Analysis of discrepancy in SNEDDS performance for a "brick dust" mebendazole between in and vitro and in-vivo estimation.

Purpose: Dendritic cells (DCs) play a critical role in regulating immune responses by influencing the balance between immune tolerance and immunogenicity. While mebendazole (MBZ) is known to polarize macrophages toward a tumor-suppressive phenotype, its effect on DCs remains unclear. This study investigates the effects of MBZ on the phenotype and inflammatory profile of human monocyte-derived dendritic cells (moDCs). Methods: Peripheral blood mononuclear cells (PBMCs) were separated from the obtained blood from healthy donors using Ficoll density gradient centrifugation. Then, monocytes were isolated via plastic adhesion and subsequently differentiated into moDCs. Cells were treated with MBZ and LPS or just LPS, and then surface markers and inflammatory/anti-inflammatory gene expression were measured using flow cytometry and real-time PCR. Results: The study compared surface marker expression and gene expression of inflammatory and anti-inflammatory cytokines between moDCs and MBZ-moDCs. MBZ-moDCs showed significantly higher CD86 surface expression but lower CD11c and HLA-DR expression in comparison to moDCs. Additionally, MBZ-moDCs exhibited increased IL-12, IL-18, IL-1β, and TNF-α gene levels and decreased IL-10 and IDO levels. Conclusion: MBZ holds significant potential for reshaping immunotherapy by exerting a profound impact on dendritic cells. By comprehending the intricate interaction between MBZ and dendritic cell function, innovative interventions can be developed.

Mebendazole (MBZ), a broad-spectrum benzimidazole anthelmintic widely applied in veterinary medicine and aquaculture, has raised increasing concerns about its potential residues in foods of animal origin. In this work, a high-affinity and specific monoclonal antibody (mAb) was generated using a newly designed hapten containing a carboxylic spacer at the N1 site of the benzimidazole ring. The obtained mAb exhibited an IC50 of 0.13 ng/mL with negligible cross-reactivity against related compounds. By combining this mAb with time-resolved fluorescent microspheres, a time-resolved fluorescence immunochromatographic assay (TRFIA) was developed for rapid and quantitative MBZ detection. The TRFIA achieved a detection limit of 1.02 μg/kg in fortified mutton and carp samples, with recovery rates ranging from 83.5% to 114.5% and coefficients of variation below 10.8%. Results correlated strongly with LC-MS/MS (R2 > 0.97). This TRFIA provides a highly sensitive, reliable, and cost-effective platform for on-site screening of MBZ residues in animal-derived foods.

Pharmacological evaluation on benzimidazole anthelmintics for eradication of the gill fluke Microcotyle sebastis infesting a black rockfish, Sebastes schlegelii.

Ovarian cancer (OvCa) remains the leading cause of gynecological cancer mortality, with most patients developing chemoresistance. Drug repurposing offers promising alternatives, with mebendazole (MBZ) showing anticancer activity. This study evaluates MBZ efficacy using Spectral Domain Optical Coherence Tomography (SD-OCT). We conducted longitudinal imaging of 40 wild-type (WT) and cisplatin-resistant (CPR) OVCAR8 multicellular tumor spheroids over 11 days. Four analyses were performed: volume analysis, optical attenuation analysis, uniformity analysis, and texture feature analysis. Volume analysis showed MBZ reduced spheroid growth in both groups, with greater effects in CPR-MCTs. Optical attenuation analysis revealed increased necrotic tissue ratios in treated spheroids. Uniformity analysis demonstrated MBZ targets heterogeneous tissues effectively. Texture analysis identified significant structural changes, with 866 altered features in CPR spheroids versus 124 in WT spheroids. Cell viability assays confirmed MBZ's effectiveness against standard and chemo-resistant OVCAR8 tumors. This study demonstrates SD-OCT's utility for noninvasive therapy monitoring in 3D cancer models.

Synergistic approach of salt formation and polymer-mediated stabilization to enhance the biopharmaceutical performance of Mebendazole.

Mebendazole (MBZ), an anthelmintic, was incorporated into nanosponges to improve its delivery. The nanosponges were prepared using polyvinyl alcohol (PVA) as an emulsifying agent and ethylene cellulose as a polymer, via emulsion solvent diffusion. The formulation was optimized using Central Composite Design (CCD) and evaluated for various physicochemical properties, including production yield, entrapment efficiency, particle size, zeta potential and in vitro release. Analytical techniques like Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry, Field emission scanning electron microscopy (FESEM) and X-ray Diffraction were used for evaluation. The production yield was 91.21 %, and entrapment efficiency was 89.13 %. Characterization confirmed successful encapsulation and nanosponge formation. FESEM showed porous, spherical structures and the zeta potential was +11.2 mV with particle size ranging from 514 nm to 554 nm. The in vitro drug release was 86.66 %, and capsule disintegration and content of active were found to be adequate. Stability studies indicated that the capsules were stable. These results suggest that mebendazole-loaded nanosponges effectively address challenges associated with conventional mebendazole formulations.

Cancer drug resistance significantly reduces the effectiveness of current anticancer treatments. Multiple dysregulated signaling pathways drive cancer initiation, progression, and related drug resistance. This highlights the need for developing new multi-targeting drugs that are more cost-effective, have fewer side effects, and remain effective against cancer. Drug repurposing offers a promising solution to expensive targeted therapies and helps overcome drug resistance. Mebendazole (MBZ), albendazole, flubendazole, and oxfendazole are broad-spectrum anti-helminthic drugs from the benzimidazole family. Therefore, MBZ demonstrated potential in suppressing the growth of various cancer cells, both in vitro and in vivo. Consequently, we thoroughly reviewed MBZ as a therapeutic option against cancer and related drug resistance. In this study, we identified MBZ as a promising cancer treatment that works through multiple mechanisms such as regulating tumor angiogenesis, autophagy, and apoptosis, modulating key signaling pathways, boosting antitumor immune responses, and inhibiting matrix metalloproteinases activity-all of which are major factors in cancer drug resistance. Additionally, the development of new MBZ delivery systems aims to address its pharmacokinetic limitations. While the anticancer effects of MBZ are encouraging, further research is needed before it can be used clinically. Extensive data from in vitro, in vivo, and clinical trials support MBZ's anticancer potential and highlight the need for innovative delivery methods, including polymeric nanoparticles, nanostructured lipid formulations, micelles, nanosuspensions, and beyond.

<i>Background:</i> The anti-epileptic NKCC1 inhibitor Bumetanide (BUM) and the microtubule acting anthelminthic agent Mebendazole (MEB), have anti-cancer properties. Tumor & its environment generate neuronal hyperactivity that aggravates the clinical outcome suggesting that their combination might block hyperactivity (BUM) and augment cell death (MEB). <i>Methods:</i> We tested the effects of the combo on i) NKCC1 activity in human cell lines, ii) electrical activity recorded from mouse hippocampal neurons & tumors freshly resected from patients, iii) glioblastoma-brain co-cultures, iv) cell death in human tumoroids. <i>Results:</i> BUM efficiently inhibited NKCC1 & unexpectedly, MEB applications also via a likely indirect action. In rodent hippocampal neurons, BUM blocked GABAergic Giant Depolarizing Potentials and seizures and co-applications of MEB produced a fourfold increase of BUM's efficacy. In freshly removed brain tumors, E GABA reversal recorded with single GABA channels was highly depolarized (close to -25 mV) in keeping with NKCC1 over activity. BUM fully blocked ongoing epileptic activity. In GBM-Brain cultures, the combo produced stronger effects then independent applications of MEB or BUM. In tumoroids, the combo also efficiently produced strong cell death & morphological changes in some tumors. <i>Conclusion:</i> The combination of BUM & MEB acts complementarily on brain tumors, the former blocking seizures, and the latter producing cell death. Their combination increases their hyperactivity inhibitory actions and cell death. The combo might therefore be used to treat brain tumors combining 2 different mechanisms and targets.

Abstract Background Mebendazole (MBZ) is an anti-helminthic that has shown antitumor activity in mice with gliomas and subsequently in medulloblastoma models. Safety and tolerability have been demonstrated in adults with brain tumors but not explored in children as a monotherapy. We characterized the safety and maximum tolerated dose of oral MBZ in pediatric patients with refractory or progressive brain tumors and assessed progression-free survival (PFS) as a secondary objective. Methods Patients up to 21 years of age with refractory or progressive brain tumors were enrolled at 2 centers in a 3 + 3 design with 3 doses of MBZ (1250, 1875, or 2500 mg/m2/day). MBZ was taken orally 3 times per day and continued until there were signs of toxicity or clinical/radiographic progression. Safety and tolerability were analyzed with descriptive statistics. Results There were 17 patients enrolled between 2017 and 2022 with diffuse intrinsic pontine gliomas, high-grade astrocytomas, diffuse midline gliomas, glioblastoma multiform, ependymoma, and nonspecific gliomas. At all 3 dose levels, MBZ was well-tolerated with no dose-limiting toxicities. 121 adverse events (AE) including 69 AEs possibly/probably related to MBZ occurred—the most common being decreased lymphocyte count (n = 6). Six grade 3 (anorexia, dehydration, hypokalemia, increased GGT, blood bilirubin increased, and aspartate aminotransferase increased) and 1 grade 4 (vomiting) were reported. The mean PFS was 7.6 weeks (range of 2 to 24 weeks). Conclusions MBZ is safe and tolerable in treating refractory or progressive pediatric brain tumors, with doses up to 2500 mg/m2/day. There was limited evidence of single-agent efficacy.

Mebendazole (MBZ) is an anthelmintic drug that was repurposed as an anti-cancer agent. This study aimed at formulating MBZ into stearylamine tailored spanlastics dispersed in nanogel for enhancing MBZ anti-tumor efficacy against skin cancer. MBZ spanlastics were prepared by thin film hydration using 21 × 31 factorial design. The formulation variables were the total amount (mg) of Span 60 and Tween 80 in the formulations and the ratio between Span 60 and Tween 80. Optimal spanlastics formulation was composed of 400mg of Span 60 and Tween 80 in a ratio of 2:1 and showed EE% of 78 ± 2.9% and PS of 284.00 ± 35.36nm. Stearylamine (20mg) was added to the optimized formulation and showed acceptable positive charge (zeta potential = 47.53 ± 1.50mV). It was dispersed in 30% Tetronic®1107 solution to form a nanogel. MBZ nanogel was assessed for their cytotoxic effect on cell proliferation against human malignant melanoma and epidermoid carcinoma cell lines and showed 38.70 ± 1.70% and 48.60 ± 0.50% (respectively) cell proliferation compared to the control group (100%). Finally, its permeation through Wistar rat skin was tested. SA-spanlastics nanogel holds potential as an effective nanocarrier for boosting MBZ anti-cancer efficacy.

Helminth infection is highly prevalent in indigenous chickens reared in semi-scavenging/ scavenging systems in Bangladesh. Here, we estimated the prevalence of gizzard worm infection in indigenous chickens, the detection of the worm-induced pathologies, the development of ex vivo cultural protocol, and anthelmintic efficacy. We randomly collected and examined 390 chickens and isolated worms from the gizzard and proventriculus. The isolated worms were identified as Cheilospirura hamulosa Diesing, 1861. The overall prevalence of C. hamulosa was 33.1% (129 out of 390). Prevalence of the worm was almost similar in both sexes but significantly (p<0.05) higher in adult chickens (44.3%) and in the summer season (47.1%). In heavy infections, C. hamulosa destroyed the muscular layer of the gizzard. The presence of brown necrotic tissues and curd-like caseous materials was detected in the affected gizzards. In severe cases, the horny lining of the gizzard was inflamed, necrotized and marked by multiple holes and brick-red colored spots. Liquefied, fetid materials oozed out from the muscular layer in extensive cases. Histopathological examination showed marked infiltrations of eosinophils. In serum-supplemented M199 and DMEM, adult C. hamulosa survived well and reproduced. Levamisole (LEV) and ivermectin (IVM) efficiently killed the worm. However, albendazole (ABZ), mebendazole (MBZ) and piperazine (PPZ) did not kill the worms. Our results suggest that C. hamulosa is highly prevalent in semi-scavenging chickens in Bangladesh. LEV and IVM can be used to treat and control the infection in chickens.

Drug resistance is the main challenge in treating parasitic diseases, including cystic echinococcosis (CE). Hence, the current study aims to investigate the effect of nanocapsules containing albendazole (ABZ), mebendazole (MBZ), and praziquantel (PZQ) on treating hydatid cysts in mice using these high-potency drugs. A total of 78 female white laboratory mice (BALB/C mice), 8 weeks old and weighing 25 g, were intraperitoneally injected with 1500 live protoscoleces of Echinococcus granulosus. The first group received ABZ nanocapsules, group 2 received MBZ nanocapsules, group 3 received PZQ nanocapsules, group 4 received ABZ + MBZ nanocapsules, group 5 received ABZ + PZQ nanocapsules, and group 6 received MBZ + PZQ nanocapsules. Each group also had a control group, which received the non-nanocapsulated drugs (group 7-12). Group 13 received no treatment and served as the negative control, just receiving phosphate-buffered saline (PBS). A thorough examination of the cysts' physical properties, including size, quantity, and weight, was carried out. According to our results, the polymeric nanocapsules are sphere-like and of different sizes. The total number of cysts in all nanocapsule groups significantly decreased compared to the control group. In the total weight of the cysts, ABZ + MBZ nanocapsules, ABZ + PZQ nanocapsules, and MBZ + PZQ nanocapsules had the least total cyst weight, showing that the use of the medicinal combination had a better effect on the penetration and weight reduction of the cysts. In conclusion, the findings showed that ABZ, MBZ, and PZQ significantly reduced the size, weight, and number of hydatid cysts in the mouse model used in this study.

Improved antiparasitic effects of mebendazole using chitosan and zinc oxide nanocomposites for drug delivery in Trichinella spiralis infected mice during the muscular phase.

Mebendazole induces ZBP-1 mediated PANoptosis of acute myeloid leukemia cells by targeting TUBA1A and exerts antileukemia effect.

Mebendazole (MBZ), a benzimidazole anthelmintic and cytoskeleton-disrupting compound, exhibits antitumor properties; however, its action on ovarian cancer (OC) is not clearly understood. This study evaluates the effect of MBZ on OC cell lines OVCAR3 and OAW42, focusing on cell proliferation, migration, invasion, and cancer stemness. The underlying mechanisms, including cytoskeletal disruption, epithelial-mesenchymal transition (EMT), and signaling pathways, were explored. MBZ inhibited OVCAR3 and OAW42 cell proliferation in a dose- and time-dependent manner. Additionally, MBZ significantly impedes migration, spheroid invasion, colony formation, and stemness. In addition, it reduced actin polymerization and down-regulated CSC markers (e.g., CD24, CD44, EpCAM). Moreover, MBZ suppressed MMP-9 activity and inhibited the EMT marker as judged by decreased N-Cadherin and Vimentin and increased E-Cadherin. Furthermore, MBZ induced G2/M cell cycle arrest by modulating Cyclin B1, CDC25C, and WEE1. Also, it triggered apoptosis by disrupting mitochondrial membrane potential. Mechanistic studies revealed a significant downregulation of Girdin, an Akt modulator, along with reduced p-Akt, p-IKKα/β, and p-NF-κB, indicating MBZ's novel mechanism of action through the Girdin-mediated Akt/IKKα/β/NF-κB signaling axis. Thus, by targeting Girdin, MBZ presents a promising repurposed therapeutic strategy to inhibit cancer cell proliferation and metastasis in ovarian cancer.

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment. However, the underlying mechanism of NPC radioresistance remains poorly understood, and the promising radiosensitizer for NPC radiotherapy is also lacked. Overexpression of USP5 and EphA2 has been linked to various cancers, and both the proteins have attracted considerable attention for the development of new anti-cancer drugs. Here, we report that USP5 interacts with EphA2, and increases EphA2 protein stability and expression by ubiquitin proteasome pathway in the NPC cells. Mebendazole (MBZ), a broad-spectrum anthelmintic drug, transcriptionally inhibits USP5 expression, and then promotes EphA2 ubiquitination degradation in the NPC cells. Functionally, USP5 enhances in vitro and in vivo NPC cell radioresistance via stabilizing EphA2, and MBZ decreases in vitro and in vivo NPC cell radioresistance via targeting USP5/EphA2 axis. Moreover, the levels of USP5 and EphA2 are significantly higher in the radioresistant NPCs than those in the radiosensitive NPCs, and both proteins for predicting patient prognosis are superior to individual protein. These findings suggest that USP5 binds and stabilizes EphA2 by ubiquitin proteasome pathway to promote NPC radioresistance, and MBZ increases NPC radiosensitivity by targeting USP5/EphA2 axis, and is a potential radiosensitizer in NPC and perhaps in other cancers.

H3K27-altered diffuse midline glioma (DMG) is a universally fatal disease with no available therapeutic strategies apart from palliative radiotherapy. Repurposing marketed non-cancer drugs in oncology is emerging as a fast-tracking approach to speed up the development of new treatment options, urgently needed for DMG. Repurposed anthelmintic mebendazole (MBZ) is in the spotlight against brain tumors, because it joins promising anticancer properties with high neuropenetrance, favorable pharmacokinetic and safety profile. Although MBZ is undergoing Phase I/II trials against brain tumors, including DMG, MBZ anticancer properties and the underlying mechanisms of actions have poorly been characterized in DMG preclinical models. We found that MBZ robustly reduced cell viability in six out of seven DMG cell lines with either K27M-mutated or wild-type H3. All IC50 values (range 102 to 958 nM) fell in a clinically attainable range. The antiproliferative MBZ properties were mediated by an arrest of DMG cells in the G2/M phase with a concomitant upregulation of the key cell cycle regulators p21 and p27, whereas p53 upregulation and activation were cell context-dependent. At the same growth-inhibitory concentrations, MBZ triggered apoptotic cell death, as evidenced by higher levels of the apoptotic markers caspase-3 and PARP cleavage. Consistently, Annexin V-Propidium iodide (PI) double staining showed MBZ dose-dependent increase in both stages of apoptosis. Of interest, the combination of MBZ with the first-in-class imipridone ONC201 sinergistically increased the antiproliferative effects in two DMG cell lines as assessed by combination scores with different algorithms, showing additive effects in two others cell lines. Mechanistically, the combination potentiated the proapoptotic activity of either MBZ or ONC201, while not changing the cytokinetic perturbations induced by the single drugs. Finally, one pair of ONC201-sensitive and ONC201-resistant DMG cell lines with acquired resistance showed same responsiveness to MBZ with similar values of IC50 and Emax. In conclusion, MBZ demonstrates high growth-inhibitory/proapoptotic activity, chemosensitization property to ONC201 and the ability to overcome ONC201 resistance in DMG cell cultures, proposing as a new low-toxicity therapeutic for DMG, with a potential to be used in second-line treatment and/or in combination protocols.

Serve as one of common cancer in the mouth, oral tongue squamous cell carcinoma (OTSCC) is a serious problem affecting human oral health. The aim of this study was to evaluate the effects of mebendazole (MBZ) alone and combined with paclitaxel on the proliferation and occurrence of OTSCC and its molecular mechanism. Cell viability, apoptosis, cell cycle distribution, and the expression of PI3K, p-PI3K, AKT, and p-AKT were evaluated by Cell Counting Kit-8 (CCK-8), flow cytometry, and Western blot, respectively. Immunofluorescence was used to assess changes in microtubule morphology of CAL-27 and UM-SCC-1 cells with α-tubulin antibody labeling. The CCK-8 assay revealed a dose-dependent inhibitory effect of both MBZ and paclitaxel on CAL-27 and UM-SCC-1 cells. The apoptosis assay showed significantly elevated levels of apoptosis-specific markers, cleaved caspase-3, and cleaved PARP, in the combined treatment group compared to the control and single-agent groups. The combination of MBZ and paclitaxel showed enhanced inhibition of key PI3K/AKT pathway proteins' phosphorylation and reduced expression of Cyclin B and PCNA compared to the control. The α-tubulin staining area was notably reduced in the combined treatment group relative to the other groups. Both MBZ and paclitaxel treatments inhibited of cell proliferation and microtubule formation by reducing the PI3K/AKT pathway in CAL-27 and UM-SCC-1 cells, with the combination demonstrating synergistic effects. Our study suggests MBZ and paclitaxel as potential agents for the treatment of OTSCC.

The objective is to develop the drug system of mebendazole (MBZ) as an antiparasitic drug via the self-assembly of MBZ with nano chitosan (Cs) and zinc oxide nanoparticles (ZnO NPs). The method of nanocomposite was fabricated by the precipitation method. Sixty male Swiss albino mice (25–30 g) were used, equally divided into six groups; group 1 (G1) included the negative control, and the other five groups (G2, G3, G4, G5, and G6) were infected with 200 Trichinella spiralis (T. spiralis) larvae. G2 refers to the positive control (infected without treatment), G3 is treated with 200 mg/kg/day of MBZ, while G4, G5, and G6 were treated with Cs@MBZ (400 mg/kg/day), Cs-MBZ@ZnO full dose of MBZ, and Cs-MBZ@ZnO half dose of MBZ starting from the 3rd dpi for three successive days for the treatment of the intestinal phase of infection. Results of the adult worm counts in all treated groups showed the highest percent (96.4%) reduction in G5 and G6. Improvement of the intestinal histopathological changes and the lowest intensity of vascular endothelial growth factor (VEGF) expression in the intestinal tissue were observed in groups G5 and G6 compared to the control group. The conclusion of biochemical results showed a significant increase in levels of aspartate transferase (AST), alanine transaminase (ALT), and globulin in the infected control group and a decrease in all treated groups. We recommended using the modified drug MBZ as an alternative drug to MBZ for trichinellid treatment, but the results need to be applied clinically.