title: Antiangiogenic effect of sulindac sulfide could be secondary to induction of apoptosis and cell cycle arrest.
abstract: BACKGROUND
  The development of colon cancer is probably angiogenesis-dependent. Recently, sulindac sulfide was shown to possess anti-angiogenic activity. In the present work, the question of whether this activity reflects a specific interaction with angiogenesis or is secondary to the effect of sulindac sulfide on the survival of endothelial cells was addressed.
  
  
  METHODS
  Endothelial and normal mouse fibroblast cell lines were incubated with non-steroidal anti-inflammatory drugs (NSAIDs), arachidonic acid (AA) and prostaglandin E2 (PGE2). Cell viability (survival), PGE2 synthesis, cell cycle and apoptosis were measured. Western blotting and semi-quantitative RT-PCR multiplex methods verified the changes in the levels of pro-apoptotic proteins and their expressions, respectively.
  
  
  RESULTS
  Sulindac sulfide and celecoxib inhibited the survival of endothelial cells, whereas other NSAIDs were ineffective. In contrast to celecoxib, sulindac sulfide did not affect the survival of normal fibroblast cells. Both agents inhibited the production of PGE2 from AA and arrested the cell cycle in the S-phase. Moreover, sulindac sulfide activated caspases 3 and 8, decreased the levels of Bax and Bid proteins, caused cleavage of PARP and increased the expressions of the bax and caspase 3 genes.
  
  
  CONCLUSIONS
  The results suggest that the anti-angiogenic activity of sulindac sulfide is secondary to the inhibition of endothelial cell survival resulting from cell cycle arrest and apoptosis.
authors.affiliation: National Institute of Public Health, Department of Pharmacology, Warsaw, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Flis
authors.forename: D
authors.initials: D
authors.lastname: Soltysiak-Pawluczuk
authors.forename: A
authors.initials: A
authors.lastname: Jedrych
authors.forename: Z
authors.initials: Z
authors.lastname: Jastrzebski
authors.forename: M
authors.initials: M
authors.lastname: Remiszewska
authors.forename: J
authors.initials: J
authors.lastname: Splawinski
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000494:pharmacology; D041702:BALB 3T3 Cells; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D013467:Sulindac; D016718:Arachidonic Acid; C025462:sulindac sulfide; D000068579:Celecoxib; D015232:Dinoprostone