Discovery of degradable niclosamide derivatives able to specially inhibit small cell lung cancer (SCLC)

He, Xing‐Gang; Li, Maolin; Ye, Wenchong; Zhou, Wen

doi:10.1016/j.bioorg.2020.104574

Cited by 14 publications

(4 citation statements)

References 37 publications

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“…Gassen et al [49] found that NCL activates autophagy and inhibits the mTOR pathway in SARS-CoV-2, which might explain the prolonged antiviral effect of NCL. NCL plays a crucial role in the activation of p53 in small cell lung cancer [50] and viral infections [51]; therefore, it may attenuate the survival of SARS-CoV-2. Of ) on the SARS-CoV-2-mediated inflammatory signaling pathways and release of proinflammatory cytokines interest, most of enveloped RNA viruses including SARS-CoV-2 and HIV-1 activate mTOR pathway during their replications, thus disruption of this pathway may interfere with viral replication and pathogenesis [72].…”

Section: Covid-19 and Niclosamidementioning

confidence: 99%

Niclosamide for Covid-19: bridging the gap

et al. 2021

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Aim/purpose Niclosamide (NCL) is an anthelminthic drug, which is widely used to treat various diseases due to its pleiotropic anti-inflammatory and antiviral activities. NCL modulates of uncoupling oxidative phosphorylation and different signaling pathways in human biological processes . The wide-spectrum antiviral effect of NCL makes it a possible candidate for recent pandemic SARS-CoV-2 infection and may reduce Covid-19 severity. Therefore, the aim of the present study was to review and clarify the potential role of NCL in Covid-19. Methods This study reviewed and highlighted the protective role of NCL therapy in Covid-19. A related literature search in PubMed, Scopus, Web of Science, Google Scholar, and Science Direct was done. Results NCL has noteworthy anti-inflammatory and antiviral effects. The primary antiviral mechanism of NCL is through neutralization of endosomal PH and inhibition of viral protein maturation. NCL acts as a proton carrier, inhibits homeostasis of endosomal PH, which limiting of viral proliferation and release. The anti-inflammatory effects of NCL are mediated by suppression of inflammatory signaling pathways and release of pro-inflammatory cytokines. However, the major limitation in using NCL is low aqueous solubility, which reduces oral bioavailability and therapeutic serum concentration that reducing the in vivo effect of NCL against SARS-CoV-2. Conclusions NCL has anti-inflammatory and immune regulatory effects by modulating the release of pro-inflammatory cytokines, inhibition of NF-κB /NLRP3 inflammasome and mTOR signaling pathway. NCL has an anti-SARS-CoV-2 effect via interruption of viral life-cycle and/or induction of cytopathic effect. Prospective clinical studies and clinical trials are mandatory to confirm the potential role of NCL in patients with Covid-19 concerning the severity and clinical outcomes.

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Section: Covid-19 and Niclosamidementioning

confidence: 99%

Niclosamide for Covid-19: bridging the gap

et al. 2021

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“…In the past decade, increasing interest in leveraging niclosamide as an anticancer agent has led to the discovery that niclosamide targets a wide range of pathways such as regulation of Wnt/β-catenin 18,19 , mTORC1 20–22 , STAT3 23–25 , NF-κB 25,26 , and Notch signaling pathways. 27,28 Several literature reports indicate niclosamide’s activity in several cancers such as adrenocortical carcinoma 29 , head and neck cancer 30 , colon cancer 31 , leukemia 32 , lung cancer 33 , glioblastomas 34 , renal cell carcinoma 35 , prostate cancer 36 , ovarian cancer 37 , and breast cancer 38 . Pyrvinium pamoate has also been utilized as an anticancer agent due to its ability to modulate mitochondrial activity.…”

Section: Introductionmentioning

confidence: 99%

Repurposing mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 for cancer therapy

Schumacher,

Iyer,

Rumbley

et al. 2024

Preprint

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Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors. To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested. In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies warrant further investigation into targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes.

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“…In recent years, different biological activities have been attributed to this molecule, allowing a repositioning of this drug as a good candidate for the treatment of tumor diseases [2]. Latest studies, conducted both in vitro and in vivo, have shown that NCS can act as an anticancer drug against colon, lung, breast, and prostate cancer [3,4], and in accordance with the dose used in clinical studies [5,6] and by applying the method of normalizing body surface area (BSA) [7], proposed by the Food and Drug Administration, the therapeutic dose of NCS is around 50 mg for a person weighing 70 kg. This drug has recently been described as a potent Stat3 inhibitor capable of suppressing Stat3 phosphorylation at Tyr705 and transcript activity [8,9]; moreover, a correlation between Stat3 and the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice has been demonstrated [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Direct cyclodextrin-based powder extrusion 3D printing for one-step production of the BCS class II model drug niclosamide

Pistone

Racaniello

Arduino

et al. 2022

Drug Deliv. and Transl. Res.

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Niclosamide (NCS) is a drug that has been used as an anthelmintic and anti-parasitic drug for about 40 years. Recently, some studies have highlighted its potential in treating various tumors, allowing a repositioning of this drug. Despite its potential, NCS is a Biopharmaceutical Classification System (BCS) Class II drug and is consequently characterized by low aqueous solubility, poor dissolution rate and reduced bioavailability, which limits its applicability. In this work, we utilize a very novel technique, direct powder extrusion (DPE) 3D printing, which overcomes the limitations of previously used techniques (fused deposition modelling, FDM) to achieve direct extrusion of powder mixtures consisting of NCS, hydroxypropyl methylcellulose (HPMC, Affinisol 15 LV), hydroxypropyl-β-cyclodextrin (HP-β-CD) and polyethylene glycol (PEG) 6000. For the first time, direct printing of powder blends containing HP-β-CD was conducted. For all tablets, in vitro dissolution studies showed sustained drug release over 48 h, but for tablets containing HP-β-CD, the release was faster. Solid-state characterization studies showed that during extrusion, the drug lost its crystal structure and was evenly distributed within the polymer matrix. All printed tablets have exhibited good mechanical and physical features and a stability of the drug content for up to 3 months. This innovative printing technique has demonstrated the possibility to produce personalized pharmaceutical forms directly from powders, avoiding the use of filament used by FDM. Graphical abstract

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Discovery of degradable niclosamide derivatives able to specially inhibit small cell lung cancer (SCLC)

Cited by 14 publications

References 37 publications

Niclosamide for Covid-19: bridging the gap

Niclosamide for Covid-19: bridging the gap

Repurposing mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 for cancer therapy

Direct cyclodextrin-based powder extrusion 3D printing for one-step production of the BCS class II model drug niclosamide

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