title: Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid.
abstract: OBJECTIVE
  Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti-angiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate.
  
  
  METHODS
  Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos.
  
  
  RESULTS
  Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser(78) phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H(2)S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity.
  
  
  CONCLUSIONS
  S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: Y
authors.initials: Y
authors.lastname: Jia
authors.forename: L
authors.initials: L
authors.lastname: Field
authors.forename: L A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: A
authors.initials: A
authors.lastname: Sparatore
authors.forename: P
authors.initials: P
authors.lastname: Del Soldato
authors.forename: A L
authors.initials: AL
authors.lastname: Sowers
authors.forename: G C
authors.initials: GC
authors.lastname: Yeh
authors.forename: T W
authors.initials: TW
authors.lastname: Moody
authors.forename: D A
authors.initials: DA
authors.lastname: Wink
authors.forename: R
authors.initials: R
authors.lastname: Ramchandran
authors.forename: D D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000781:Anethole Trithione / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D012995:Solubility; D014635:Valproic Acid / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D014635:Valproic Acid; D000781:Anethole Trithione