title: Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.
abstract: 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.
authors: Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Nan
authors: N
authors: Li
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Xi
authors: X
authors: Chen
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Bing
authors: B
authors: Zhu
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Verónica
authors: V
authors: Ramírez-Alcántara
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Joshua C
authors: JC
authors: Canzoneri
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Kevin
authors: K
authors: Lee
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Sara
authors: S
authors: Sigler
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Bernard
authors: B
authors: Gary
authors: Drug Discovery Division, Southern Research, Birmingham, Alabama, USA.
authors: Yonghe
authors: Y
authors: Li
authors: Drug Discovery Division, Southern Research, Birmingham, Alabama, USA.
authors: Wei
authors: W
authors: Zhang
authors: INCELL Corporation LLC, San Antonio, Texas, USA.
authors: Mary P
authors: MP
authors: Moyer
authors: Department of Chemistry, University of South Alabama, Mobile, Alabama, USA.
authors: E Alan
authors: EA
authors: Salter
authors: Department of Chemistry, University of South Alabama, Mobile, Alabama, USA.
authors: Andrzej
authors: A
authors: Wierzbicki
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Adam B
authors: AB
authors: Keeton
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
authors: Gary A
authors: GA
authors: Piazza
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D017209:Apoptosis; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism*; D003198:Computer Simulation; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007192:Indenes / Q000737:chemistry*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013467:Sulindac / Q000737:chemistry; D000077022:Survivin; D014158:Transcription, Genetic; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C000609868:ADT-094; D000081:Acetamides; C107489:BIRC5 protein, human; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D007192:Indenes; D051034:Inhibitor of Apoptosis Proteins; D010726:Phosphodiesterase Inhibitors; D034741:RNA, Small Interfering; D000077022:Survivin; D051176:beta Catenin; D019938:Cyclin D1; D013467:Sulindac; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human
keywords: PDE10; PDE5; colorectal cancer; sulindac; β-catenin