known TP53 status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT (Ser-473) phosphorylation, and increased p53, p21, and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. Additionally, p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to Auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to Auranofin in GSCs. The combination of Auranofin and L-BSO synergistically increased ROS, decreased IC50s, and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased the expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combining Auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose Auranofin and PPL in GBM.

PMID:39456455 | DOI:10.3390/antiox13101201

Biomolecules. 2024 Sep 30;14(10):1236. doi: 10.3390/biom14101236.

ABSTRACT

Lymphangioleiomyomatosis (LAM) is a rare genetic lung disease. Unfortunately, treatment with the mTORC1 inhibitor Rapamycin only slows disease progression, and incomplete responses are common. Thus, there remains an urgent need to identify new targets for the development of curative LAM treatments. Nitazoxanide (NTZ) is an orally bioavailable antiprotozoal small molecule drug approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in children and adults, with a demonstrated mTORC1 inhibitory effect in several human cell lines. NTZ's excellent safety profile characterized by its more than 20 years of clinical use makes it a promising candidate for repurposing. Our rationale for this study was to further investigate NTZ's effect using in vitro and in vivo LAM models and to elucidate the underlying molecular mechanism beyond mTORC1 inhibition. For this purpose, we investigated cell proliferation, cell viability, and changes in protein phosphorylation and expression in primary human cell cultures derived from LAM lung samples before translating our results into a syngeneic mouse model utilizing Tsc2-null cells. NTZ reduced cell growth for all tested cell lines at a dose of about 30 µM. Lower doses than that had no effect on cell viability, but doses above 45 µM lowered the viability by about 10 to 15% compared to control. Interestingly, our western blot revealed no inhibition of mTORC1 and only a mild effect on active ß-Catenin. Instead, NTZ had a pronounced effect on reducing pAkt. In the mouse model, prophylactic NTZ treatment via the intraperitoneal and oral routes had some effects on reducing lung lesions and improving body weight retention, but the results remain inconclusive.

PMID:39456169 | DOI:10.3390/biom14101236

Curr Oncol. 2024 Oct 8;31(10):6032-6049. doi: 10.3390/curroncol31100450.

ABSTRACT

Ritonavir is a protease inhibitor initially developed for HIV treatment that is now used as a pharmacokinetic booster for other antiretrovirals due to it being a cytochrome P450 3A4 enzyme and P-glycoprotein inhibitor. Consequently, ritonavir is of special interest for repurposing in other diseases. It had an important role in battling the COVID-19 pandemic as a part of the developed drug Paxlovid® in association with nirmatrelvir and has shown effects in hepatitis and other pathogenic diseases. Ritonavir has also shown promising results in overcoming drug resistance and enhancing the efficacy of existing chemotherapeutic agents in oncology. Evidence of cancer repurposing potential was demonstrated in cancers such as ovarian, prostate, lung, myeloma, breast, and bladder cancer, with several mechanisms of action presented. In vitro studies indicate that ritonavir alone can inhibit key pathways involved in cancer cell survival and proliferation, causing apoptosis, cell cycle arrest, endoplasmic reticulum stress, and metabolic stress due to the inhibition of molecules like heat shock protein 90 and cyclin-dependent kinases. Ritonavir also causes resistant cells to become sensitized to anticancer drugs like gemcitabine or docetaxel. These findings indicate that repurposing ritonavir, either on its own or in combination with other medications, could be a promising approach for treating various diseases. This is particularly relevant in cancer therapy, where ritonavir repurposing is the central focus of this review.

PMID:39451754 | DOI:10.3390/curroncol31100450