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Immune Network Aug 2020The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion,... (Review)
Review
The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion, metastasis, and survival. Benzimidazole anthelmintics have broad-spectrum action to remove parasites both in human and veterinary medicine. In addition to being antiparasitic agents, benzimidazole anthelmintics are known to exert anticancer activities, such as the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, anti-angiogenesis, and blockage of glucose transport. These antitumorigenic effects even extend to cancer cells resistant to approved therapies and when in combination with conventional therapeutics, enhance anticancer efficacy and hold promise as adjuvants. Above all, these anthelmintics may offer a broad, safe spectrum to treat cancer, as demonstrated by their long history of use as antiparasitic agents. The present review summarizes central literature regarding the anticancer effects of benzimidazole anthelmintics, including albendazole, parbendazole, fenbendazole, mebendazole, oxibendazole, oxfendazole, ricobendazole, and flubendazole in cancer cell lines, animal tumor models, and clinical trials. This review provides valuable information on how to improve the quality of life in patients with cancers by increasing the treatment options and decreasing side effects from conventional therapy.
PubMed: 32895616
DOI: 10.4110/in.2020.20.e29 -
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 -
Cancer Letters Dec 2021While flubendazole has been used as a macrofilaricide in humans and animals for some 40 years, work in vitro and in preclinical models over the last decade has suggested... (Review)
Review
While flubendazole has been used as a macrofilaricide in humans and animals for some 40 years, work in vitro and in preclinical models over the last decade has suggested its potential use as an anticancer agent. This article reviews recent studies in a range of tumor types indicating novel functions for flubendazole in its control of processes associated with tumor growth, spread and renewal including ferroptosis, autophagy, cancer stem-like cell killing and suppression of intratumoral myeloid-derived suppressor cell accumulation and programmed cell death protein 1. Flubendazole's potential use in clinical oncology will require further understanding of its mechanistic roles, range of inhibition of cancer types, capacity for adjunctive therapy and possible reformulation for enhanced solubility, bioavailability and potency.
Topics: Antinematodal Agents; Cell Proliferation; Drug Repositioning; Ferroptosis; Humans; Mebendazole; Neoplasms; Neoplastic Stem Cells; Programmed Cell Death 1 Receptor
PubMed: 34520820
DOI: 10.1016/j.canlet.2021.09.013 -
Nanomedicine (London, England) 2024To investigate the therapeutic potential of mebendazole (MBZ)-loaded nanostructured lipid carriers (NLCs). NLC-MBZ was prepared and characterized to evaluate the and...
To investigate the therapeutic potential of mebendazole (MBZ)-loaded nanostructured lipid carriers (NLCs). NLC-MBZ was prepared and characterized to evaluate the and anticancer effects and the inhibitory effect on RanGTP and its potential as an antimetastatic treatment . NLC-MBZ exhibited a size and charge of 155 ± 20 nm and -27 ± 0.5 mV, respectively, with 90.7% encapsulation. Free MBZ and NLC-MBZ had a 50% inhibitory concentration of 610 and 305 nM, respectively, against MDA-MB-231 cell lines. NLC-MBZ decreased tumor size, suppressed tumor lung metastases, and lowered the expression of , , and while boosting the proteins. NLC-MBZ displayed antiangiogenic potential and resulted in a reduced rate of lung metastasis .
Topics: Mebendazole; Humans; Animals; Breast Neoplasms; Female; Cell Line, Tumor; Mice; Lung Neoplasms; Drug Carriers; Lipids; Mice, Inbred BALB C; Antineoplastic Agents; Mice, Nude
PubMed: 38661720
DOI: 10.2217/nnm-2023-0351 -
Parasitology Sep 2019Recently, we introduced an epoxy group to mebendazole by a reaction with epichlorohydrin and obtained two isoforms, mebendazole C1 (M-C1) and mebendazole C2 (M-C2). The...
Recently, we introduced an epoxy group to mebendazole by a reaction with epichlorohydrin and obtained two isoforms, mebendazole C1 (M-C1) and mebendazole C2 (M-C2). The in vitro effects of mebendazole derivatives at different concentrations on Echinococcus multilocularis protoscoleces and metacestodes as well as cytotoxicity in rat hepatoma (RH) cells were examined. The results demonstrated that the solubility of the two derivatives was greatly improved compared to mebendazole. The mortality of protoscoleces in vitro reached to 70-80% after 7 days of exposure to mebendazole or M-C2, and M-C2 showed higher parasiticidal effects than mebendazole (P > 0.05). The parasiticidal effect of M-C1 was low, even at a concentration of 30 µm. The percentage of damaged metacestodes that were treated with mebendazole and M-C2 in vitro at different concentrations were similar, and M-C1 exhibited insignificant effects on metacestodes. Significant morphological changes on protoscoleces and metacestodes were observed after treatment with mebendazole and M-C2. In addition, the introduction of an epoxy group to mebendazole also reduced its cytotoxicity in RH cells. Our results demonstrate that the introduction of an epoxy group not only improved the solubility of mebendazole, but also increased its parasiticidal effects on E. multilocularis and reduced its cytotoxicity in RH cells.
Topics: Animals; Antinematodal Agents; Cell Line; Cell Survival; Echinococcus multilocularis; Hepatocytes; Mebendazole; Parasitic Sensitivity Tests; Rats; Solubility; Survival Analysis
PubMed: 31057131
DOI: 10.1017/S0031182019000386 -
Chemical Communications (Cambridge,... Feb 2022This study presents the activity of a series of 1,8-naphthalimide-carborane/metallacarborane conjugates against sp. The carborane conjugates were the least active....
This study presents the activity of a series of 1,8-naphthalimide-carborane/metallacarborane conjugates against sp. The carborane conjugates were the least active. Selected conjugates with cobaltacarborane (5 and 6) showed high activity. Their lethal concentration (LC) values are substantially lower than that of the drug mebendazole.
PubMed: 35098961
DOI: 10.1039/d1cc07075d -
Parasites & Vectors Jul 2021Alveolar echinococcosis (AE) is a fatal zoonosis caused by the larvae of Echinococcus multilocularis. However, current chemotherapy treatment options are based on...
BACKGROUND
Alveolar echinococcosis (AE) is a fatal zoonosis caused by the larvae of Echinococcus multilocularis. However, current chemotherapy treatment options are based on benzimidazoles [albendazole (ABZ) and mebendazole], which have limited efficacy. Therefore, novel drugs are necessary for the treatment of this disease.
METHODS
The anthelmintic effects of crocin were tested on E. multilocularis metacestodes, germinal cells and protoscoleces in vitro. Human foreskin fibroblasts (HFFs) and Reuber rat hepatoma (RH) cells were used to assess cytotoxicity. The in vivo efficacy of crocin was investigated in mice following secondary infection with E. multilocularis. Furthermore, collagen deposition and degradation in host tissues around the metacestodes were evaluated.
RESULTS
In vitro, crocin had a median effective concentration of 11.36 μM against cultured E. multilocularis metacestodes, while it reduced germinal cell viability at a median inhibitory concentration of 10.05 μM. Crocin was less toxic to HFFs and RH mammalian cell lines than to metacestodes. Transmission electron microscopy revealed that crocin treatment resulted in structural damage in the germinal layer. In addition, 60.33 ± 3.06% of protoscoleces were killed by treatment with 10 μM crocin for 7 days, indicating that crocin has a parasiticidal effect. In vivo, the metacestode weight was significantly reduced after the administration of crocin at 50 mg/kg and 100 mg/kg (55.1 and 68.1%, respectively). Metacestode pathology showed structural disruption of the germinal and laminated layers after crocin treatment. The crocin- and ABZ-treated groups presented significant increases in the levels of interleukin (IL)-2 and IL-4. Furthermore, crocin inhibited the expression of matrix metalloproteinases (MMPs) (MMP2 and MMP9) and promoted collagen deposition in the metacestode.
CONCLUSIONS
Crocin was demonstrated to exert parasiticidal activity against E. multilocularis in vitro and in vivo, and can be developed as a novel drug for the treatment of AE.
Topics: Animals; Anthelmintics; Carotenoids; Cell Line; Disease Models, Animal; Echinococcosis; Echinococcus multilocularis; Fibroblasts; Foreskin; Humans; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Specific Pathogen-Free Organisms
PubMed: 34256821
DOI: 10.1186/s13071-021-04866-4 -
Frontiers in Bioscience (Landmark... Apr 2023Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most... (Review)
Review
Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most malignant histologies, and intense preclinical and clinical research is needed to develop more effective therapeutic interventions against these tumors, most of which meet the FDA definition for orphan diseases. Increased attention is being paid to the repositioning of already-approved drugs for new anticancer indications as a fast-tracking strategy for identifying new and more effective therapies. Two pediatric CNS tumors, posterior fossa ependymoma (EPN-PF) type A and diffuse midline glioma (DMG) H3K27-altered, share loss of H3K27 trimethylation as a common epigenetic hallmark and display early onset and poor prognosis. These features suggest a potentially common druggable vulnerability. Successful treatment of these CNS tumors raises several challenges due to the location of tumors, chemoresistance, drug blood-brain barrier penetration, and the likelihood of adverse side effects. Recently, increasing evidence demonstrates intense interactions between tumor cell subpopulations and supportive tumor microenvironments (TMEs) including nerve, metabolic, and inflammatory TMEs. These findings suggest the use of drugs, and/or multi-drug combinations, that attack both tumor cells and the TME simultaneously. In this work, we present an overview of the existing evidence concerning the most preclinically validated noncancer drugs with antineoplastic activity. These drugs belong to four pharmacotherapeutic classes: antiparasitic, neuroactive, metabolic, and anti-inflammatory. Preclinical evidence and undergoing clinical trials in patients with brain tumors, with special emphasis on pediatric EPN-PF and DMG, are summarized and critically discussed.
Topics: Humans; Child; Drug Repositioning; Ependymoma; Brain Neoplasms; Central Nervous System Neoplasms; Blood-Brain Barrier; Tumor Microenvironment
PubMed: 37114548
DOI: 10.31083/j.fbl2804077 -
Toxicology and Applied Pharmacology Sep 2023Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the...
Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.
Topics: Humans; Mebendazole; Stomach Neoplasms; Cell Line, Tumor; Molecular Docking Simulation; Antineoplastic Agents; Glucose
PubMed: 37473966
DOI: 10.1016/j.taap.2023.116630 -
Journal of Chemical Information and... Aug 2022Recent experimental evidence suggests that mebendazole, a popular antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibits acute myeloid leukemia cell...
Recent experimental evidence suggests that mebendazole, a popular antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibits acute myeloid leukemia cell growth. In this study we use quantum mechanics (QM), molecular similarity, and molecular dynamics (MD) calculations to predict possible binding poses of mebendazole to the adenosine triphosphate (ATP) binding site of Hsp90. Extensive conformational searches and minimization of the five mebendazole tautomers using the MP2/aug-cc-pVTZ theory level resulted in 152 minima. Mebendazole-Hsp90 complex models were subsequently created using the QM optimized conformations and protein coordinates obtained from experimental crystal structures that were chosen through similarity calculations. Nine different poses were identified from a total of 600 ns of explicit solvent, all-atom MD simulations using two different force fields. All simulations support the hypothesis that mebendazole is able to bind to the ATP binding site of Hsp90.
Topics: Adenosine Triphosphate; HSP90 Heat-Shock Proteins; Humans; Mebendazole; Molecular Conformation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation
PubMed: 35867562
DOI: 10.1021/acs.jcim.2c00290