title: Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival.
abstract: OBJECTIVE
  Sphingosine kinase 1 catalyses formation of the bioactive lipid, sphingosine 1-phosphate, which protects cancer cells from apoptosis. Therefore, sphingosine kinase 1 is a novel target for intervention with anti-cancer agents. We have assessed the effect of the anti-cancer agent, resveratrol and its dimers (ampelopsin A and balanocarpol) on sphingosine kinase 1 activity and on survival of MCF-7 breast cancer cells.
  
  
  METHODS
  Ampelopsin A and balanocarpol were purified from Hopea dryobalanoides and their effect on sphingosine kinase 1 activity and expression, [(3)H] thymidine incorporation, ERK-1/2 phosphorylation and PARP activity assessed in MCF-7 cells.
  
  
  RESULTS
  Resveratrol, ampelopsin A and balanocarpol were novel inhibitors of sphingosine kinase 1 activity. Balanocarpol was a mixed inhibitor (with sphingosine) of sphingosine kinase 1 with a K(ic) = 90 ± 10 µM and a K(iu) of ∼500 µM. Balanocarpol and ampelopsin A also induced down-regulation of sphingosine kinase 1 expression and reduced DNA synthesis, while balanocarpol stimulated PARP cleavage in MCF-7 breast cancer cells. Resveratrol was a competitive inhibitor (with sphingosine) of sphingosine kinase 1 with a K(ic) = 160 ± 40 µM, reduced sphingosine kinase 1 expression and induced PARP cleavage in MCF-7 cells.
  
  
  CONCLUSIONS
  Each molecule of balanocarpol may bind at least two sphingosine kinase 1 catalytic molecules to reduce the activity of each simultaneously. These findings suggest that resveratrol, ampelopsin A and balanocarpol could perturb sphingosine kinase 1-mediated signalling and this might explain their activity against MCF-7 breast cancer cells.
authors.affiliation: Cell Biology and Pharmaceutical Sciences Groups, Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, UK.
authors.forename: Keng Gat
authors.initials: KG
authors.lastname: Lim
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Gray
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077185:Resveratrol; D013267:Stilbenes; D000099157:Sphingosine Kinase