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Int J Mol Sci ; 22(10)2021 May 14.
Article in English | MEDLINE | ID: mdl-34069111

ABSTRACT

In colon cancer, wingless (Wnt)/ß-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/ß-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and ß-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/ß-catenin/glycogen synthase kinase-3ß (GSK-3ß) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/ß-catenin/GSK-3ß signaling.


Subject(s)
Antiparasitic Agents/pharmacology , Colonic Neoplasms/drug therapy , Nitro Compounds/pharmacology , Thiazoles/pharmacology , Wnt Signaling Pathway/drug effects , Animals , Antiparasitic Agents/chemistry , Apoptosis/drug effects , Apoptosis/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , Glycogen Synthase Kinase 3 beta/metabolism , HCT116 Cells , Humans , Male , Mice , Molecular Docking Simulation , Nitro Compounds/chemistry , Proliferating Cell Nuclear Antigen/immunology , Proliferating Cell Nuclear Antigen/metabolism , Thiazoles/chemistry , Xenograft Model Antitumor Assays , beta Catenin/metabolism
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