Encountering Aberrant Wnt Signalling - Therapeutic Strategies in Cancer Biology and Pathology - page 45

The non-steroidal anti-inflammatory agent sulindac has been found to interfere
with Wnt signalling. The β-catenin/TCF transcription complex targets many genes.
The metastasis promoter S100A4 is regulated by this complex. Stein et al. (2006)
found TCF binding sites in the S100A4 promoter and the β-catenin/TCF complex
directly bound S100A4 promoter and enhanced its activity. Stein et al. (2011) intra-
splenically xenografted colon cancer cells over expressing S100A4 and treated the
host animals with sulindac. This treatment seems to have interfered with Wnt sig-
nalling, reduced β-catenin expression and its nuclear accumulation together with a
decrease in the formation of β-catenin/TCF transcription complex, and importantly
here in the downregulation of S100A4 promoter activity and expression. The tumour
that formed in the spleen and its metastases in the liver both had reduced levels of
β-catenin and S100A4. Sulindac does operate by other means and more effective
agents such as the phospho-sulindac (OXT-328) have been described. Phospho-
sulindac is believed to be more effective than sulindac. Zhu et al. (2012) have
claimed that it targets breast CSCs in vitro and in breast cancer xenografts, inhibits
cell proliferation and induces apoptosis of breast CSCs. The demonstration of the
inhibitory effects on Wnt signalling via suppression of S100A4 provides a reason-
able basis for further investigations into the mode of action and anticancer properties
of sulindac and its derivatives.