title: A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human colon tumor cells. The basis for this activity appears to involve cyclic guanosine 3',5',-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in colon tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress tumor cell growth. PDE5 was found to be essential for colon tumor cell growth as determined by siRNA knockdown studies, elevated in colon tumor cells as compared with normal colonocytes, and associated with the tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention.
authors.affiliation: Department of Pharmacology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Whitt
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Heather N
authors.initials: HN
authors.lastname: Tinsley
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.forename: Adam B
authors.initials: AB
authors.lastname: Keeton
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Xi
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D058986:Phosphodiesterase 5 Inhibitors; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051176:beta Catenin; D013467:Sulindac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP; D015232:Dinoprostone