Pharmaceutics. 2023 Aug 21;15(8):2166. doi: 10.3390/pharmaceutics15082166.

ABSTRACT

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME.

PMID:37631380 | DOI:10.3390/pharmaceutics15082166

Pharmaceutics. 2023 Jul 28;15(8):2033. doi: 10.3390/pharmaceutics15082033.

ABSTRACT

This study aims at preparing propranolol-loaded trehalosomes (a trehalose-coated liposome) to be used as an antiproliferative agent for treating skin cancer. A factorial design was used to select the optimum formula, where trehalose, lecithin, and Tween 80 levels were studied. A total of 24 runs were prepared and characterized according to size, charge, entrapment efficiency, and release after 3 h to select the optimum formula. The optimized formula was investigated using TEM, DSC, and FTIR. Cell studies were carried out against the human melanoma cell line to measure cytotoxicity, apoptosis/necrosis, and cell cycle arrest. In silico studies were conducted to understand the interaction between propranolol and the influential receptors in melanoma. The results showed the selected formula consisted of trehalose (175 mg), lecithin (164 mg), and Tween 80 (200 mg) with a size of 245 nm, a charge of -9 mV, an EE% of 68%, and a Q3 of 62%. Moreover, the selected formula has good cytotoxicity compared to the free drug due to the synergistic effect of the drug and the designed carrier. IC50 of free propranolol and the encapsulation of propranolol were 17.48 μg/mL and 7.26 μg/mL, respectively. Also, propranolol and the encapsulation of propranolol were found to significantly increase early and late apoptosis, in addition to inducing G1 phase cell cycle arrest. An in silico virtual study demonstrated that the highest influential receptors in melanoma were the vitamin D receptor, CRH-R1, VEGFR 1, and c-Kit, which matches the results of experimental apoptotic and cell cycle analysis. In conclusion, the selected formula has good cytotoxicity compared to the free drug due to the synergistic effect of the drug and the designed carrier, which make it a good candidate as an antiproliferative agent for treating skin cancer.

PMID:37631247 | DOI:10.3390/pharmaceutics15082033

Pharmaceutics. 2023 Jul 26;15(8):2022. doi: 10.3390/pharmaceutics15082022.

ABSTRACT

Immunotherapy has changed the way many cancers are being treated. Researchers in the field of immunotherapy and tumor immunology are investigating similar questions: How can the positive benefits achieved with immunotherapies be enhanced? Can this be achieved through combinations with other agents and if so, which ones? In our view, there is an urgent need to improve immunotherapy to make further gains in the overall survival for those patients that should benefit from immunotherapy. While numerous different approaches are being considered, our team believes that drug delivery methods along with appropriately selected small-molecule drugs and drug candidates could help reach the goal of doubling the overall survival rate that is seen in some patients that are given immunotherapeutics. This review article is prepared to address how immunotherapies should be combined with a second treatment using an approach that could realize therapeutic gains 10 years from now. For context, an overview of immunotherapy and cancer angiogenesis is provided. The major targets in angiogenesis that have modulatory effects on the tumor microenvironment and immune cells are highlighted. A combination approach that, for us, has the greatest potential for success involves treatments that will normalize the tumor's blood vessel structure and alter the immune microenvironment to support the action of immunotherapeutics. So, this is reviewed as well. Our focus is to provide an insight into some strategies that will engender vascular normalization that may be better than previously described approaches. The potential for drug delivery systems to promote tumor blood vessel normalization is considered.

PMID:37631236 | DOI:10.3390/pharmaceutics15082022

Int J Mol Sci. 2023 Aug 20;24(16):12997. doi: 10.3390/ijms241612997.

ABSTRACT

Drug repositioning (DR) is the process of identifying novel therapeutic potentials for already-approved drugs and discovering new therapies for untreated diseases. DR can play an important role in optimizing the pre-clinical process of developing novel drugs by saving time and cost compared with the process of de novo drug discovery. Although the number of publications related to DR has rapidly increased, most therapeutic approaches were reported for malignant tumors. Surgical resection represents the definitive treatment for benign tumors of the central nervous system (BTCNS). However, treatment options remain limited for surgery-, chemotherapy- and radiation-refractory BTCNS, as well as malignant tumors. Meningioma, pituitary neuroendocrine tumor (PitNET), and schwannoma are the most common BTCNS. The treatment strategy using DR may be applied for refractory BTCNS, such as Grade 2 meningiomas, neurofibromatosis type 2-related schwannomatosis, and PitNETs with cavernous sinus invasion. In the setting of BTCNS, stable disease can provide significant benefit to the patient. DR may provide a longer duration of survival without disease progression for patients with refractory BTCNS. This article reviews the utility of DR for refractory BTCNS.

PMID:37629179 | DOI:10.3390/ijms241612997

Int J Mol Sci. 2023 Aug 9;24(16):12619. doi: 10.3390/ijms241612619.

ABSTRACT

Human carbonic anhydrases (hCAs) have enzymatic activities for reversible hydration of CO2 and are acknowledged as promising targets for the treatment of various diseases. Using molecular docking and molecular dynamics simulation approaches, we hit three compounds of methyl 4-chloranyl-2-(phenylsulfonyl)-5-sulfamoyl-benzoate (84Z for short), cyclothiazide, and 2,3,5,6-tetrafluoro-4-piperidin-1-ylbenzenesulfonamide (3UG for short) from the existing hCA I inhibitors and word-approved drugs. As a Zn2+-dependent metallo-enzyme, the influence of Zn2+ ion models on the stability of metal-binding sites during MD simulations was addressed as well. MM-PBSA analysis predicted a strong binding affinity of -18, -16, and -14 kcal/mol, respectively, for these compounds, and identified key protein residues for binding. The sulfonamide moiety bound to the Zn2+ ion appeared as an essential component of hCA I inhibitors. Vina software predicted a relatively large (unreasonable) Zn2+-sulfonamide distance, although the relative binding strength was reproduced with good accuracy. The selected compounds displayed potent inhibition against other hCA isoforms of II, XIII, and XIV. This work is valuable for molecular modeling of hCAs and further design of potent inhibitors.

PMID:37628799 | DOI:10.3390/ijms241612619

Bioengineering (Basel). 2023 Jul 27;10(8):890. doi: 10.3390/bioengineering10080890.

ABSTRACT

Dermatomyositis (DM) is an autoimmune disease that is classified as a type of idiopathic inflammatory myopathy, which affects human skin and muscles. The most common clinical symptoms of DM are muscle weakness, rash, and scaly skin. There is currently no cure for DM. Genetic factors are known to play a pivotal role in DM progression, but few have utilized this information geared toward drug discovery for the disease. Here, we exploited genomic variation associated with DM and integrated this with genomic and bioinformatic analyses to discover new drug candidates. We first integrated genome-wide association study (GWAS) and phenome-wide association study (PheWAS) catalogs to identify disease-associated genomic variants. Biological risk genes for DM were prioritized using strict functional annotations, further identifying candidate drug targets based on druggable genes from databases. Overall, we analyzed 1239 variants associated with DM and obtained 43 drugs that overlapped with 13 target genes (JAK2, FCGR3B, CD4, CD3D, LCK, CD2, CD3E, FCGR3A, CD3G, IFNAR1, CD247, JAK1, IFNAR2). Six drugs clinically investigated for DM, as well as eight drugs under pre-clinical investigation, are candidate drugs that could be repositioned for DM. Further studies are necessary to validate potential biomarkers for novel DM therapeutics from our findings.

PMID:37627776 | DOI:10.3390/bioengineering10080890

Antibiotics (Basel). 2023 Aug 3;12(8):1280. doi: 10.3390/antibiotics12081280.

ABSTRACT

Among the pathogenic free-living amoebae (FLA), Naegleria fowleri is the etiological agent of a fatal disease known as primary amoebic meningoencephalitis (PAM). Once infection begins, the lesions generated in the central nervous system (CNS) result in the onset of symptoms leading to death in a short period of time. Currently, there is no standardized treatment against the infection, which, due to the high virulence of the parasite, results in a high case fatality rate (>97%). Therefore, it is essential to search for new therapeutic sources that can generate a rapid elimination of the parasite. In recent years, there have already been several successful examples of drug repurposing, such as Nitroxoline, for which, in addition to its known bioactive properties, anti-Balamuthia activity has recently been described. Following this approach, the anti-Naegleria activity of Nitroxoline was tested. Nitroxoline displayed low micromolar activity against two different strains of N. fowleri trophozoites (IC50 values of 1.63 ± 0.37 µM and 1.17 ± 0.21 µM) and against cyst stages (IC50 of 1.26 ± 0.42 μM). The potent anti-parasitic activity compared to the toxicity produced (selectivity index of 3.78 and 5.25, respectively) in murine macrophages and human cell lines (reported in previous studies), together with the induction of programmed cell death (PCD)-related events in N. fowleri make Nitroxoline a great candidate for an alternative PAM treatment.

PMID:37627700 | DOI:10.3390/antibiotics12081280

Antibiotics (Basel). 2023 Jul 26;12(8):1236. doi: 10.3390/antibiotics12081236.

ABSTRACT

The aim of this work was to (i) evaluate the efficacy of a combination treatment of pentamidine with ciprofloxacin against Galleria mellonella larvae infected with an MDR strain of P. aeruginosa and (ii) determine if pentamidine acts as an efflux-pump inhibitor. Resistant clinical isolates, mutant strains overexpressing one of three RND efflux pumps (MexAB-OprM, MexCD-OprJ, and MexEF-OprN), and a strain with the same three pumps deleted were used. MIC assays confirmed that the clinical isolates and the mutants overexpressing efflux pumps were resistant to ciprofloxacin and pentamidine. The deletion of the three efflux pumps induced sensitivity to both compounds. Exposure to pentamidine and ciprofloxacin in combination resulted in the synergistic inhibition of all resistant strains in vitro, but no synergy was observed versus the efflux-pump deletion strain. The treatment of infected G. mellonella larvae with the combination of pentamidine and ciprofloxacin resulted in enhanced efficacy compared with the monotherapies and significantly reduced the number of proliferating bacteria. Our measurement of efflux activity from cells revealed that pentamidine had a specific inhibitory effect on the MexCD-OprJ and MexEF-OprN efflux pumps. However, the efflux activity and membrane permeability assays revealed that pentamidine also disrupted the membrane of all cells. In conclusion, pentamidine does possess some efflux-pump inhibitory activity, in addition to a more general disruptive effect on membrane integrity that accounts for its ability to potentiate ciprofloxacin activity. Notably, the enhanced efficacy of combination therapy with pentamidine and ciprofloxacin versus MDR P. aeruginosa strains in vivo merits further investigation into its potential to treat infections via this pathogen in patients.

PMID:37627656 | DOI:10.3390/antibiotics12081236

Antioxidants (Basel). 2023 Aug 3;12(8):1555. doi: 10.3390/antiox12081555.

ABSTRACT

Our investigation intended to analyze the effects of sulfated polysaccharides from Caulerpa racemosa (SPCr) in attenuating obesity-induced cardiometabolic syndrome via regulating the protein arginine N-methyltransferase 1-asymmetric dimethylarginine-dimethylarginine dimethylamino-hydrolase (PRMT1-DDAH-ADMA) with the mammalian target of rapamycin-Sirtuin 1-5' AMP-activated protein kinase (mTOR-SIRT1-AMPK) pathways and gut microbiota modulation. This is a follow-up study that used SPs from previous in vitro studies, consisting of 2,3-di-O-methyl-1,4,5-tri-O-acetylarabinitol, 2,3,4,6-tetra-O-methyl-D-mannopyranose, and type B ulvanobiuronicacid 3-sulfate. A total of forty rats were randomly divided into four treatment groups: Group A received a standard diet; Group B was provided with a diet enriched in cholesterol and fat (CFED); and Groups C and D were given the CFED along with ad libitum water, and daily oral supplementation of 65 or 130 mg/kg of body weight (BW) of SPCr, respectively. Group D showed the lowest low-density lipoprotein, triglyceride, total cholesterol, and blood glucose levels, and the highest HDL level compared to the other groups in this study. These results in the group fed high-dose SPCr demonstrated a significant effect compared to the group fed low-dose SPCr (p < 0.0001), as well as in total cholesterol and blood glucose (p < 0.05). Supplementation with SPCr was also observed to have an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, interleukin 10, Sirtuin 1, DDAH-II, superoxide dismutase (SOD) cardio, and AMPK, which was also followed by a downregulation of PRMT-1, TNF-α, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, and mTOR. Interestingly, gut microbiota modulation was also observed; feeding the rats with a cholesterol-enriched diet shifted the gut microbiota composition toward the Firmicutes level, lowered the Bacteroidetes level, and increased the Firmicutes level. A dose of 130 mg/kg BW of SPCr is the recommended dose, and investigation still needs to be continued in clinical trials with humans to see its efficacy at an advanced level.

PMID:37627550 | DOI:10.3390/antiox12081555

Pharmacol Ther. 2023 Aug 23:108520. doi: 10.1016/j.pharmthera.2023.108520. Online ahead of print.

ABSTRACT

Vascular anomalies (VA) are developmental anomalies of veins, arteries, lymphatics or capillaries thought to be caused by mutations in genes that drive angiogenesis. Treatments targeting these genes are limited. We review the literature for conventional medications and products from traditional medicine cultures that have been found to have antiangiogenic activity. Fewer than 50 drugs with credible human activity in VA were identified and include β blockers, monoclonal antibodies, microtubule inhibitors, multi-kinase inhibitors, PIK3CA- and RAS-MAPK pathway inhibitors, and thalidomides. Other drug categories of potential interest are ACE-inhibitors, antifungals, antimalarials, MMP9-inhibitors, and over-the-counter compounds used in Eastern traditional medicine. Low toxicity for some offers the possibility of combined use with known effective agents. In addition to already familiar drugs, others with antiangiogenic capabilities already in use in children or adults may deserve further attention for repurposing for VA.

PMID:37625520 | DOI:10.1016/j.pharmthera.2023.108520

OMICS. 2023 Aug;27(8):402-405. doi: 10.1089/omi.2023.29093.correx.

NO ABSTRACT

PMID:37624679 | DOI:10.1089/omi.2023.29093.correx

J Fungi (Basel). 2023 Jul 25;9(8):783. doi: 10.3390/jof9080783.

ABSTRACT

Cryptococcosis is a systemic mycosis affecting immunosuppressed individuals, caused by various Cryptococcus species. The current treatment utilizes a combination of antifungal drugs, but issues such as nephrotoxicity, restricted or limited availability in certain countries, and resistance limit their effectiveness. Repurposing approved drugs presents a viable strategy for developing new antifungal options. This study investigates the potential of glatiramer acetate (Copaxone®) as a chemotherapy candidate for Cryptococcus neoformans infection. Various techniques are employed to evaluate the effects of glatiramer acetate on the fungus, including microdilution, XTT analysis, electron and light microscopy, and physicochemical measurements. The results demonstrate that glatiramer acetate exhibits antifungal properties, with an IC50 of 0.470 mg/mL and a minimum inhibitory concentration (MIC) of 2.5 mg/mL. Furthermore, it promotes enhanced cell aggregation, facilitates biofilm formation, and increases the secretion of fungal polysaccharides. These findings indicate that glatiramer acetate not only shows an antifungal effect but also modulates the key virulence factor-the polysaccharide capsule. In summary, repurposing glatiramer acetate as a potential chemotherapy option offers new prospects for combating C. neoformans infection. It addresses the limitations associated with current antifungal therapies by providing an alternative treatment approach.

PMID:37623554 | DOI:10.3390/jof9080783

Hum Mol Genet. 2023 Aug 25:ddad139. doi: 10.1093/hmg/ddad139. Online ahead of print.

ABSTRACT

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant associations with PCa risk, including 16 previously reported proteins and eight novel proteins. Of them, 14 proteins showed negative associations and 10 showed positive associations with PCa risk. For 18 of the identified proteins, potential functional somatic changes of encoding genes were detected in PCa patients in The Cancer Genome Atlas. Genes encoding these proteins were significantly involved in cancer-related pathways. We further identified drugs targeting the identified proteins, which may serve as candidates for drug repurposing for treating PCa. In conclusion, this study identifies novel protein biomarker candidates for PCa risk, which may provide new perspectives on the etiology of PCa and improve its therapeutic strategies.

PMID:37622920 | DOI:10.1093/hmg/ddad139

Biosensors (Basel). 2023 Aug 1;13(8):779. doi: 10.3390/bios13080779.

ABSTRACT

Microfluidic technology is applied across various research areas including organ-on-chip (OOC) systems. The main material used for microfluidics is polydimethylsiloxane (PDMS), a silicone elastomer material that is biocompatible, transparent, and easy to use for OOC systems with well-defined microstructures. However, PDMS-based OOC systems can absorb hydrophobic and small molecules, making it difficult and erroneous to make quantitative analytical assessments for such compounds. In this paper, we explore the use of a synthetic fluoropolymer, poly(4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxole-co-tetrafluoroethylene) (Teflon™ AF 2400), with excellent "non-stick" properties to functionalize OOC systems. Cannabinoids, including cannabidiol (CBD), are classes of hydrophobic compounds with a great potential for the treatment of anxiety, depression, pain, and cancer. By using CBD as a testing compound, we examined and systematically quantified CBD absorption into PDMS by means of an LC-MS/MS analysis. In comparison to the unmodified PDMS microchannels, an increase of approximately 30× in the CBD signal was detected with the fluoropolymer surface modification after 3 h of static incubation. Under perfusion conditions, we observed an increase of nearly 15× in the CBD signals from the surface-modified microchannels than from the unmodified microchannels. Furthermore, we also demonstrated that fluoropolymer-modified microchannels are compatible for culturing hCMEC/D3 endothelial cells and for CBD perfusion experiments.

PMID:37622865 | DOI:10.3390/bios13080779

Clin Exp Pharmacol Physiol. 2023 Aug 25. doi: 10.1111/1440-1681.13817. Online ahead of print.

ABSTRACT

The hypothalamic-pituitary-gonadal (HPG) axis is an important regulatory mechanism involved primarily in the development and regulation of the reproductive systems. The suppression of the HPG axis by gonadotropin-releasing hormone (GnRH) analogues is expected to be effective for the treatment of sex hormone-dependent diseases, such as endometriosis, uterine fibroid, prostate cancer, benign prostatic hyperplasia (BPH) and polycystic ovary syndrome (PCOS). Despite the established involvement of GnRH signalling in these disorders, the therapeutic efficacy of small molecular GnRH antagonists for BPH and PCOS has not been adequately evaluated in non-clinical studies. Therefore, the purpose of the present study was to evaluate the potential of linzagolix, a small molecular GnRH antagonist, as a potential new treatment option for BPH and PCOS. Dogs and rats exhibiting normal prostates and dogs diagnosed with prostatic hyperplasia were used to evaluate the effects of linzagolix in BPH. The effects of linzagolix were also examined in a rat model of PCOS induced by repeated administration of letrozole, an aromatase inhibitor. Linzagolix reduced serum luteinizing hormone and testosterone levels in male rats and normal or BPH model dogs and suppressed prostate weight without testosterone depletion, suggesting the existence of an optimal therapeutic testosterone level for BPH treatment. In a PCOS rat model, linzagolix improved both insulin resistance and ovarian dysfunction. Treatment with linzagolix decreased follicle-stimulating hormone levels, but did not alter serum luteinizing hormone and testosterone levels. These results indicate that linzagolix may provide a new treatment option for GnRH-related disorders, such as BPH and PCOS.

PMID:37622483 | DOI:10.1111/1440-1681.13817

Front Mol Biosci. 2023 Aug 9;10:1158912. doi: 10.3389/fmolb.2023.1158912. eCollection 2023.

ABSTRACT

Plasmodium falciparum is a unicellular, intracellular protozoan parasite, and the causative agent of malaria in humans, a deadly vector borne infectious disease. A key phase of malaria pathology, is the invasion of human erythrocytes, resulting in drastic remodeling by exported parasite proteins, including molecular chaperones and co-chaperones. The survival of the parasite within the human host is mediated by P. falciparum heat shock protein 70s (PfHsp70s) and J domain proteins (PfJDPs), functioning as chaperones-co-chaperones partnerships. Two complexes have been shown to be important for survival and pathology of the malaria parasite: PfHsp70-x-PFE0055c (exported); and PfHsp70-2-PfSec63 (endoplasmic reticulum). Virtual screening was conducted on the drug repurposing library, the Pandemic Response Box, to identify small-molecules that could specifically disrupt these chaperone complexes. Five top ranked compounds possessing preferential binding affinity for the malarial chaperone system compared to the human system, were identified; three top PfHsp70-PfJDP binders, MBX 1641, zoliflodacin and itraconazole; and two top J domain binders, ezetimibe and a benzo-diazepinone. These compounds were validated by repeat molecular dockings and molecular dynamics simulation, resulting in all the compounds, except for MBX 1461, being confirmed to bind preferentially to the malarial chaperone system. A detailed contact analysis of the PfHsp70-PfJDP binders identified two different types of modulators, those that potentially inhibit complex formation (MBX 1461), and those that potentially stabilize the complex (zoliflodacin and itraconazole). These data suggested that zoliflodacin and itraconazole are potential novel modulators specific to the malarial system. A detailed contact analysis of the J domain binders (ezetimibe and the benzo-diazepinone), revealed that they bound with not only greater affinity but also a better pose to the malarial J domain compared to that of the human system. These data suggested that ezetimibe and the benzo-diazepinone are potential specific inhibitors of the malarial chaperone system. Both itraconazole and ezetimibe are FDA-approved drugs, possess anti-malarial activity and have recently been repurposed for the treatment of cancer. This is the first time that such drug-like compounds have been identified as potential modulators of PfHsp70-PfJDP complexes, and they represent novel candidates for validation and development into anti-malarial drugs.

PMID:37621993 | PMC:PMC10445141 | DOI:10.3389/fmolb.2023.1158912

Autophagy. 2023 Aug 24:1-3. doi: 10.1080/15548627.2023.2250165. Online ahead of print.

ABSTRACT

Differentiation and fate decisions are critical for the epithelial cells lining the proximal tubule (PT) of the kidney, but the signals involved remain unknown. Defective cystine mobilization from lysosomes through CTNS (cystinosin, lysosomal cystine transporter), which is mutated in cystinosis, triggers the dedifferentiation and dysfunction of the PT cells, causing kidney disease and severe metabolic complications. Using preclinical models and physiologically relevant cellular systems, along with functional assays and a generative artificial intelligence (AI)-powered engine, we found that cystine storage imparted by CTNS deficiency stimulates Ragulator-RRAG GTPase-dependent recruitment of MTORC1 and its constitutive activation. In turn, this diverts the catabolic trajectories and differentiating states of PT cells toward growth and proliferation, disrupting homeostasis and their specialized functions. Therapeutic MTORC1 inhibition by using low doses of rapamycin corrects lysosome function and differentiation downstream of cystine storage and ameliorates PT dysfunction in preclinical models of cystinosis. These discoveries suggest that cystine may act as a lysosomal fasting signal that tailors MTORC1 signaling to direct fate decisions in the kidney PT epithelium, highlighting novel therapeutic paradigms for cystinosis and other lysosome-related disorders.

PMID:37621073 | DOI:10.1080/15548627.2023.2250165

Sci Rep. 2023 Aug 23;13(1):13763. doi: 10.1038/s41598-023-40994-w.

ABSTRACT

Aberrant metabolism has been identified as a main driver of cancer. Profiling of metabolism-related pathways in cancer furthers the understanding of tumor plasticity and identification of potential metabolic vulnerabilities. In this prospective controlled study, we established transcriptomic profiles of metabolism-related pathways in endometrial cancer (EC) using a novel method, NanoString nCounter Technology. Fifty-seven ECs and 30 normal endometrial specimens were studied using the NanoString Metabolic Panel, further validated by qRT-PCR with a very high similarity. Statistical analyses were by GraphPad PRISM and Weka software. The analysis identified 11 deregulated genes (FDR ≤ 0.05; |FC|≥ 1.5) in EC: SLC7A11; SLC7A5; RUNX1; LAMA4; COL6A3; PDK1; CCNA1; ENO1; PKM; NR2F1; and NAALAD2. Gene ontology showed direct association of these genes with 'central carbon metabolism (CCM) in cancer'. Thus, 'CCM in cancer' appears to create one of the main metabolic axes in EC. Further, transcriptomic data were functionally validated with drug repurposing on three EC cell lines, with several drug candidates suggested. These results lay the foundation for personalized therapeutic strategies in this cancer. Metabolic plasticity represents a promising diagnostic and therapeutic option in EC.

PMID:37612452 | DOI:10.1038/s41598-023-40994-w

Bioinformatics. 2023 Aug 23:btad524. doi: 10.1093/bioinformatics/btad524. Online ahead of print.

ABSTRACT

MOTIVATION: Identifying drug-protein interactions (DPIs) is a critical step in drug repositioning, which allows reuse of approved drugs that may be effective for treating a different disease and thereby alleviates the challenges of new drug development. Despite the fact that a great variety of computational approaches for DPI prediction have been proposed, key challenges, such as extendable and unbiased similarity calculation, heterogeneous information utilization and reliable negative sample selection, remain to be addressed.

RESULTS: To address these issues, we propose a novel, unified multi-view graph autoencoder framework, termed MULGA, for both DPI and drug repositioning predictions. MULGA is featured by: (i) a multi-view learning technique to effectively learn authentic drug affinity and target affinity matrices; (ii) a graph autoencoder to infer missing DPI interactions; and (iii) a new "guilty-by-association"-based negative sampling approach for selecting highly reliable non-DPIs. Benchmark experiments demonstrate that MULGA outperforms state-of-the-art methods in DPI prediction and the ablation studies verify the effectiveness of each proposed component. Importantly, we highlight the top drugs shortlisted by MULGA that target the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), offering additional insights into and potentially useful treatment option for COVID-19. Together with the availability of datasets and source codes, we envision that MULGA can be explored as a useful tool for DPI prediction and drug repositioning.

AVAILABILITY AND IMPLEMENTATION: MULGA is publicly available for academic purposes at https://github.com/jianiM/MULGA/.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:37610353 | DOI:10.1093/bioinformatics/btad524

Anticancer Agents Med Chem. 2023 Aug 22. doi: 10.2174/1871520623666230822100006. Online ahead of print.

ABSTRACT

BACKGROUND: Targeted therapies, specifically ErbB family tyrosine kinase inhibitors, have demonstrated potential for improving outcomes in patients with ErbB2-positive breast cancer. Despite their effectiveness, these therapies are associated with limitations, including high costs, side effects, drug resistance, lack of specificity, and toxicity. To overcome these challenges, drug repurposing has emerged as a promising strategy in breast cancer treatment.

OBJECTIVE: The aim of this investigation was to assess the influence of calcitriol on breast cancer cell lines expressing ErbB2 and comparing its effects with the conventional treatment, neratinib.

METHODS: We employed an MTT test to determine cell viability and utilized staining techniques to assess cell apoptosis. Flow cytometry was used to evaluate cell cycle arrest, while a scratch wound healing test was performed to examine cancer cell migration ability. Additionally, gene expression studies were conducted for calcitriol and neratinib to support our hypothesis regarding the ErbB2 gene.

RESULTS: The repurposing of calcitriol demonstrated enhanced efficacy in suppressing cancer cell growth in ErbB2-positive breast cancer. Proportionally, calcitriol significantly reduced the viability of SK-BR-3 cells, similar to neratinib. Furthermore, calcitriol exhibited significant cytotoxicity against neratinib and substantially reduced breast cancer cell growth. These findings were corroborated by the wound healing assay, cell cycle arrest analysis, and gene expression studies, demonstrating comparable efficacy to the standard treatment, neratinib.

CONCLUSION: The findings from this investigation offer compelling proof that highlights the promising role of calcitriol as an adjuvant drug with antiproliferative and antitumoral effects in the management of ErbB2-positive breast carcinoma patients. Therefore, we recommend further evaluation of calcitriol in clinical settings, particularly for the treatment of ErbB2-positive breast cancer, as it shows promise as a valuable therapeutic option.

PMID:37608657 | DOI:10.2174/1871520623666230822100006