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Sulindac sulfone is most effective in modulating beta-catenin-mediated transcription in cells with mutant APC

Wen-Chi L Chang1, Lynette C Everley, Gordon R Pfeiffer

  • 1Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. wen-chi.chang@fccc.edu

Annals of the New York Academy of Sciences
|December 31, 2005
PubMed

Insights

Sulindac sulfone, a nonsteroidal anti-inflammatory drug metabolite, effectively reduces beta-catenin and related proteins in specific cancer cells. Its mechanism involves modulating the APC/beta-catenin pathway, depending on cellular mutations.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Sulindac sulfone, a metabolite of sulindac, lacks cyclooxygenase activity but is known to inhibit tumorigenesis.
  • Its anti-cancer mechanism, often attributed to apoptosis induction, is not fully understood.
  • The adenomatous polyposis coli (APC)/beta-catenin pathway is crucial in colorectal cancer development.

Purpose of the Study:

  • To investigate the effect of sulindac metabolites on beta-catenin levels and the APC/beta-catenin pathway in vitro.
  • To compare the potency of sulindac sulfone and its sulfide metabolite in regulating this pathway.
  • To determine if sulindac sulfone's efficacy is dependent on the mutational status of APC and beta-catenin.

Main Methods:

  • Treatment of various colon cancer cell lines (SW480, HCA7, LS174, Caco-2) with sulindac metabolites.
  • Quantification of cellular levels of beta-catenin, pro-caspase 3, cyclin D1, and PPARdelta.
  • Assessment of TCF-mediated transcriptional activity.

Main Results:

  • Sulindac sulfone significantly decreased total cellular beta-catenin, pro-caspase 3, cyclin D1, and PPARdelta in SW480 cells.
  • These effects were more potent than those observed with the sulindac sulfide metabolite.
  • No significant changes in pro-caspase 3 or beta-catenin were observed in HCA7, LS174, or Caco-2 cells.
  • A dose-dependent reduction in TCF-mediated transcriptional activity was noted in SW480 cells.

Conclusions:

  • Sulindac sulfone can modulate the APC/beta-catenin pathway in vitro.
  • The compound's efficacy is contingent upon the specific mutational status of APC and beta-catenin within the cells.
  • These findings provide insights into the molecular mechanisms underlying sulindac sulfone's anti-cancer properties.

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