title: Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors.
abstract: BACKGROUND
  Specificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of sulindac and its metabolites were due, in part, to targeting downregulation of Sp transcription factors.
  
  
  METHODS
  The functional effects of sulindac, sulindac sulfone and sulindac sulfide on colon cancer cell proliferation were determined by cell counting. Effects of these compounds on expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes were determined by western blot analysis of whole cell lysates and in transient transfection assays using GC-rich constructs.
  
  
  RESULTS
  Sulindac and its metabolites inhibited RKO and SW480 colon cancer cell growth and the order of growth inhibitory potency was sulindac sulfide>>sulindac sulfone>sulindac. Treatment of SW480 and RKO cells with sulindac sulfide downregulated expression of Sp1, Sp3 and Sp4 proteins. Sulindac sulfide also decreased expression of several Sp-regulated genes that are critical for cancer cell survival, proliferation and angiogenesis and these include survivin, bcl-2, epidermal growth factor receptor (EGFR), cyclin D1, p65 subunit of NFκB and vascular endothelial growth factor (VEGF). Sulindac sulfide also induced reactive oxygen species (ROS) and decreased the level of microRNA-27a in colon cancer cells, which resulted in the upregulation of the Sp-repressor ZBTB10 and this resulted in downregulation of Sp proteins.
  
  
  CONCLUSIONS
  The results suggest that the cancer chemotherapeutic effects of sulindac in colon cancer cells are due, in part, to its metabolite sulindac sulfide which downregulates Sp transcription factors and Sp-regulated pro-oncogenic gene products.
authors.affiliation: Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX, 77843-4466, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK, 73104, USA.
authors.forename: Satya S
authors.initials: SS
authors.lastname: Pathi
authors.affiliation: Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX, 77843-4466, USA. ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D051703:Sp Transcription Factors / Q000096:biosynthesis*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051703:Sp Transcription Factors; D013467:Sulindac; C025462:sulindac sulfide