Eur J Pharmacol. 2022 May 14:175031. doi: 10.1016/j.ejphar.2022.175031. Online ahead of print.

ABSTRACT

Skin cancer is one of the most common forms of cancer. Several million people are estimated to have affected with this condition worldwide. Skin cancer generally includes melanoma and non-melanoma with the former being the most dangerous. Chemotherapy has been one of the key therapeutic strategies employed in the treatment of skin cancer, especially in advanced stages of the disease. It could be also used as an adjuvant with other treatment modalities depending on the type of skin cancer. However, there are several shortfalls associated with the use of chemotherapy such as non-selectivity, tumour resistance, life-threatening toxicities, and the exorbitant cost of medicines. Furthermore, new drug discovery is a lengthy and costly process with minimal likelihood of success. Thus, drug repurposing (DR) has emerged as a new avenue where the drug approved formerly for the treatment of one disease can be used for the treatment of another disease like cancer. This approach is greatly beneficial over the de novo approach in terms of time and cost. Moreover, there is minimal risk of failure of repurposed therapeutics in clinical trials. There are a considerable number of studies that have reported on drugs repurposed for the treatment of skin cancer. Thus, the present manuscript offers a comprehensive overview of drugs that have been investigated as repurposing candidates for the efficient treatment of skin cancers mainly melanoma and its oncogenic subtypes, and non-melanoma. The prospects of repurposing phytochemicals against skin cancer are also discussed. Furthermore, repurposed drug delivery via topical route and repurposed drugs in clinical trials are briefed. Based on the findings from the reported studies discussed in this manuscript, drug repurposing emerges to be a promising approach and thus is expected to offer efficient treatment at a reasonable cost in devitalizing skin cancer.

PMID:35580707 | DOI:10.1016/j.ejphar.2022.175031

Nucleic Acids Res. 2022 May 17:gkac384. doi: 10.1093/nar/gkac384. Online ahead of print.

ABSTRACT

Cancer is a heterogeneous disease characterized by unregulated cell growth and promoted by mutations in cancer driver genes some of which encode suitable drug targets. Since the distinct set of cancer driver genes can vary between and within cancer types, evidence-based selection of drugs is crucial for targeted therapy following the precision medicine paradigm. However, many putative cancer driver genes can not be targeted directly, suggesting an indirect approach that considers alternative functionally related targets in the gene interaction network. Once potential drug targets have been identified, it is essential to consider all available drugs. Since tools that offer support for systematic discovery of drug repurposing candidates in oncology are lacking, we developed CADDIE, a web application integrating six human gene-gene and four drug-gene interaction databases, information regarding cancer driver genes, cancer-type specific mutation frequencies, gene expression information, genetically related diseases, and anticancer drugs. CADDIE offers access to various network algorithms for identifying drug targets and drug repurposing candidates. It guides users from the selection of seed genes to the identification of therapeutic targets or drug candidates, making network medicine algorithms accessible for clinical research. CADDIE is available at https://exbio.wzw.tum.de/caddie/ and programmatically via a python package at https://pypi.org/project/caddiepy/.

PMID:35580047 | DOI:10.1093/nar/gkac384

Invest Ophthalmol Vis Sci. 2022 May 2;63(5):17. doi: 10.1167/iovs.63.5.17.

ABSTRACT

PURPOSE: Proliferative vitreoretinopathy (PVR) remains an unresolved clinical challenge and can lead to frequent revision surgery and blindness vision loss. The aim of this study was to characterize the microenvironment of epiretinal PVR tissue, in order to shed more light on the complex pathophysiology and to unravel new treatment options.

METHODS: A total of 44 tissue samples were analyzed in this study, including 19 epiretinal PVRs, 13 epiretinal membranes (ERMs) from patients with macular pucker, as well as 12 internal limiting membranes (ILMs). The cellular and molecular microenvironment was assessed by cell type deconvolution analysis (xCell), RNA sequencing data and single-cell imaging mass cytometry. Candidate drugs for PVR treatment were identified in silico via a transcriptome-based drug-repurposing approach.

RESULTS: RNA sequencing of tissue samples demonstrated distinct transcriptional profiles of PVR, ERM, and ILM samples. Differential gene expression analysis revealed 3194 upregulated genes in PVR compared with ILM, including FN1 and SPARC, which contribute to biological processes, such as extracellular matrix (ECM) organization. The xCell and IMC analyses showed that PVR membranes were composed of macrophages, retinal pigment epithelium, and α-SMA-positive myofibroblasts, the latter predominantly characterized by the co-expression of immune cell signature markers. Finally, 13 drugs were identified as potential therapeutics for PVR, including aminocaproic acid and various topoisomerase-2A inhibitors.

CONCLUSIONS: Epiretinal PVR membranes exhibit a unique and complex transcriptional and cellular profile dominated by immune cells and myofibroblasts, as well as a variety of ECM components. Our findings provide new insights into the pathophysiology of PVR and suggest potential targeted therapeutic options.

PMID:35579905 | DOI:10.1167/iovs.63.5.17

Curr Drug Deliv. 2022 May 16. doi: 10.2174/1567201819666220516163242. Online ahead of print.

ABSTRACT

With the advent of ivermectin, tremendous improvement in public health has been observed, especially in the treatment of onchocerciasis and lymphatic filariasis that created chaos mostly in rural, sub-Saharan Africa and Latin American countries. The discovery of ivermectin became a boon to millions of people that had suffered in the pandemic and still hold its pharmacological potential against these. Ivermectin continued to surprise scientists because of its notable role in the treatment of various other tropical diseases (Chagas, leishmaniasis, worm infections, etc.) and is viewed as the safest drug with the least toxic effects. The current review highlights its role in unexplored avenues towards forging ahead of the repositioning of this multitargeted drug in cancer, viral (the evaluation of the efficacy of ivermectin against SARS-Cov-2 is under investigation) and bacterial infection and malaria. This article also provides a glimpse of regulatory considerations of drug repurposing and current formulation strategies. Due to its broad-spectrum activity, multitargeted nature and promising efforts are put towards the repurposing of this drug throughout the field of medicine. This single drug originated from a microbe, changed the face of global health by proving its unmatched success and progressive efforts continue in maintaining its bequestnin the management of global health by decreasing the burden of various diseases worldwide.

PMID:35578879 | DOI:10.2174/1567201819666220516163242

Med Chem Res. 2022 May 12:1-7. doi: 10.1007/s00044-022-02903-0. Online ahead of print.

ABSTRACT

The COVID-19 pandemic spurred a broad interest in antiviral drug discovery. The SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) are attractive antiviral drug targets given their vital roles in viral replication and modulation of host immune response. Structurally disparate compounds were reported as Mpro and PLpro inhibitors from either drug repurposing or rational design. Two polyphenols dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) were recently reported as SARS-CoV-2 Mpro inhibitors. With our continuous interest in studying the mechanism of inhibition and resistance of Mpro inhibitors, we report herein our independent validation/invalidation of these two natural products. Our FRET-based enzymatic assay showed that neither dieckol nor PGG inhibited SARS-CoV-2 Mpro (IC50 > 20 µM), which is in contrary to previous reports. Serendipitously, PGG was found to inhibit the SARS-CoV-2 PLpro with an IC50 of 3.90 µM. The binding of PGG to PLpro was further confirmed in the thermal shift assay. However, PGG was cytotoxic in 293T-ACE2 cells (CC50 = 7.7 µM), so its intracellular PLpro inhibitory activity could not be quantified by the cell-based Flip-GFP PLpro assay. In addition, we also invalidated ebselen, disulfiram, carmofur, PX12, and tideglusib as SARS-CoV-2 PLpro inhibitors using the Flip-GFP assay. Overall, our results call for stringent hit validation, and the serendipitous discovery of PGG as a putative PLpro inhibitor might worth further pursuing. Graphical abstract.

PMID:35578732 | PMC:PMC9095416 | DOI:10.1007/s00044-022-02903-0

Heliyon. 2022 May 11:e09387. doi: 10.1016/j.heliyon.2022.e09387. Online ahead of print.

ABSTRACT

The alarming pandemic situation of novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection, high drug development cost and slow process of drug discovery have made repositioning of existing drugs for therapeutics a popular alternative. It involves the repurposing of existing safe compounds which results in low overall development costs and shorter development timeline. In the present study, a computational network-biology approach has been used for comparing three candidate drugs i.e. quercetin, N-acetyl cysteine (NAC), and 2-deoxy-glucose (2-DG) to be effectively repurposed against COVID-19. For this, the associations between these drugs and genes of Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) diseases were retrieved and a directed drug-gene-gene-disease interaction network was constructed. Further, to quantify the associations between a target gene and a disease gene, the shortest paths from the target gene to the disease genes were identified. A vector DV was calculated to represent the extent to which a disease gene was influenced by these drugs. Quercetin was quantified as the best among the three drugs, suited for repurposing with DV of -70.19, followed by NAC with DV of -39.99 and 2-DG with DV of -13.71. The drugs were also assessed for their safety and efficacy balance (in terms of therapeutic index) using network properties. It was found that quercetin was a forerunner than other two drugs.

PMID:35578630 | PMC:PMC9093055 | DOI:10.1016/j.heliyon.2022.e09387

J Mol Model. 2022 May 16;28(6):153. doi: 10.1007/s00894-022-05138-3.

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) enters the cell by interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of spike (S) protein. In the cell, the viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme is essential for its life cycle and controls coronavirus replication. Therefore, the S-RBD and 3CLpro are hot targets for drug discovery against SARS-CoV-2. This study was to identify repurposing drugs using in silico screening, docking, and molecular dynamics simulation. The study identified bentiamine, folic acid, benfotiamine, and vitamin B12 against the RBD of S protein and bentiamine, folic acid, fursultiamine, and riboflavin to 3CLpro. The strong and stable binding of these safe and cheap vitamins at the important residues (R403, K417, Y449, Y453, N501, and Y505) in the S-protein-ACE2 interface and 3CLpro binding site residues especially active site residues (His 41 and Cys 145), indicating that they could be valuable repurpose drugs for inhibiting SARS-CoV-2 entry into the host and replication.

PMID:35578055 | PMC:PMC9110024 | DOI:10.1007/s00894-022-05138-3

Commun Biol. 2022 May 16;5(1):462. doi: 10.1038/s42003-022-03424-7.

ABSTRACT

Fractures and related complications are a common challenge in the field of skeletal tissue engineering. Vitamin D and calcium are the only broadly available medications for fracture healing, while zinc has been recognized as a nutritional supplement for healthy bones. Here, we aimed to use polaprezinc, an anti-ulcer drug and a chelate form of zinc and L-carnosine, as a supplement for fracture healing. Polaprezinc induced upregulation of osteogenesis-related genes and enhanced the osteogenic potential of human bone marrow-derived mesenchymal stem cells and osteoclast differentiation potential of mouse bone marrow-derived monocytes. In mouse experimental models with bone fractures, oral administration of polaprezinc accelerated fracture healing and maintained a high number of both osteoblasts and osteoclasts in the fracture areas. Collectively, polaprezinc promotes the fracture healing process efficiently by enhancing the activity of both osteoblasts and osteoclasts. Therefore, we suggest that drug repositioning of polaprezinc would be helpful for patients with fractures.

PMID:35577977 | DOI:10.1038/s42003-022-03424-7

Expert Rev Anti Infect Ther. 2022 May 16. doi: 10.1080/14787210.2022.2078308. Online ahead of print.

ABSTRACT

INTRODUCTION: Antibiotic resistance is one of the biggest public health threats worldwide. Currently, antibiotic-resistant bacteria kill 700,000 people every year. These data represent the near future in which we find ourselves, a "post-antibiotic era" where the identification and development of new treatments are key. This review is focused on the current and emerging antimicrobial therapies which can solve this global threat.

AREAS COVERED: Through a literature search using databases such as Medline and Web of Science, and search engines such as Google Scholar, different antimicrobial therapies were analyzed, including pathogen-oriented therapy, phagotherapy, microbiota and antivirulent therapy. Additionally, the development pathways of new antibiotics were described, emphasizing on the potential advantages that the combination of a drug repurposing strategy with the application of mathematical prediction models could bring to solve the problem of AMRs.

EXPERT OPINION: This review offers several starting points to solve a single problem: reducing the number of AMR. The data suggest that the strategies described could provide many benefits to improve antimicrobial treatments. However, the development of new antimicrobials remains necessary. Drug repurposing, with the application of mathematical prediction models, is considered to be of interest due to its rapid and effective potential to increase the current therapeutic arsenal.

PMID:35576494 | DOI:10.1080/14787210.2022.2078308

Front Surg. 2022 Apr 27;9:868187. doi: 10.3389/fsurg.2022.868187. eCollection 2022.

ABSTRACT

Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) - a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. In vitro studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by β-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without β-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.

PMID:35574555 | PMC:PMC9091963 | DOI:10.3389/fsurg.2022.868187

Pain Res Manag. 2022 May 5;2022:1466478. doi: 10.1155/2022/1466478. eCollection 2022.

ABSTRACT

INTRODUCTION: Osteoarthritis is a disease characterized by progressive wear and tear of the joint, with the knee being the most affected region. These patients have reduced mobility and mobility, among other symptoms. Thus, it is necessary to know the variables that influence the ability to walk.

OBJECTIVE: To analyze how much the gait capacity, in the performance of the six-minute walk test, can be influenced by the maximum isometric strength of the quadriceps or by kinesiophobia in women with knee osteoarthritis.

MATERIALS AND METHODS: This is a cross-sectional study with a sample of 49 women diagnosed with osteoarthritis. The evaluation was carried out in a single moment. Variables studied isometric quadriceps strength, level of fear of movement (kinesiophobia), and ability to walk. Simple linear regression analyzes were performed, with gait ability as the dependent variable and maximum isometric strength and kinesiophobia as independent. Data were presented with mean and standard deviation and were analyzed by the SPSS Statistic 22.0 software, considering p < 0.05 as significant.

RESULTS: The maximum isometric strength presents a significant difference, directly interfering with the gait ability; as kinesiophobia does not show a statistically significant difference, it does not directly interfere with the ability to walk.

CONCLUSION: Maximal quadriceps isometric strength directly interferes with gait ability in women with knee osteoarthritis, thus suggesting the inclusion of this strategy in treatment programs for this population.

PMID:35573645 | PMC:PMC9098341 | DOI:10.1155/2022/1466478

Nat Aging. 2021 Dec;1(12):1175-1188. doi: 10.1038/s43587-021-00138-z. Epub 2021 Dec 6.

ABSTRACT

We developed an endophenotype disease module-based methodology for Alzheimer's disease (AD) drug repurposing and identified sildenafil as a potential disease risk modifier. Based on retrospective case-control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25-0.39, P<1.0×10-8). Propensity score stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts we tested (diltiazem, glimepiride, losartan and metformin) after adjusting age, sex, race, and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho-tau expression in AD patient-induced pluripotent stem cells-derived neuron models, supporting mechanistically its potential beneficial effect in Alzheimer's disease. The association between sildenafil use and decreased incidence of AD does not establish causality or its direction, which requires a randomized clinical trial approach.

PMID:35572351 | PMC:PMC9097949 | DOI:10.1038/s43587-021-00138-z

Struct Chem. 2022 May 11:1-13. doi: 10.1007/s11224-022-01960-w. Online ahead of print.

ABSTRACT

The spread of coronavirus infectious disease (COVID-19) is associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has risked public health more than any other infectious disease. Researchers around the globe use multiple approaches to identify an effective approved drug (drug repurposing) that treats viral infections. Most of the drug repurposing approaches target spike protein or main protease. Here we use transmembrane serine protease 2 (TMPRSS2) as a target that can prevent the virus entry into the cell by interacting with the surface receptors. By hypothesizing that the TMPRSS2 binders may help prevent the virus entry into the cell, we performed a systematic drug screening over the current approved drug database. Furthermore, we screened the Enamine REAL fragments dataset against the TMPRSS2 and presented nine potential drug-like compounds that give us clues about which kinds of groups the pocket prefers to bind, aiding future structure-based drug design for COVID-19. Also, we employ molecular dynamics simulations, binding free energy calculations, and well-tempered metadynamics to validate the obtained candidate drug and fragment list. Our results suggested three potential FDA-approved drugs against human TMPRSS2 as a target. These findings may pave the way for more drugs to be exposed to TMPRSS2, and testing the efficacy of these drugs with biochemical experiments will help improve COVID-19 treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11224-022-01960-w.

PMID:35571866 | PMC:PMC9091140 | DOI:10.1007/s11224-022-01960-w

Front Pharmacol. 2022 Apr 27;13:856804. doi: 10.3389/fphar.2022.856804. eCollection 2022.

ABSTRACT

Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.

PMID:35571097 | PMC:PMC9093689 | DOI:10.3389/fphar.2022.856804

Eur J Heart Fail. 2022 May 15. doi: 10.1002/ejhf.2540. Online ahead of print.

ABSTRACT

AIMS: Chronic Heart Failure (CHF) is a systemic syndrome with a poor prognosis and a need for novel therapies. We investigated whether whole-blood transcriptomic profiling can provide new mechanistic insights into cardiovascular (CV) mortality in CHF.

METHODS AND RESULTS: Transcriptome profiles were generated at baseline from 944 CHF patients from the BIOSTAT-CHF Study - of whom 626 survived and 318 died from a CV cause during a follow-up of 21 months. Multivariable analysis, including adjustment for cell count, identified 1,153 genes (6.5%) that were differentially expressed between those that survived or died and strongly related to a validated clinical risk score for adverse prognosis. The differentially expressed genes mainly belonged to 5 non-redundant pathways: Adaptive immune response, proteasome-mediated ubiquitin-dependent protein catabolic process, T-cell co-stimulation, positive regulation of T-cell proliferation and erythrocyte development. These five pathways were selectively related (RV coefficients >0.20) with seven circulating protein biomarkers of CV mortality (FGF23, sST2, adrenomedullin, hepcidin, pentraxin-3, WFDC2 and IL-6) revealing an intricate relationship between immune and iron homeostasis. The pattern of survival-associated gene expression matched with 29 perturbagen-induced transcriptome signatures in the iLINCS drug-repurposing database, identifying drugs, approved for other clinical indications, that were able to reverse in vitro the molecular changes associated with adverse prognosis in CHF.

CONCLUSION: Systematic modeling of the whole blood protein-coding transcriptome defined molecular pathways that provide a link between clinical risk factors and adverse cardiovascular prognosis in CHF, identifying both established and new potential therapeutic targets.

PMID:35570197 | DOI:10.1002/ejhf.2540

Cancer Lett. 2022 May 11:215717. doi: 10.1016/j.canlet.2022.215717. Online ahead of print.

ABSTRACT

Aberrant activities of various cell cycle and DNA repair proteins promote cancer growth and progression and render them resistant to therapies. Here, we demonstrate that the anti-depressant imipramine blocks growth of triple-negative (TNBC) and estrogen receptor-positive (ER+) breast cancers by inducing cell cycle arrest and by blocking heightened homologous recombination (HR) and non-homologous end joining-mediated (NHEJ) DNA repair activities. Our results reveal that imipramine inhibits the expression of several cell cycle- and DNA repair-associated proteins including E2F1, CDK1, Cyclin D1, and RAD51. In addition, we show that imipramine inhibits the growth of ER + breast cancers by inhibiting the estrogen receptor- α (ER-α) signaling. Our studies in preclinical mouse models and ex vivo explants from breast cancer patients show that imipramine sensitizes TNBC to the PARP inhibitor olaparib and endocrine resistant ER + breast cancer to anti-estrogens. Our studies suggest that repurposing imipramine could enhance routine care for breast cancer patients. Based on these results, we designed an ongoing clinical trial, where we are testing the efficacy of imipramine for treating patients with triple-negative and estrogen receptor-positive breast cancer. Since aberrant DNA repair activity is used by many cancers to survive and become resistant to therapy, imipramine could be used alone and/or with currently used drugs for treating many aggressive cancers.

PMID:35568265 | DOI:10.1016/j.canlet.2022.215717

Molecules. 2022 Apr 24;27(9):2742. doi: 10.3390/molecules27092742.

ABSTRACT

Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.

PMID:35566091 | DOI:10.3390/molecules27092742

Molecules. 2022 Apr 23;27(9):2723. doi: 10.3390/molecules27092723.

ABSTRACT

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) was first identified in the province of Wuhan, China. Since then, there have been over 400 million confirmed cases and 5.8 million deaths by COVID-19 reported worldwide. The urgent need for therapies against SARS-CoV-2 led researchers to use drug repurposing approaches. This strategy allows the reduction in risks, time, and costs associated with drug development. In many cases, a repurposed drug can enter directly to preclinical testing and clinical trials, thus accelerating the whole drug discovery process. In this work, we will give a general overview of the main developments in COVID-19 treatment, focusing on the contribution of the drug repurposing paradigm to find effective drugs against this disease. Finally, we will present our findings using a new drug repurposing strategy that identified 11 compounds that may be potentially effective against COVID-19. To our knowledge, seven of these drugs have never been tested against SARS-CoV-2 and are potential candidates for in vitro and in vivo studies to evaluate their effectiveness in COVID-19 treatment.

PMID:35566073 | DOI:10.3390/molecules27092723

Cancers (Basel). 2022 Apr 30;14(9):2255. doi: 10.3390/cancers14092255.

ABSTRACT

Nowadays, the identification of new therapeutic targets that allow for the development of treatments, which as monotherapy, or in combination with other existing treatments can contribute to improve response rates, prognosis and survival of oncologic patients, is a priority to optimize healthcare within sustainable health systems. Recent studies have demonstrated the role of Substance P (SP) and its preferred receptor, Neurokinin 1 Receptor (NK-1R), in human cancer and the potential antitumor activity of NK-1R antagonists as an anticancer treatment. In this review, we outline the relevant studies published to date regarding the SP/NK-1R complex as a key player in human cancer and also evaluate if the repurposing of already marketed NK-1R antagonists may be useful in the development of new treatment strategies to overcome cancer resistance.

PMID:35565383 | DOI:10.3390/cancers14092255

Cancers (Basel). 2022 Apr 24;14(9):2126. doi: 10.3390/cancers14092126.

ABSTRACT

Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented.

PMID:35565259 | DOI:10.3390/cancers14092126