Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells

Park, Deok-Bae; Lee, Jung‐Hee; Yoon, Sang‐Pil

doi:10.4196/kjpp.2022.26.5.377

Cited by 11 publications

(7 citation statements)

References 49 publications

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“…This mechanism is similar to that of anticancer drugs targeting microtubules in cancer cells, such as paclitaxel and vinca alkaloids such as vincristine and vinblastine [6]. Studies have shown that FBZ exerts anticancer effects by inhibiting reactive oxygen species (ROS) production in cancer cells [7,8], arresting the G2/M phase [9,10], and impairing glucose metabolism [11]. Furthermore, the interest in FBZ has been fueled by a report of anticancer effects of FBZ in an American patient [12].…”

Section: Introductionmentioning

confidence: 88%

Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma

Jung,

Kim,

Joo

2023

CIMB

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Fenbendazole (FBZ) has been safely used as an antiparasitic agent in animals for decades, and the anticancer effects of FBZ have been studied through various mechanisms. However, there is a lack of in vivo studies that include lymphoma. Therefore, this study examined the effects of FBZ on EL-4 cells and a mouse T lymphoma model. FBZ induced G2/M phase arrest in EL-4 cells, resulting in cell death and decreased metabolic activity. However, FBZ had no anticancer effects on an EL-4 mouse lymphoma model in vivo, as evident by rapid weight loss and tumor growth comparable to the control. The FBZ-treated EL-4 cells expressed higher levels of PD-L1 and CD86, which are associated with T cell immunity in the tumor microenvironment (TME), than the controls. Furthermore, the hematoxylin and eosin staining of the FBZ-treated tumor tissues showed a starry sky pattern, which is seen in actively proliferating cancer tissues, and an immunohistochemical analysis revealed a high percentage of immunosuppressive M2 macrophages. These changes in the immune activity in the TME contradict the results of the in vitro experiments, and further studies are needed to determine the detailed mechanisms by which FBZ induces these responses.

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Section: Introductionmentioning

confidence: 88%

Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma

Jung,

Kim,

Joo

2023

CIMB

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“…Infrared (IR) spectra were measured on a PerkinElmer Spectrum 400 Fourier transform (FT)-IR and FT-NIR Spectrometer of the 4000−400 cm −1 transmission range; frequencies (ν) are expressed in inverse centimeters. Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Model VNMRS ( 1 H, 400 MHz; 13 C, 100 MHz) at UNAM's NMR facilities. Chemical shifts (δ) are expressed in parts per million relative to internal tetramethylsilane; coupling constants (J) are expressed in hertz (Hz).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…Carbendazim [ CBZ , methyl (1 H -benzimidazol-2-yl)carbamate] derivatives are a group of antiparasitic drugs used for the treatment of helminthic infections . The broad-spectrum anthelmintic activity and moderate toxicity of these compounds have led to their widespread prescription in human and veterinary medicine. − Albendazole ( ABZ ), fenbendazole ( FBZ ), and mebendazole ( MBZ ) (Figure A) are some of the most widely used CBZ derivatives of which recent works have also demonstrated their potential use as anticancer agents. − These compounds induce G2/M cell cycle arrest and apoptosis in different human cancer cell lines by inhibiting the tubulin polymerization during cell division. − Although several studies have pinpointed these compounds as candidates for clinical repositioning, further structural modifications are required to improve their potency and safety. − …”

Section: Introductionmentioning

confidence: 99%

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations

Cano-González,

Espinosa-Mendoza,

Matadamas-Martínez

et al. 2023

J. Chem. Inf. Model.

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Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/β-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.

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“…Fenbendazole and oxibendazole are anti-parasitic drugs that have been shown to act through multiple mechanisms including microtubule destabilization, G2/M arrest, and apoptosis (36,37). Both drugs produced complex CP profiles modifying all the compartments in various ways, most notably higher SYTO14 intensity in the nucleolus and reduced MitoTracker signal in mitochondria.…”

Section: Comparing Space With Cellprofiler Using Jump Consortium Refe...mentioning

confidence: 99%

SPACe (Swift Phenotypic Analysis of Cells): an open-source, single cell analysis of Cell Painting data

Stossi,

Singh,

Marini

et al. 2024

Preprint

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Phenotypic profiling by high throughput microscopy has become one of the leading tools for screening large sets of perturbations in cellular models. Of the numerous methods used over the years, the flexible and economical Cell Painting (CP) assay has been central in the field, allowing for large screening campaigns leading to a vast number of data-rich images. Currently, to analyze data of this scale, available open-source software (i.e., CellProfiler) requires computational resources that are not available to most laboratories worldwide. In addition, the image-embedded cell-to-cell variation of responses within a population, while collected and analyzed, is usually averaged and unused. Here we introduce SPACe (SwiftPhenotypicAnalysis ofCells), an open source, Python-based platform for the analysis of single cell image-based morphological profiles produced by CP experiments. SPACe can process a typical dataset approximately ten times faster than CellProfiler on common desktop computers without loss in mechanism of action (MOA) recognition accuracy. It also computes directional distribution-based distances (Earth Mover’s Distance – EMD) of morphological features for quality control and hit calling. We highlight several advantages of SPACe analysis on CP assays, including reproducibility across multiple biological replicates, easy applicability to multiple (∼20) cell lines, sensitivity to variable cell-to-cell responses, and biological interpretability to explain image-based features. We ultimately illustrate the advantages of SPACe in a screening campaign of cell metabolism small molecule inhibitors which we performed in seven cell lines to highlight the importance of testing perturbations across models.

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Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells

Cited by 11 publications

References 49 publications

Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma

Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations

SPACe (Swift Phenotypic Analysis of Cells): an open-source, single cell analysis of Cell Painting data

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