Some characteristics of activity of potential chemotherapeutics – benzimidazole derivatives

Błaszczak-Świątkiewicz, Katarzyna; Mikiciuk-Olasik, Elżbieta

doi:10.1016/j.advms.2015.01.004

Cited by 15 publications

(5 citation statements)

References 17 publications

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“…Recent studies reveal that, apart from executing apoptosis, chemotherapy drug–activated caspase-3 can also induce secondary necrosis/pyroptosis in cancer cells. Benzimidazole derivatives have multiple biological activities, such as anti-parasitic, anti-viral, and anti-cancer, especially on various cancer cells with high cytotoxicity ( Barot et al, 2013 ; Błaszczak-Świątkiewicz and Mikiciuk-Olasik, 2015 ). Trichlorobendazole is a benzimidazole compound, but it has remained unclear whether triclabendazole has a certain pharmacological effect on cancer therapy and its underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

Liang

Liu

et al. 2021

Front. Pharmacol.

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Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME–N-terminal fragment cleavage and pyroptosis were reduced by caspase-3–specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

Liang

Liu

et al. 2021

Front. Pharmacol.

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“…The cytotoxicity of 240 and 241 was determined by WST‐1 test on human lung arenocarcinoma A549 cell line and they were reported to show good correlation of cytotoxicity . Active antitubercular compound 242 exhibited very low toxicity against a normal cell line .…”

Section: Pharmacokinetics/pharmacodynamics Of Benzimdazolementioning

confidence: 99%

Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine

Ajani

Aderohunmu

Ikpo

et al. 2016

Archiv der Pharmazie

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Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research. They are structural isosteres of naturally occurring nucleotides, which allows them to interact with the biopolymers of living systems. Hence, there is a need to couple the latest information with the earlier documentations to understand the current status of the benzimidazole nucleus in medicinal chemistry research. This present work unveils the benzimidazole core as a multifunctional nucleus that serves as a resourceful tool of information for synthetic modifications of old existing candidates in order to tackle drug resistance bottlenecks in therapeutic medicine. This manuscript deals with the recent advances in the synthesis of benzimidazole derivatives, the widespread biological activities as well as pharmacokinetic reports. These present them as a toolbox for fighting infectious diseases and also make them excellent candidates for future drug design.

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“…The most promising attribute of these chemical components is their potential to cause DNA damage by generating cytotoxic agents [ 8 ]. The benzimidazole derivatives have been significant as potential agents for damaging the DNA of cancer cells and have been intensively investigated to explore their anticancer properties [ 9 ]. In fuberidazole, the benzimidazole nucleus is categorized as a potential pharmacophore in medicinal chemistry, and its extraction from natural sources, such as cyanocobalamin, has further extended its pharmaceutical applications [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring novel fluorine-rich fuberidazole derivatives as hypoxic cancer inhibitors: Design, synthesis, pharmacokinetics, molecular docking, and DFT evaluations

et al. 2023

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Sixteen fuberidazole derivatives as potential new anticancer bioreductive prodrugs were prepared and characterized. The in vitro anticancer potential was examined to explore their cytotoxic properties by employing apoptosis, DNA damage, and proliferation tests on chosen hypoxic cancer cells. Eight substances (Compound 5a, 5c, 5d, 5e, 5g, 5h, 5i, and 5m) showed promising cytotoxicity values compared to the standard control. The potential of compounds was also examined through in silico studies (against human serum albumin), including chem-informatics, to understand the structure-activity relationship (SAR), pharmacochemical strength, and the mode of interactions responsible for their action. The DFT calculations revealed that only the 5b compound showed the lowest ΔET (2.29 eV) while 5i showed relatively highest βtot (69.89 x 10–31 esu), highest αave (3.18 x 10–23 esu), and dipole moment (6.49 Debye). This study presents a novel class of fuberidazole derivatives with selectivity toward hypoxic cancer cells.

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Some characteristics of activity of potential chemotherapeutics – benzimidazole derivatives

Cited by 15 publications

References 17 publications

Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine

Exploring novel fluorine-rich fuberidazole derivatives as hypoxic cancer inhibitors: Design, synthesis, pharmacokinetics, molecular docking, and DFT evaluations

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