Abstract 3707: Sulindac sulfide inhibits growth and induces apoptosis of human colon tumor cells by a cGMP-dependent pathway leading to suppression of β-catenin transcription activity

Abstract

Abstract Sulindac and other nonsteroidal anti-inflammatory drugs have shown promise for chemoprevention of colorectal cancer, but toxicities arising from cyclooxygenase (COX) inhibition limit their clinical use. Previous reports suggest that sulindac may exert its antitumor effects by a COX-independent target involving cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition, although the specific isozymes involved and mechanism have not been well defined. In this study, we show that sulindac sulfide (SS) inhibits the growth of human colon tumor cells, HCT116, HT29 and SW480 with IC50 values of 60-80μmol/L. Within this concentration range, SS did not affect the growth of human-derived normal colonic epithelial cells, NCM460. Furthermore, SS induced apoptosis of colon tumor cells but not NCM460 cells. SS inhibited cGMP PDE activity in colon tumor cell lysates with minimal effect on cGMP PDE activity in NCM460 cell lysates. By determining the sensitivity of all eleven PDE isozymes to SS, the cGMP-specific PDE5 was found to be the most sensitive with an IC50 value for enzyme inhibition of 38µmol/L. In addition, PDE5 was found to be overexpressed in colon tumor cell lines compared with NCM460 cells. Knockdown of PDE5 expression in colon tumor cells with siRNA resulted in a significant reduction of tumor cell growth and increased apoptosis. Moreover, SS increased intracellular cGMP levels, activated protein kinase G (PKG) and suppressed the expression of β-catenin in colon tumor cells. SS also inhibited the transcriptional activity of β-catenin and reduced the expression of the β-catenin regulated proteins cyclin D1 and survivin, which are important mediators of tumor cell proliferation and apoptosis, respectively. Our results suggest that the chemopreventive properties of sulindac are closely associated with PDE5 inhibition and involve the activation of cGMP signaling to suppress β-catenin mediated transcriptional activity. Funding provided by NIH/NCI grants CA131378 and CA148817. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3707. doi:10.1158/1538-7445.AM2011-3707