Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10

Oncotarget. 2015 Sep 29;6(29):27403-15. doi: 10.18632/oncotarget.4741.


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.

Keywords: PDE10; PDE5; colorectal cancer; sulindac; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetamides / chemistry*
  • Apoptosis
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Proliferation
  • Colonic Neoplasms / metabolism*
  • Computer Simulation
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
  • Cyclin D1 / metabolism
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Indenes / chemistry*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Inhibitory Concentration 50
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphoric Diester Hydrolases / metabolism*
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Sulindac / chemistry
  • Survivin
  • Transcription, Genetic
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / metabolism*


  • ADT-094
  • Acetamides
  • BIRC5 protein, human
  • CCND1 protein, human
  • CTNNB1 protein, human
  • Indenes
  • Inhibitor of Apoptosis Proteins
  • Phosphodiesterase Inhibitors
  • RNA, Small Interfering
  • Survivin
  • beta Catenin
  • Cyclin D1
  • Sulindac
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human