Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness

Joe, Natalie; Godet, Inês; Milki, Nubaira; Ain, Noor Ul; Oza, Harsh H.; Riggins, Gregory J.; Gilkes, Daniele M.

doi:10.1186/s13058-022-01591-3

Cited by 10 publications

(11 citation statements)

References 45 publications

(67 reference statements)

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“…Nair et al [7] have previously demonstrated that cytoskeletal drugs (such as tubulin binder MBZ) are more effective against cancers with high predicted migration capacity. Consistently, MBZ has been shown to slow down tumor growth and/or prevent metastatic spread of TNBC in animal models using multiple cell lines [14,38,39]. To our knowledge, no studies were comparing MBZ effect on tumor growth and/or survival for distinct breast cancer isotypes.…”

Section: Mbz Reduced the Migration Of Tnbc Cell Lines Mda-mb-231 And ...mentioning

confidence: 84%

“…MBZ was successfully tested in multiple preclinical tumor models, including glioma [11,13,45] and TNBC [14,38]. Several active and/or recruiting clinical trials investigating the anticancer effect of MBZ, alone or in combination with other drugs, are currently registered at clinicaltrials.gov [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…In the study of CNS tumors, drug repurposing efforts have highlighted the benzimidazole anti-helminthic class, including mebendazole (MBZ), albendazole (ABZ), and fenbendazole (FBZ) [10,11]. This drug class is widely used in the control of human and animal parasitic infections by disrupting microtubule function, and via this mechanism, it has demonstrated e cacy against paclitaxel and doxorubicinresistant cancer cells [12], glioma and metastatic TNBC [10,13,14]. MBZ and ABZ have been used against CNS pathologies (e.g., neurocysticercosis and cerebral echinococcosis) [15][16][17], indicating su cient CNS bioavailability.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease

Rodrigues,

Chernikova,

Wang

et al. 2024

Preprint

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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. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo 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.

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Section: Mbz Reduced the Migration Of Tnbc Cell Lines Mda-mb-231 And ...mentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease

Rodrigues,

Chernikova,

Wang

et al. 2024

Preprint

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“…Breast cancer (BC) is the most common tumor in women (Joe et al, 2022). Among them, triple-negative breast cancer (TNBC) is the most invasive subtype of BC, featured by the lack of estrogen and progesterone receptors, and the poor or lack of expression of human epidermal growth factor-2 (HER-2) (Sixto-Lopez, Ordaz-Pichardo, Gomez-Vidal, Rosales-Hernandez, & Correa-Basurto, 2023; .…”

Section: Discussionmentioning

confidence: 99%

Establishment and verification of a nomogram to predict risk and prognostic factors of triple-negative breast cancer with organ metastasis based on the SEER cohort study

Niu

Chen

et al. 2023

Preprint

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Background:This study aims to identify the risk and prognostic factors of TNBC patients with organ metastasis, furthermore, establish and validate a nomogram to forecast the overall survival (OS). Methods:The Surveillance, Epidemiology, and End Results (SEER) database was used to collect the clinicopathological data of TNBC patients from 2010 to 2020. All the TNBC patients were divided into two groups: no organ metastasis cohort (n = 32154) and organ metastasis cohort (n = 1199) based on the presence or absence of organ metastasis, including liver, lung, bone, and brain). TNBC patients with organ metastasis were further randomly assigned into a training cohort and testing cohort in a 7:3 ratio. Univariate and multivariate Cox regression analyses were used to identify the independent prognostic factors. A nomogram was developed to predict the OS for TNBC patients with organ metastasis. The calibration curve, receiver operating characteristic (ROC) area under the curve (AUC), and the decision curve analysis (DCA) were used to estimate the accuracy and clinical effectiveness of the nomogram. Results: The median OS after organ metastasis was 12 months and 62 months in the group without organ metastasis. The 2-year survival rate in the liver metastasis cohort was 14.88%, the bone metastasis cohort was 22.17%, the lung metastasis cohort was 25.17% and the brain metastasis cohort was 12.08%. Multivariate Cox regression analysis revealed that age, T stage, surgery, and chemotherapy were independent factors affecting prognosis in the group with organ metastasis. The nomogram was established by the aforementioned variables. Conclusions:TNBC patients with organ metastasis had a worse prognosis. Age, T stage, surgery, and chemotherapy were independent prognostic factors of TNBC patients with organ metastasis. The nomogram was recommended for TNBC patients with organ metastasis and helped to make personalized clinical treatment plans.

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“…Additionally, it has proven effective in reducing tumor growth and lung and liver metastasis. Furthermore, MBZ can diminish CSC characteristics, attributed to its ability to target the expression of β4 integrin [59]. Additionally, MBZ reduced the hypoxia response in BC cells and a mouse model of BC by targeting both HIF-1α-and HIF-1β-mediated transcription [60].…”

Section: Sensitization Of Bc Cells With Anthelmintic Drugsmentioning

confidence: 99%

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing

Malla,

Viswanathan,

Makena

et al. 2024

Cancers

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Cancer persists as a global challenge necessitating continual innovation in treatment strategies. Despite significant advancements in comprehending the disease, cancer remains a leading cause of mortality worldwide, exerting substantial economic burdens on healthcare systems and societies. The emergence of drug resistance further complicates therapeutic efficacy, underscoring the urgent need for alternative approaches. Drug repurposing, characterized by the utilization of existing drugs for novel clinical applications, emerges as a promising avenue for addressing these challenges. Repurposed drugs, comprising FDA-approved (in other disease indications), generic, off-patent, and failed medications, offer distinct advantages including established safety profiles, cost-effectiveness, and expedited development timelines compared to novel drug discovery processes. Various methodologies, such as knowledge-based analyses, drug-centric strategies, and computational approaches, play pivotal roles in identifying potential candidates for repurposing. However, despite the promise of repurposed drugs, drug repositioning confronts formidable obstacles. Patenting issues, financial constraints associated with conducting extensive clinical trials, and the necessity for combination therapies to overcome the limitations of monotherapy pose significant challenges. This review provides an in-depth exploration of drug repurposing, covering a diverse array of approaches including experimental, re-engineering protein, nanotechnology, and computational methods. Each of these avenues presents distinct opportunities and obstacles in the pursuit of identifying novel clinical uses for established drugs. By examining the multifaceted landscape of drug repurposing, this review aims to offer comprehensive insights into its potential to transform cancer therapeutics.

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Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness

Cited by 10 publications

References 45 publications

Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease

Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease

Establishment and verification of a nomogram to predict risk and prognostic factors of triple-negative breast cancer with organ metastasis based on the SEER cohort study

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing

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