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Journal of Thoracic Disease Feb 2024The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the...
BACKGROUND
The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell.
METHODS
Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed to investigate the role of MBZ in NSCLC tumor growth.
RESULTS
The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC .
CONCLUSIONS
In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.
PubMed: 38505087
DOI: 10.21037/jtd-23-1978 -
Chemical Biology & Drug Design Mar 2024Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental...
Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental validation, and it has shown anti-cancer effects on some human cancer cell lines, but little is known about the anti-angiogenesis effects and anti-prostate cancer effects. In this study, we analyzed the binding modes and kinetic analysis of flubendazole with VEGFR2 and first demonstrated that flubendazole suppressed VEGF-stimulated cell proliferation, wound-healing migration, cell invasion and tube formation of HUVEC cells, and decreased the phosphorylation of extracellular signal-regulated kinase and serine/threonine kinase Akt, which are the downstream proteins of VEGFR2 that are important for cell growth. What's more, our results showed that flubendazole decreased PC-3 cell viability and proliferation ability, and suppressed PC-3 cell wound healing migration and invasion across a Matrigel-coated Transwell membrane in a concentration-dependent manner. The antiproliferative effects of flubendazole were due to induction of G2-M phase cell cycle arrest in PC-3 cells with decreasing expression of the Cyclin D1 and induction of cell apoptosis with the number of apoptotic cells increased after flubendazole treatment. These results indicated that flubendazole could exert anti-angiogenic and anticancer effects by inhibiting cell cycle and inducing cell apoptosis.
Topics: Humans; PC-3 Cells; Vascular Endothelial Growth Factor A; Angiogenesis; Kinetics; Cell Movement; Cell Proliferation; Angiogenesis Inhibitors; Human Umbilical Vein Endothelial Cells; Vascular Endothelial Growth Factor Receptor-2; Proto-Oncogene Proteins c-akt; Mebendazole
PubMed: 38480495
DOI: 10.1111/cbdd.14503 -
Research Square Feb 2024Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common...
PURPOSE
Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD.
METHODS
A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. migration assays were used to evaluate cell migration capacity and the effect of MBZ. For testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry.
RESULTS
Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model.
CONCLUSIONS
We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug's potential utility as an alternative therapeutic for TNBC LMD.
PubMed: 38405839
DOI: 10.21203/rs.3.rs-3915392/v1 -
Expert Opinion on Pharmacotherapy Feb 2024Globally, Ascaris lumbricoides is the commonest helminthic infection that affects people in underdeveloped countries and returning immigrants in industrialized nations.... (Review)
Review
INTRODUCTION
Globally, Ascaris lumbricoides is the commonest helminthic infection that affects people in underdeveloped countries and returning immigrants in industrialized nations. This article aims to provide latest updates on the epidemiology, clinical manifestations, and pharmacotherapy of ascariasis.
AREAS COVERED
A PubMed search was conducted using Clinical Queries and the key terms 'human ascariasis' OR 'Ascaris lumbricoides.' Ascaris lumbricoides is highly endemic in tropical and subtropic regions and among returning immigrants in industrialized nations. Predisposing factors include poor sanitation and poverty. The prevalence is greatest in young children. Most infected patients are asymptomatic. Patients with A. lumbricoides infection should be treated with anti-helminthic drugs to prevent complications from migration of the worm. Mebendazole and albendazole are indicated for children and nonpregnant women. Pregnant individuals should be treated with pyrantel pamoate.
EXPERT OPINION
Cure rates with anthelmintic treatment are high. No emerging pharmacotherapy can replace these existing drugs of good efficacy, safety profile and low cost for public health. It is opinioned that advances in the management of ascariasis include diagnostic accuracy at affordable costs, Emodepside is highly effective in single doses against ascarids in mammals and in human trials. The drug could be registered for human use in multiple neglected tropical diseases.
PubMed: 38372051
DOI: 10.1080/14656566.2024.2319686 -
Infectious Diseases of Poverty Feb 2024Current soil-transmitted helminth (STH) control guidelines endorse the use of albendazole or mebendazole for school-based targeted preventive chemotherapy (PC), yet... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Current soil-transmitted helminth (STH) control guidelines endorse the use of albendazole or mebendazole for school-based targeted preventive chemotherapy (PC), yet their reduced efficacy against Strongyloides stercoralis and Trichuris trichiura presents significant limitations. Emerging evidence indicates that community-wide PC [or mass drug administration (MDA)] using ivermectin, commonly used in other neglected tropical disease (NTD) control programs, may play an important role in controlling these parasites. We conducted a systematic review and meta-analysis to evaluate the effectiveness of ivermectin PC in reducing STH prevalence in endemic populations.
METHODS
We searched Pubmed, EMBASE, and Web of Science on February 14, 2023, for studies that investigated the effectiveness of ivermectin PC, either alone or in combination with other anthelmintic drugs, on STH infections, and provided a measure of STH prevalence before and after PC. We calculated pooled prevalence reductions for each STH using random-effects meta-analyses. Our protocol is available on PROSPERO (registration number CRD42023401219).
RESULTS
A total of 21 were eligible for the systematic review, of which 15 were eligible for meta-analysis. All studies delivered ivermectin through MDA. The pooled prevalence reduction of S. stercoralis following MDA with ivermectin alone was 84.49% (95% CI 54.96-94.66) across five studies and 81.37% (95% CI 61.62-90.96) across seven studies with or without albendazole. The prevalence reduction of T. trichiura was 49.93% (95% CI 18.23-69.34) across five studies with ivermectin alone, and 89.40% (95% CI 73.66-95.73) across three studies with the addition of albendazole. There was high heterogeneity for all syntheses (I > 65%).
CONCLUSIONS
This study underscores the key role of ivermectin-based MDA in addressing limitations in current global STH guidelines in terms of limited efficacy against S. stercoralis and T. trichiura. Based on these findings, revising international STH guidelines to include ivermectin is a promising option to progress the control and eventual elimination of STHs and other NTDs.
Topics: Animals; Humans; Ivermectin; Albendazole; Mass Drug Administration; Soil; Helminthiasis; Anthelmintics; Helminths; Prevalence
PubMed: 38369483
DOI: 10.1186/s40249-024-01185-5 -
Cell Reports Feb 2024The lateral root angle or gravitropic set-point angle (GSA) is an important trait for root system architecture (RSA) that determines the radial expansion of the root...
The lateral root angle or gravitropic set-point angle (GSA) is an important trait for root system architecture (RSA) that determines the radial expansion of the root system. The GSA therefore plays a crucial role for the ability of plants to access nutrients and water in the soil. Only a few regulatory pathways and mechanisms that determine GSA are known. These mostly relate to auxin and cytokinin pathways. Here, we report the identification of a small molecule, mebendazole (MBZ), that modulates GSA in Arabidopsis thaliana roots and acts via the activation of ethylene signaling. MBZ directly acts on the serine/threonine protein kinase CTR1, which is a negative regulator of ethylene signaling. Our study not only shows that the ethylene signaling pathway is essential for GSA regulation but also identifies a small molecular modulator of RSA that acts downstream of ethylene receptors and that directly activates ethylene signaling.
Topics: Mebendazole; Arabidopsis; Cytokinins; Ethylenes; Indoleacetic Acids
PubMed: 38358890
DOI: 10.1016/j.celrep.2024.113763 -
Veterinary Parasitology Apr 2024We evaluated the effect of 4 anthelmintic treatments on the viability of Trichinella spiralis encysted muscle larvae (ML) 55 days post infection (PI) in experimentally...
We evaluated the effect of 4 anthelmintic treatments on the viability of Trichinella spiralis encysted muscle larvae (ML) 55 days post infection (PI) in experimentally infected pigs. Muscle larvae were isolated from pig muscle by artificial digestion after oral treatment of pigs with Levamisole (8 mg/kg, daily for 5 days) and Mebendazole (50 mg/kg, daily for 5 days); Doramectin (0.3 mg/kg, single IM injection), and Moxidectin (0.5 mg/kg, single pour on). Isolated larvae from treated pigs were orally inoculated into mice to assess viability of ML from each treatment. Only Mebendazole treatment of pigs significantly reduced ML viability in mice. The effect of timing of the effective Mebendazole treatment on ML from a longer term infection was then examined in a second experiment. Analysis revealed that Mebendazole treatment of pigs with 250 mg/kg over 3 days (83 mg/kg/day) or 5 days (50 mg/kg/day) reduced numbers of ML recovered from pig tissues compared to untreated, infected controls, and rendered ML non-infective to mice; Mebendazole treatment of pigs with 250 mg/kg in a single dose was not effective in reducing ML numbers recovered from pigs or in impacting ML infectivity to mice. An examination of the lowest effective dose of Mebendazole on encysted ML was determined in a third experiment. Mebendazole of pigs with 5, 50, or 100 mg/kg over 3 days demonstrated that 5 or 50 mg/kg over 3 days insufficient to reduce infectivity in recovered ML, while 100 mg/kg (and 83 g from experiment 2) over 3 days significantly reduces infectivity of ML. This procedure provides a means to evaluate the efficacy of various anthelmintic treatments on the viability of Trichinella spiralis ML in pig tissues, and identified Mebendazole, at 83-100 mg/kg administered over a 3-5 day period as an anthelmintic which renders encysted Trichinella spiralis ML from pig tissues non-infective. As risk from Trichinella significantly impacts acceptance of pork from pasture-raised pigs, these data provide a method, especially for producers of these high-risk pigs, to eliminate the potential of Trichinella transmission from infected pork.
Topics: Swine; Mice; Animals; Trichinella spiralis; Mebendazole; Trichinellosis; Larva; Trichinella; Muscles; Anthelmintics; Rodent Diseases
PubMed: 38330532
DOI: 10.1016/j.vetpar.2024.110140 -
Blood Cancer Journal Feb 2024Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors...
Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.
Topics: Humans; Animals; Mice; Core Binding Factor Alpha 2 Subunit; Leukemia, Myeloid, Acute; Homoharringtonine; Blood Platelets; Blood Platelet Disorders; Proto-Oncogene Proteins c-bcl-2
PubMed: 38316746
DOI: 10.1038/s41408-024-00981-4 -
Current Pediatric Reviews Jan 2024Pinworm infestation is an important public health problem worldwide, especially among children 5 to 10 years of age in developing countries with temperate climates. The...
BACKGROUND
Pinworm infestation is an important public health problem worldwide, especially among children 5 to 10 years of age in developing countries with temperate climates. The problem is often overlooked because of its mild or asymptomatic clinical manifestations.
OBJECTIVE
The purpose of this article was to familiarize pediatricians with the diagnosis and management of pinworm infestation.
METHODS
A search was conducted in August 2023 in PubMed Clinical Queries using the key terms "Enterobius vermicularis," OR "enterobiasis," OR "pinworm." The search strategy included all clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article.
RESULTS
Enterobiasis is a cosmopolitan parasitosis caused by Enterobius vermicularis. It affects approximately 30% of children worldwide and up to 60% of children in some developing countries. Predisposing factors include poor socioeconomic conditions, inadequate sanitation, poor personal hygiene, and overcrowding. Children aged 5 to 14 years have shown the highest prevalence of enterobiasis.. Egg transmission is mainly by the fecal-oral route. Approximately 30 to 40% of infested patients do not show any clinical symptoms of the disease. For symptomatic patients, the most common presenting symptom is nocturnal pruritus ani. The diagnosis of E. vermicularis infection is best established by the cellophane tape test. The sensitivity of one single test is around 50%; however, the sensitivity increases to approximately 90% with tests performed on three different mornings. If a worm is visualized in the perianal area or the stool, a pathological examination of the worm will yield a definitive diagnosis. As pinworms and eggs are not usually passed in the stool, examination of the stool is not recommended. The drugs of choice for the treatment of pinworm infestation are mebendazole (100 mg), pyrantel pamoate (11 mg/kg, maximum 1 g), and albendazole (400 mg), all of the above-mentioned drugs are given in a single dose and repeated in two weeks. Mebendazole and albendazole are both adulticidal and ovicidal, whereas pyrantel pamoate is only adulticidal. Given their safety and effectiveness, mebendazole and albendazole are currently the best available drugs for the treatment of pinworm infestation. For pregnant women, pyrantel is preferred to mebendazole and albendazole. Treatment of all household members should be considered, especially if there are multiple or repeated symptomatic infections because reinfection is common even when effective medication is given.
CONCLUSION
In spite of effective treatment of pinworm infestation, recurrences are common. Recurrences are likely due to repeated cycles of reinfection (particularly, autoinfection) because of the short life span of adult pinworms. Good personal hygiene, such as frequent handwashing, especially after bowel movements and before meals, clipping of fingernails, avoidance of finger-sucking, nail-biting, and scratching in the anogenital area, are important preventive measures. Treatment of all household members should be considered, especially if there are multiple or repeated symptomatic infections.
PubMed: 38288810
DOI: 10.2174/0115733963283507240115112552 -
Tropical Medicine and Infectious Disease Dec 2023An estimated 1.5 billion people are infected with soil-transmitted helminths (hookworms, and ). These infections are targeted for elimination by the World Health...
An estimated 1.5 billion people are infected with soil-transmitted helminths (hookworms, and ). These infections are targeted for elimination by the World Health Organization (WHO) by 2030, with the main interventions being mass drug administration using albendazole or mebendazole. Tanzania is one of the endemic countries; it has been implementing MDA to school-aged children for more than a decade and the infection prevalence and intensity of infection have declined. Thus, at this point, the monitoring and evaluation of infection prevalence and intensity of infections, and assessing drug efficacy is crucial and requires accurate diagnostic tests. The currently used standard diagnostic test, the Kato-Katz (KK) technique, has several limitations and the WHO is calling for the development and evaluation of new diagnostic tests. The Lab-on-a-disk (LOD) was developed and tested in the endemic areas of north-western Tanzania to evaluate its sensitivity and specificity using KK and the formol-ether concentration technique. The results showed that when using a duplicate KK slide, the LOD had a sensitivity and specificity of 37.2% (95% CI: 30.7-43.9) and 67.3% (95% CI: 63.1-71.3%). Using four KK slides as a standard technique, the overall sensitivity and specificity were 37.7% (95% CI: 33.1-42.6) and 70.7% (95% CI: 65.5-75.6). The LOD attained high specificity but low sensitivity especially in detecting eggs of . The LOD technique has potential as a promising diagnostic test, but its sensitivity still requires improvement.
PubMed: 38276635
DOI: 10.3390/tropicalmed9010005