Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10
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Nan Li1, Xi Chen2, Bing Zhu2, Verónica Ramírez-Alcántara2, Joshua C. Canzoneri2, Kevin Lee2, Sara Sigler2, Bernard Gary2, Yonghe Li3, Wei Zhang3, Mary P. Moyer4, E. Alan Salter5, Andrzej Wierzbicki5, Adam B. Keeton2, Gary A. Piazza2
1Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA
2Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
3Drug Discovery Division, Southern Research, Birmingham, Alabama, USA
4INCELL Corporation LLC, San Antonio, Texas, USA
5Department of Chemistry, University of South Alabama, Mobile, Alabama, USA
Gary A. Piazza, e-mail: [email protected]
Keywords: colorectal cancer, sulindac, PDE5, PDE10, β-catenin
Received: April 13, 2015 Accepted: July 13, 2015 Published: July 25, 2015
Previous studies suggest the anti-inflammatory drug, sulindac inhibits tumorigenesis by a COX independent mechanism involving cGMP PDE inhibition. Here we report that the cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and that inhibitors and siRNAs can selectively suppress colon tumor cell growth. Combined treatment with inhibitors or dual knockdown suppresses tumor cell growth to a greater extent than inhibition from either isozyme alone. A novel sulindac derivative, ADT-094 was designed to lack COX-1/-2 inhibitory activity but have improved potency to inhibit PDE5 and 10. ADT-094 displayed >500 fold higher potency to inhibit colon tumor cell growth compared with sulindac by activating cGMP/PKG signaling to suppress proliferation and induce apoptosis. Combined inhibition of PDE5 and 10 by treatment with ADT-094, PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses β-catenin, TCF transcriptional activity, and the levels of downstream targets, cyclin D1 and survivin. These results suggest that dual inhibition of PDE5 and 10 represents novel strategy for developing potent and selective anticancer drugs.
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