Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival

Keng Gat Lim, Alexander I Gray, Susan Pyne, Nigel J Pyne

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.
Ampelopsin A and balanocarpol were purified from Hopea dryobalanoides and their effect on sphingosine kinase 1 activity and expression, [3H] thymidine incorporation, ERK-1/2 phosphorylation and PARP activity assessed in MCF-7 cells.
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 Kic= 90 +/- 10 mu M and a Kiu of similar to 500 mu M. 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 Kic= 160 +/- 40 mu M, reduced sphingosine kinase 1 expression and induced PARP cleavage in MCF-7 cells.
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.
This article is commented on by Hergst and Yun, pp. 16031604 of this issue. To view this commentary visit
Original languageEnglish
Pages (from-to)1605-1616
Number of pages12
JournalBritish Journal of Pharmacology
Volume166
Issue number5
Early online date21 Jun 2012
DOIs
Publication statusPublished - Jul 2012

Keywords

  • resveratrol dimers
  • novel sphingosine kinase 1 inhibitors
  • sphingosine kinase 1 expression
  • cancer cell growth
  • sphingosine 1-phosphate
  • ampelopsin A
  • balanocarpol
  • inhibitor kinetics
  • polyADP ribose polymerase
  • extracellular signal-regulated kinase
  • resveratrol
  • proliferation
  • cancer
  • apoptosis
  • sphingosine kinase 1

Cite this