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

Nan Li, Xi Chen, Bing Zhu, Verónica Ramírez-Alcántara, Joshua C. Canzoneri, Kevin Lee, Sara Sigler, Bernard Gary, Yonghe Li, Wei Zhang, Mary P. Moyer, E. Alan Salter, Andrzej Wierzbicki, Adam B. Keeton, Gary A. Piazza

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 , 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 , PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses ß-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.

Original languageEnglish (US)
Pages (from-to)27403-27415
Number of pages13
JournalOncotarget
Volume6
Issue number29
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Colorectal cancer
  • PDE10
  • PDE5
  • Sulindac
  • Β-catenin

ASJC Scopus subject areas

  • Oncology

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