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Journal of Advanced Research Sep 2023Idiopathic pulmonary fibrosis (IPF), a life-threatening interstitial lung disease, is characterized by excessive activation and proliferation of fibroblasts and...
INTRODUCTION
Idiopathic pulmonary fibrosis (IPF), a life-threatening interstitial lung disease, is characterized by excessive activation and proliferation of fibroblasts and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) accompanied by a large amount of extracellular matrix aggregation. There are no therapies to reverse pulmonary fibrosis, and nintedanib and pirfenidone could only slow down the decline of lung function of IPF patients and delay their survival time. Niclosamide (Ncl) is an antihelminthic drug approved by FDA, which has been reported to have pleiotropic pharmacological activities in recent years, but it's almost complete insolubility in water limits its clinical application.
OBJECTIVES
To improve the water solubility of Ncl, explore its ability to reverse BLM-induced pulmonary fibrosis and its specific mechanism of action.
METHODS
The Niclosamide-loaded nanoparticles (Ncl-NPs) were formed by emulsification solvent evaporation method. A mouse model induced by bleomycin (BLM) was established to evaluate its effects and mechanisms of inhibiting and reversing fibrosis in vivo. The cell models treated by transforming growth factor-β1 (TGF-β1) were used to examine the mechanism of Ncl-NPs inhibiting fibrosis in vitro. Flow cytometry, IHC, IL-4-induced macrophage model and co-culture system were used to assess the effect of Ncl-NPs on M2 polarization of macrophages.
RESULTS
The Ncl-NPs improved the poor water solubility of Ncl. The lower dose of Ncl-NPs (2.5 mg/kg) showed the same effect of reversing established pulmonary fibrosis as free Ncl (5 mg/kg). Mechanistic studies revealed that Ncl-NPs blocked TGF-β/Smad and signaling transducer and activator of transcription 3 (Stat3) signaling pathways and inhibited the M2 polarization of macrophages. Additionally, H&E staining of the tissues initially showed the safety of Ncl-NPs.
CONCLUSION
These results indicate Ncl-NPs may serve as a new idea for the treatment of pulmonary fibrosis.
Topics: Mice; Animals; Niclosamide; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Extracellular Matrix; Alveolar Epithelial Cells
PubMed: 36347425
DOI: 10.1016/j.jare.2022.10.018 -
Molecular Cancer Therapeutics Aug 2017Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR...
Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide-sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide- and enzalutamide-resistant CWR22Rv1, enzalutamide-resistant C4-2B (C4-2B MDVR), and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide- and enzalutamide-resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide-resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can resensitize bicalutamide-resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost-effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy. .
Topics: Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Male; Mice; Niclosamide; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Tosyl Compounds
PubMed: 28500234
DOI: 10.1158/1535-7163.MCT-16-0912 -
International Journal of Molecular... Jan 2023Salicylanilides are pharmacologically active compounds with a wide spectrum of biological effects. Halogenated salicylanilides, which have been used for decades in human... (Review)
Review
Salicylanilides are pharmacologically active compounds with a wide spectrum of biological effects. Halogenated salicylanilides, which have been used for decades in human and veterinary medicine as anthelmintics, have recently emerged as candidates for drug repurposing in oncology. The most prominent example of salicylanilide anthelmintic, that is intensively studied for its potential anticancer properties, is niclosamide. Nevertheless, recent studies have discovered extensive anticancer potential in a number of other salicylanilides. This potential of their anticancer action is mediated most likely by diverse mechanisms of action such as uncoupling of oxidative phosphorylation, inhibition of protein tyrosine kinase epidermal growth factor receptor, modulation of different signaling pathways as Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways or induction of B-Raf V600E inhibition. Here we provide a comprehensive overview of the current knowledge about the proposed mechanisms of action of anticancer activity of salicylanilides based on preclinical in vitro and in vivo studies, or structural requirements for such an activity.
Topics: Humans; Salicylanilides; Niclosamide; Anthelmintics; Signal Transduction
PubMed: 36675241
DOI: 10.3390/ijms24021728 -
ACS Infectious Diseases May 2020The recent outbreak of coronavirus disease 2019 (COVID-19) highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns,... (Review)
Review
The recent outbreak of coronavirus disease 2019 (COVID-19) highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns, niclosamide, an FDA-approved anthelminthic drug, was found to be effective against various viral infections with nanomolar to micromolar potency such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus, indicating its potential as an antiviral agent. In this brief review, we summarize the broad antiviral activity of niclosamide and highlight its potential clinical use in the treatment of COVID-19.
Topics: Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Repositioning; Humans; Middle East Respiratory Syndrome Coronavirus; Niclosamide; Pandemics; Pneumonia, Viral; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32125140
DOI: 10.1021/acsinfecdis.0c00052 -
Pflugers Archiv : European Journal of... Feb 2024Inflammatory airway diseases like cystic fibrosis, asthma and COVID-19 are characterized by high levels of pulmonary cytokines. Two well-established antiparasitic drugs,...
Inflammatory airway diseases like cystic fibrosis, asthma and COVID-19 are characterized by high levels of pulmonary cytokines. Two well-established antiparasitic drugs, niclosamide and ivermectin, are intensively discussed for the treatment of viral inflammatory airway infections. Here, we examined these repurposed drugs with respect to their anti-inflammatory effects in airways in vivo and in vitro. Niclosamide reduced mucus content, eosinophilic infiltration and cell death in asthmatic mouse lungs in vivo and inhibited release of interleukins in the two differentiated airway epithelial cell lines CFBE and BCi-NS1.1 in vitro. Cytokine release was also inhibited by the knockdown of the Ca-activated Cl channel anoctamin 1 (ANO1, TMEM16A) and the phospholipid scramblase anoctamin 6 (ANO6, TMEM16F), which have previously been shown to affect intracellular Ca levels near the plasma membrane and to facilitate exocytosis. At concentrations around 200 nM, niclosamide inhibited inflammation, lowered intracellular Ca, acidified cytosolic pH and blocked activation of ANO1 and ANO6. It is suggested that niclosamide brings about its anti-inflammatory effects at least in part by inhibiting ANO1 and ANO6, and by lowering intracellular Ca levels. In contrast to niclosamide, 1 µM ivermectin did not exert any of the effects described for niclosamide. The present data suggest niclosamide as an effective anti-inflammatory treatment in CF, asthma, and COVID-19, in addition to its previously reported antiviral effects. It has an advantageous concentration-response relationship and is known to be well tolerated.
Topics: Mice; Animals; Anoctamin-1; Ivermectin; Niclosamide; Anoctamins; Asthma; Lung; Phospholipid Transfer Proteins; Calcium; Inflammation; Anti-Inflammatory Agents; COVID-19; Chloride Channels
PubMed: 37979051
DOI: 10.1007/s00424-023-02878-w -
Biology of Reproduction Apr 2020Endometriosis is a common gynecological disease, which causes chronic pelvic pain and infertility in women of reproductive age. Due to limited efficacy of current...
Endometriosis is a common gynecological disease, which causes chronic pelvic pain and infertility in women of reproductive age. Due to limited efficacy of current treatment options, a critical need exists to develop new and effective treatments for endometriosis. Niclosamide is an efficacious and FDA-approved drug for the treatment of helminthosis in humans that has been used for decades. We have reported that niclosamide reduces growth and progression of endometriosis-like lesions via targeting STAT3 and NFĸB signaling in a mouse model of endometriosis. To examine the effects of niclosamide on macrophage-induced inflammation in endometriosis, a total of 29 stage III-IV endometrioma samples were used to isolate human endometriotic stromal cells (hESCs). M1 or M2 macrophages were isolated and differentiated from fresh human peripheral blood samples. Then, hESCs were cultured in conditioned media (CM) from macrophages with/without niclosamide. Niclosamide dose dependently reduced cell viability and the activity of STAT3 and NFκB signaling in hESCs. While macrophage CM stimulated cell viability in hESCs, niclosamide inhibited this stimulation. Macrophage CM stimulated the secretion of proinflammatory cytokines and chemokines from hESCs. Most of these secreted factors were inhibited by niclosamide. These results indicate that niclosamide is able to reduce macrophage-induced cell viability and cytokine/chemokine secretion in hESCs by inhibiting inflammatory mechanisms via STAT3 and/or NFκB signaling.
Topics: Animals; Anticestodal Agents; Cell Survival; Cells, Cultured; Endometriosis; Female; Gene Expression Regulation; Humans; Inflammation; Macrophages; Mice; NF-kappa B; Niclosamide; STAT3 Transcription Factor; Stromal Cells
PubMed: 31950153
DOI: 10.1093/biolre/ioaa010 -
Bioorganic & Medicinal Chemistry Letters Sep 2022Roughly 268,000 new cases of prostate cancer and 34,000 deaths from prostate cancer are projected by the American Cancer Society to occur in the United States in 2022....
Roughly 268,000 new cases of prostate cancer and 34,000 deaths from prostate cancer are projected by the American Cancer Society to occur in the United States in 2022. Androgen receptor is a key protein in the proliferation and survival of prostate cancer cells and has been revealed to be overexpressed in 30% to 50% of castration-resistant prostate cancer patients. One promising approach to reducing the level of this protein is Proteolysis Targeting Chimeras (PROTACs) that is an emerging drug discovery technology. PROTACs are hetero-bifunctional molecules where one end binds to a protein of interest and the other to an E3 ligase ligand, initiating the Ubiquitin-Proteasome Pathway for protein degradation. Two PROTACs with niclosamide as androgen receptor ligand and VHL-032 as the E3 ligase ligand have been designed and synthesized for suppressing proliferation of androgen receptor-positive prostate cancer cells via degrading androgen receptor. The in vitro antiproliferative assessment suggested that they can selectively suppress PC-3, LNCaP, and 22Rv1 prostate cancer cell proliferation, but cannot inhibit DU145 cell proliferation. However, the mechanism of both compounds in suppressing prostate cancer cell proliferation is not through the AR PROTAC mechanism because they did not degrade AR in our Western Blotting assay up to 1 µM.
Topics: Humans; Male; Ligands; Niclosamide; Prostatic Neoplasms; Proteolysis; Receptors, Androgen; Ubiquitin-Protein Ligases
PubMed: 35772635
DOI: 10.1016/j.bmcl.2022.128870 -
Cancers Jul 2021The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic...
The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.
PubMed: 34298652
DOI: 10.3390/cancers13143437 -
European Journal of Medicinal Chemistry May 2022Niclosamide, a widely-used anthelmintic drug, inhibits SARS-CoV-2 virus entry through TMEM16F inhibition and replication through autophagy induction, but the relatively...
Niclosamide, a widely-used anthelmintic drug, inhibits SARS-CoV-2 virus entry through TMEM16F inhibition and replication through autophagy induction, but the relatively high cytotoxicity and poor oral bioavailability limited its application. We synthesized 22 niclosamide analogues of which compound 5 was found to exhibit the best anti-SARS-CoV-2 efficacy (IC = 0.057 μ M) and compounds 6, 10, and 11 (IC = 0.39, 0.38, and 0.49 μ M, respectively) showed comparable efficacy to niclosamide. On the other hand, compounds 5, 6, 11 contained higher stability in human plasma and liver S9 enzymes assay than niclosamide, which could improve bioavailability and half-life when administered orally. Fluorescence microscopy revealed that compound 5 exhibited better activity in the reduction of phosphatidylserine externalization compared to niclosamide, which was related to TMEM16F inhibition. The AI-predicted protein structure of human TMEM16F protein was applied for molecular docking, revealing that 4'-NO of 5 formed hydrogen bonding with Arg809, which was blocked by 2'-Cl in the case of niclosamide.
Topics: Antiviral Agents; Humans; Molecular Docking Simulation; Niclosamide; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35344901
DOI: 10.1016/j.ejmech.2022.114295 -
Oncotarget 2022Glioblastoma multiforme (GBM) is one of the deadliest cancers of the brain. Its ability to infiltrate healthy brain tissues renders it difficult to remove surgically....
Glioblastoma multiforme (GBM) is one of the deadliest cancers of the brain. Its ability to infiltrate healthy brain tissues renders it difficult to remove surgically. Furthermore, it exhibits high rates of radio- and chemoresistance, making the survival rates of patients with GBM poor. Therefore, novel effective therapies for GBM remain urgently in demand. Niclosamide is an anti-helminthic drug and recently it has been receiving attention due to its reported anticancer effects in cancer models, including GBM. Furthermore, camptothecin (CPT) is a naturally-occurring alkaloid and has been previously reported to be a potential chemotherapeutic agent by targeting the nuclear topoisomerase I. In the present study, the possible combined chemotherapeutic effects of niclosamide and CPT on the human glioblastoma cell line U87 MG was investigated by MTT assay and western blot analysis. Niclosamide exhibited synergistic activities with CPT to suppress the proliferation of U87 MG cells. Additionally, niclosamide suppressed cell proliferation and induced cell death mainly by triggering ER stress and autophagy, whilst CPT induced cell apoptosis mainly through p53-mediated mitochondrial dysfunction and activation of the MAPK (ERK/JNK) pathways. Overall, these findings suggest that co-administration of niclosamide and CPT may provide a novel therapeutic treatment strategy for GBM.
Topics: Antineoplastic Agents; Apoptosis; Brain Neoplasms; Camptothecin; Cell Line, Tumor; DNA Topoisomerases, Type I; Glioblastoma; Humans; Niclosamide; Tumor Suppressor Protein p53
PubMed: 35548329
DOI: 10.18632/oncotarget.28227