Poster Presentation 26th Lorne Cancer Conference 2014

The NSAID sulindac activates pro-inflammatory NF-kB and AP-1 signalling but also causes apoptosis of colon cancer cells.  (#184)

Dessislava Mladenova 1 , Laurent Pangon 1 , Nicola Currey 1 , Irvin Ng 1 , Elizabeth A Musgrove 1 , Shane T Grey 1 2 , Maija RJ Kohonen-Corish 1 2 3
  1. Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW, Australia
  3. School of Medicine, University of Western Sydney, Sydney, NSW, Australia

The non-steroidal anti-inflammatory drug (NSAID) sulindac is known to prevent colorectal cancer. This potent anti-tumorigenic effect is mediated through multiple cellular pathways but is also accompanied by gastrointestinal side effects, such as colon inflammation. We have recently shown that, apart from chemoprevention, a diet containing sulindac can cause up-regulation of pro-inflammatory and pro-tumorigenic factors and new cancers in the colon of p53 or Msh2 deficient mice (1). The aim of this study was to determine the signalling pathways that mediate this pro-inflammatory cytokine activation.

Sulindac treatment of mice increased NF-kB target gene expression in the proximal colon within one week. Sulindac sulfide, the active metabolite, caused up-regulation of NF-kB signalling in HCT15, HCT116, SW480 and SW620 colon cancer cells. This involved degradation of IkBa, nuclear localisation of p65(RelA) and increased expression of IL-8, ICAM1 and AP20 within 2-4 hours and was inhibited by the NFkB inhibitor PDTC. Sulindac sulfide also induced activation of the AP-1 transcription factor, which co-operated with NF-kB in up-regulating the chemokine IL-8. Transcriptional activation of NF-kB target genes was most prominent in conditions where sulindac sulfide caused apoptosis but the majority of cells were viable. In TNFa-stimulated conditions the drug treatment inhibited phosphorylation of IkBa. This is consistent with previous studies indicating that sulindac sulfide inhibits NF-kB signalling in TNFa-stimulated cells. 

This study shows for the first time that sulindac sulfide can induce pro-inflammatory NF-kB and AP-1 signalling and an anti-tumorigenic response, such as apoptosis, in the same experimental conditions (2). Therefore, these results provide insights into the effect of sulindac on pro-inflammatory signalling pathways, and a better understanding of the mechanism of sulindac-induced gastrointestinal side effects.

1. Mladenova D, et al 2011. The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon. Gut 60: 350-360.

2. Mladenova D, et al 2013. Sulindac sulfide activates NF-kB signalling in colorectal cancer cells. Cell Communication and Signaling (in press).