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Lee KJ , Chang WL , Chen X , Valiyaveettil J , Ramirez-Alcantara V , Gavin E , Musiyenko A , Madeira da Silva L , Annamdevula NS , Leavesley SJ , Ward A , Mattox TE , Lindsey AS , Andrews J , Zhu B , Wood C , Neese A , Nguyen A , Berry K , Maxuitenko YY , Moyer MP , Nurmemmedov E , Gorman G , Coward L , Zhou G , Keeton AB , Cooper HS , Clapper ML , Piazza GA
Suppression of colon tumorigenesis in mutant Apc mice by a novel PDE10 inhibitor that reduces oncogenic β-catenin
Cancer Prev Res (Phila). 2021 Sep 28
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Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-cyclooxygenase inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10. The concentration range by which ADT 061 inhibited colon cancer cell growth was identical to concentrations that inhibit recombinant PDE10. ADT 061 inhibited PDE10 by a competitive mechanism and did not affect the activity of other PDE isozymes at concentrations that inhibit colon cancer cell growth. Treatment of colon cancer cells with ADT 061 activated cGMP/PKG signaling, induced phosphorylation of oncogenic β-catenin, inhibited Wnt-induced nuclear translocation of β-catenin, and suppressed TCF/LEF transcription at concentrations that inhibit cancer cell growth. Oral administration of ADT 061 resulted in high concentrations in the colon mucosa and significantly suppressed the formation of colon adenomas in the Apc+/min-FCCC mouse model of colorectal cancer (CRC) without discernable toxicity. These results support the development of ADT 061 for the treatment or prevention of adenomas in individuals at risk of developing CRC.
1940-6215 Lee, Kevin J Orcid: 0000-0003-3233-5537 Chang, Wen-Chi L Chen, Xi Valiyaveettil, Jacob Ramirez-Alcantara, Veronica Gavin, Elaine Musiyenko, Alla Madeira da Silva, Luciana Orcid: 0000-0002-7805-4039 Annamdevula, Naga S Orcid: 0000-0003-3219-413x Leavesley, Silas J Orcid: 0000-0002-2684-9534 Ward, Antonio Mattox, Tyler E Lindsey, Ashley S Orcid: 0000-0002-4367-7068 Andrews, Joel Zhu, Bing Wood, Charles Orcid: 0000-0002-0228-1497 Neese, Ashleigh Nguyen, Ashley Berry, Kristy Maxuitenko, Yulia Y Moyer, Mary Pat Orcid: 0000-0002-0297-8921 Nurmemmedov, Elmar Gorman, Greg Orcid: 0000-0003-4306-8884 Coward, Lori Zhou, Gang Keeton, Adam B Cooper, Harry S Orcid: 0000-0001-7574-1928 Clapper, Margie L Orcid: 0000-0001-7712-5109 Piazza, Gary A Orcid: 0000-0003-4418-887x Journal Article United States Cancer Prev Res (Phila). 2021 Sep 28:canprevres.0208.2021. doi: 10.1158/1940-6207.CAPR-21-0208.