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Novel read through agent: ZKN-0013 demonstrates efficacy in APCmin model of familial adenomatous polyposis
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Novel read through agent: ZKN-0013 demonstrates efficacy in APCmin model of familial adenomatous polyposis
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Novel read through agent: ZKN-0013 demonstrates efficacy in APCmin model of familial adenomatous polyposis
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Journal Article
Novel read through agent: ZKN-0013 demonstrates efficacy in APCmin model of familial adenomatous polyposis
2023
Overview
Familial adenomatous polyposis (FAP) is a precancerous, colorectal disease characterized by hundreds to thousands of adenomatous polyps caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Approximately 30% of these mutations are premature termination codons (PTC), resulting in the production of a truncated, dysfunctional APC protein. Consequently, the β-catenin degradation complex fails to form in the cytoplasm, leading to elevated nuclear levels of β-catenin and unregulated β-catenin/wnt-pathway signaling. We present in vitro and in vivo data demonstrating that the novel macrolide, ZKN-0013, promotes read through of premature stop codons, leading to functional restoration of full-length APC protein. Human colorectal carcinoma SW403 and SW1417 cells harboring PTC mutations in the APC gene showed reduced levels of nuclear β-catenin and c-myc upon treatment with ZKN-0013, indicating that the macrolide-mediated read through of premature stop codons produced bioactive APC protein and inhibited the β-catenin/wnt-pathway. In a mouse model of adenomatous polyposis coli, treatment of APCmin mice with ZKN-0013 caused a significant decrease in intestinal polyps, adenomas, and associated anemia, resulting in increased survival. Immunohistochemistry revealed decreased nuclear β-catenin staining in the epithelial cells of the polyps in ZKN-0013-treated APCmin mice, confirming the impact on the β-catenin/wnt-pathway. These results indicate that ZKN-0013 may have therapeutic potential for the treatment of FAP caused by nonsense mutations in the APC gene.Key messages• ZKN-0013 inhibited the growth of human colon carcinoma cells with APC nonsense mutations.• ZKN-0013 promoted read through of premature stop codons in the APC gene.• In APCmin mice, ZKN-0013 treatment reduced intestinal polyps and their progression to adenomas.• ZKN-0013 treatment in APCmin mice resulted in reduced anemia and increased survival.
