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

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 Kic= 90 ± 10 µM and a Kiu 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 Kic= 160 ± 40 µM, reduced sphingosine kinase 1 expression and induced PARP cleavage in MCF‐7 cells. CONCLUSIONS AND IMPLICATIONS 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. LINKED ARTICLE This article is commented on by Hergst and Yun, pp. 1603–1604 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2012.01898.x