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International Journal of Molecular... Jan 2023Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical... (Review)
Review
Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood-brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention to MBZ repurposing has recently increased because of its potential therapeutic versatility and significant clinical implications, such as reducing medical care costs and optimizing existing therapies. Using new treatments is essential, particularly when current therapeutics for patients with brain cancer fail.
Topics: Male; Animals; Mebendazole; Antiparasitic Agents; Cell Line, Tumor; Hedgehog Proteins; Antineoplastic Agents; Brain Neoplasms; Head and Neck Neoplasms; Anti-Infective Agents; Glioma
PubMed: 36674870
DOI: 10.3390/ijms24021334 -
Annals of Internal Medicine Oct 1979The broad-spectrum of activity and safety of mebendazole remain, after 5 years of clinical experience, unique features of this anthelmintic. Through microtubular...
The broad-spectrum of activity and safety of mebendazole remain, after 5 years of clinical experience, unique features of this anthelmintic. Through microtubular destruction, mebendazole kills helminths by inhibiting glucose uptake into susceptible parasites. The drug's poor absorption does not appear to affect clinical efficacy except, perhaps, in the treatment of systemic helminth infections. Mebendazole is generally considered the drug of choice for trichuriasis and has therapeutic advantages over other anthelmintics in the treatment of enterobiasis and hookworm infections. Although mebendazole is an effective agent against ascariasis, there are preferable alternatives. Among its nonapproved uses, mebendazole shows great promise in the treatment of capillariasis and hydatid disease. Further investigation is needed to establish its role in the treatment of taeniasis, Hymenolepsis nana, strongyloidiasis, trichinosis, and Dipetalonema perstans. Undoubtedly, mebendazole will find its greatest value in the treatment of patients with multiple helminth infections.
Topics: Ascariasis; Benzimidazoles; Cestode Infections; Child; Child, Preschool; Helminthiasis; Hookworm Infections; Humans; Mebendazole; Nematode Infections; Oxyuriasis; Trichuriasis
PubMed: 484964
DOI: 10.7326/0003-4819-91-4-582 -
International Journal of Molecular... Dec 2022Breast cancer is the most commonly diagnosed cancer worldwide and ranks first in terms of both prevalence and cancer-related mortality in women. In this study, we aimed...
Mebendazole Increases Anticancer Activity of Radiotherapy in Radiotherapy-Resistant Triple-Negative Breast Cancer Cells by Enhancing Natural Killer Cell-Mediated Cytotoxicity.
Breast cancer is the most commonly diagnosed cancer worldwide and ranks first in terms of both prevalence and cancer-related mortality in women. In this study, we aimed to evaluate the anticancer effect of mebendazole (MBZ) and radiotherapy (RT) concomitant use in triple-negative breast cancer (TNBC) cells and elucidate the underlying mechanisms of action. Breast cancer mouse models and several types of breast cancer cells, including TNBC-derived RT-resistant (RT-R) MDA-MB-231 cells, were treated with MBZ and/or RT. In mice, changes in body weight, renal and liver toxicity, tumor volume, and number of lung metastases were determined. In cells, cell viability, colony formation, scratch wound healing, Matrigel invasion, and protein expression using western blotting were determined. Our findings showed that MBZ and RT combined treatment increased the anticancer effect of RT without additional toxicity. In addition, we noted that cyclin B1, PH2AX, and natural killer (NK) cell-mediated cytotoxicity increased following MBZ + RT treatment compared to unaided RT. Our results suggest that MBZ + RT have an enhanced anticancer effect in TNBC which acquires radiation resistance through blocking cell cycle progression, initiating DNA double-strand breaks, and promoting NK cell-mediated cytotoxicity.
Topics: Humans; Female; Mice; Animals; Mebendazole; Cell Line, Tumor; Triple Negative Breast Neoplasms; Apoptosis; Killer Cells, Natural; Cell Proliferation
PubMed: 36555137
DOI: 10.3390/ijms232415493 -
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 -
Transactions of the Royal Society of... May 2009Mebendazole, a benzimidazole carbamate compound, is currently in use for human medical practice against soil-transmitted helminthiasis (STH) and enterobiasis. However,... (Review)
Review
Mebendazole, a benzimidazole carbamate compound, is currently in use for human medical practice against soil-transmitted helminthiasis (STH) and enterobiasis. However, it has been demonstrated that its spectrum of activity is broad and goes beyond those infections. Several studies provide evidence that this drug, taken at higher doses than used for STH and enterobiasis, could be sufficiently effective on some protozoa, nematodes and cestodes.
Topics: Adolescent; Animals; Antiparasitic Agents; Child; Child, Preschool; Developing Countries; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Giardiasis; Helminthiasis; Humans; Malaria; Male; Mebendazole; Treatment Outcome; Trichomonas Vaginitis
PubMed: 19195670
DOI: 10.1016/j.trstmh.2008.11.029 -
The Medical Journal of Australia Oct 1976
Topics: Benzimidazoles; Drug Tolerance; Echinococcosis; Humans; Mebendazole
PubMed: 994984
DOI: No ID Found -
Annals of Internal Medicine Mar 1984
Topics: Adult; Benzimidazoles; Female; Humans; Larva Migrans; Mebendazole
PubMed: 6696379
DOI: 10.7326/0003-4819-100-3-463_3 -
Breast Cancer Research : BCR Dec 2022Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack...
Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes. Current treatments for patients with TNBC consist of cytotoxic chemotherapies, surgery, radiation, and in some instances PARP inhibitors and immunotherapy. To advance current therapeutics, we repurposed mebendazole (MBZ), an orally available FDA-approved anthelmintic that has shown preclinical efficacy for cancers. MBZ has low toxicity in humans and efficacy in multiple cancer models including breast cancer, glioblastoma multiforme, medulloblastoma, colon cancer, pancreatic and thyroid cancer. MBZ was well-tolerated in a phase I clinical trial of adults recently diagnosed with glioma. We determined that the half-maximal inhibitory concentration (IC) of MBZ in four breast cancer cell lines is well within the range reported for other types of cancer. MBZ reduced TNBC cell proliferation, induced apoptosis, and caused G2/M cell cycle arrest. MBZ reduced the size of primary tumors and prevented lung and liver metastases. In addition, we uncovered a novel mechanism of action for MBZ. We found that MBZ reduces integrin β4 (ITGβ4) expression and cancer stem cell properties. ITGβ4 has previously been implicated in promoting "cancer stemness," which may contribute to the efficacy of MBZ. Collectively, our results contribute to a growing body of evidence suggesting that MBZ should be considered as a therapeutic to slow tumor progression and prevent metastasis.
Topics: Humans; Female; Mebendazole; Integrin beta4; Triple Negative Breast Neoplasms; Cell Line, Tumor
PubMed: 36578038
DOI: 10.1186/s13058-022-01591-3 -
The Medical Journal of Australia Aug 1976
Topics: Animals; Benzimidazoles; Echinococcosis; Humans; Mebendazole; Rabbits
PubMed: 979856
DOI: No ID Found -
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