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Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma.Cancer Research Jan 2023The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore,...
UNLABELLED
The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NAD+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and β-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and β-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.
SIGNIFICANCE
Targeting cancer metabolism using the mitochondrial uncoupler niclosamide ethanolamine leads to methylome reprogramming and differentiation in neuroblastoma, providing a therapeutic opportunity to reverse the Warburg effect and suppress tumor growth. See related commentary by Byrne and Bell, p.167.
Topics: Animals; Mice; beta Catenin; Cell Differentiation; Cell Line, Tumor; Epigenome; Ethanolamine; Ethanolamines; Hypoxia; Neuroblastoma; Niclosamide; Warburg Effect, Oncologic; Mitochondria
PubMed: 36318118
DOI: 10.1158/0008-5472.CAN-22-1029 -
Nature Communications Apr 2023Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To...
Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RT‒qPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.
Topics: Male; Mice; Animals; Zika Virus; Zika Virus Infection; Niclosamide; Complement Activation; Sequence Analysis, RNA
PubMed: 37120617
DOI: 10.1038/s41467-023-38223-z -
Frontiers in Oncology 2022The term 'magic bullet' is a scientific concept proposed by the German Nobel laureate Paul Ehrlich in 1907, describing a medicine that could specifically and efficiently... (Review)
Review
The term 'magic bullet' is a scientific concept proposed by the German Nobel laureate Paul Ehrlich in 1907, describing a medicine that could specifically and efficiently target a disease without harming the body. Oncologists have been looking for a magic bullet for cancer therapy ever since. However, the current therapies for cancers-including chemotherapy, radiation therapy, hormone therapy, and targeted therapy-pose either pan-cytotoxicity or only single-target efficacy, precluding their ability to function as a magic bullet. Intriguingly, niclosamide, an FDA-approved drug for treating tapeworm infections with an excellent safety profile, displays broad anti-cancer activity in a variety of contexts. In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK. Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1. We recently discovered that niclosamide ethanolamine (NEN) reprograms cellular metabolism through its uncoupler function, consequently remodeling the cellular epigenetic landscape to promote differentiation. Inspired by the promising results from the pre-clinical studies, several clinical trials are ongoing to assess the therapeutic effect of niclosamide in cancer patients. This current review summarizes the functions, mechanism of action, and potential applications of niclosamide in cancer therapy as a magic bullet.
PubMed: 36479072
DOI: 10.3389/fonc.2022.1004978 -
British Journal of Pharmacology Jul 2022Vaccines have reduced the transmission and severity of COVID-19, but there remains a paucity of efficacious treatment for drug-resistant strains and more susceptible... (Review)
Review
Vaccines have reduced the transmission and severity of COVID-19, but there remains a paucity of efficacious treatment for drug-resistant strains and more susceptible individuals, particularly those who mount a suboptimal vaccine response, either due to underlying health conditions or concomitant therapies. Repurposing existing drugs is a timely, safe and scientifically robust method for treating pandemics, such as COVID-19. Here, we review the pharmacology and scientific rationale for repurposing niclosamide, an anti-helminth already in human use as a treatment for COVID-19. In addition, its potent antiviral activity, niclosamide has shown pleiotropic anti-inflammatory, antibacterial, bronchodilatory and anticancer effects in numerous preclinical and early clinical studies. The advantages and rationale for nebulized and intranasal formulations of niclosamide, which target the site of the primary infection in COVID-19, are reviewed. Finally, we give an overview of ongoing clinical trials investigating niclosamide as a promising candidate against SARS-CoV-2.
Topics: Antiviral Agents; Drug Repositioning; Humans; Niclosamide; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35348204
DOI: 10.1111/bph.15843 -
Oncogene Sep 2022Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to...
Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.
Topics: Amino Acids; Colonic Neoplasms; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Niclosamide; Rectal Neoplasms; S100 Calcium-Binding Protein A4; Trans-Activators; beta Catenin
PubMed: 36008464
DOI: 10.1038/s41388-022-02407-6 -
Medicine in Drug Discovery Jun 2022While antimicrobial drug development has historically mitigated infectious diseases that are known, COVID-19 revealed a dearth of 'in-advance' therapeutics suitable for... (Review)
Review
While antimicrobial drug development has historically mitigated infectious diseases that are known, COVID-19 revealed a dearth of 'in-advance' therapeutics suitable for infections by pathogens that have not yet emerged. Such drugs must exhibit a property that is antithetical to the classical paradigm of antimicrobial development: the ability to treat infections by any pathogen. Characterisation of such 'pan-pathogen' antimicrobials requires consolidation of drug repositioning studies, a new and growing field of drug discovery. In this review, a previously-established system for evaluating repositioning studies is used to highlight 4 therapeutics which exhibit pan-pathogen properties, namely azithromycin, ivermectin, niclosamide, and nitazoxanide. Recognition of the pan-pathogen nature of these antimicrobials is the cornerstone of a novel paradigm of antimicrobial development that is not only anticipatory of pandemics and bioterrorist attacks, but cognisant of conserved anti-infective mechanisms within the host-pathogen interactome which are only now beginning to emerge. Ultimately, the discovery of pan-pathogen antimicrobials is concomitantly the discovery of a new class of antivirals, and begets significant implications for pandemic preparedness research in a world after COVID-19.
PubMed: 35098103
DOI: 10.1016/j.medidd.2022.100120 -
BioRxiv : the Preprint Server For... Aug 2023The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a...
The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease, but was recently found to possess broad-spectrum off-target effects. Here we show that, under physiological conditions, niclosamide acutely potentiates TMEM16A without having any inhibitory effect. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering niclosamide as a TMEM16A inhibitor to treat diseases such as asthma, COPD, and hypertension. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation, shining light on developing specific TMEM16A modulators to treat human diseases.
PubMed: 37577682
DOI: 10.1101/2023.07.31.551400 -
The Veterinary Clinics of North... Nov 1987Dogs and cats become infected with tapeworms by ingesting intermediate hosts that contain encysted juvenile tapeworms called larvae. The dog or cat is said to be the... (Review)
Review
Dogs and cats become infected with tapeworms by ingesting intermediate hosts that contain encysted juvenile tapeworms called larvae. The dog or cat is said to be the definitive host because it shelters the sexually reproductive, egg-producing stage of the tapeworm. The intermediate hosts, which are vertebrates in the case of Taenia and Mesocestoides and insects in the case of Dipylidium and Hymenolepis, become infected by ingesting unhatched but infective tapeworm eggs discharged in the feces of the dog or cat. The relatively less common Diphyllobothrium and Spirometra tapeworms discharge eggs that are undeveloped when passed in the feces and must fall into water to undergo development to the coracidium stage. Diphyllobothrium and Spirometra may have two or three aquatic intermediate hosts in series. The first of these, a copepod, ingests the free-swimming coracidium or ciliated oncosphere that has hatched from the egg. The final intermediate host containing the larva (plerocercoid) infective for the dog or cat is an aquatic vertebrate (fish, frog, water snake). Thus, dogs and cats become infected with tapeworms by eating uncooked meat or fish or by ingesting certain insects. These intermediate hosts are infected with juvenile tapeworms called larvae, which are the infective form for the dog or cat. The intermediate hosts, in turn, become infected by ingesting tapeworm eggs discharged in the feces of the dog or cat or, in the case of Diphyllobothrium and Spirometra, by ingesting coracidia that have subsequently developed in and hatched from such eggs. By far the most common tapeworms of dogs and cats in North America are D. caninum, T. pisiformis, and T. hydatigena. Therefore, the most common sources of tapeworm infection are, respectively, fleas, wild rabbits, and the uncooked meat and offal of ruminants and swine. Whenever a dose of tapeworm remedy is administered or dispensed, the client should be informed of these potential sources of reinfection. There is considerable overlap in the spectra of activity of currently available cestocides. Mebendazole, fenbendazole, niclosamide, bunamidine, and praziquantel are all effective against Taenia spp. Bunamidine is the drug of choice against Spirometra, Diphyllobothrium, and Mesocestoides. Praziquantel is the drug of choice against Echinococcus and Dipylidium.
Topics: Animals; Cat Diseases; Cats; Cestoda; Cestode Infections; Dog Diseases; Dogs; Intestinal Diseases, Parasitic
PubMed: 3328390
DOI: 10.1016/s0195-5616(87)50003-1 -
Cellular Signalling Jan 2018Niclosamide is an oral antihelminthic drug used to treat parasitic infections in millions of people worldwide. However recent studies have indicated that niclosamide may... (Review)
Review
Niclosamide is an oral antihelminthic drug used to treat parasitic infections in millions of people worldwide. However recent studies have indicated that niclosamide may have broad clinical applications for the treatment of diseases other than those caused by parasites. These diseases and symptoms may include cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, and systemic sclerosis. Among the underlying mechanisms associated with the drug actions of niclosamide are uncoupling of oxidative phosphorylation, and modulation of Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways. Here we provide a brief overview of the biological activities of niclosamide, its potential clinical applications, and its challenges for use as a new therapy for systemic diseases.
Topics: Animals; Anthelmintics; Arthritis, Rheumatoid; Diabetes Mellitus, Type 2; Disease Models, Animal; Endometriosis; Female; Humans; Infections; Mice; Neoplasms; Niclosamide; Rats; Scleroderma, Systemic; Xenograft Model Antitumor Assays
PubMed: 28389414
DOI: 10.1016/j.cellsig.2017.04.001