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

Lim, Keng Gat and Gray, Alexander I and Pyne, Susan and Pyne, Nigel J (2012) Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival. British Journal of Pharmacology, 166 (5). pp. 1605-1616. ISSN 1476-5381 (https://doi.org/10.1111/j.1476-5381.2012.01862.x)

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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

ORCID iDs

Lim, Keng Gat, Gray, Alexander I, Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584 and Pyne, Nigel J ORCID logoORCID: https://orcid.org/0000-0002-5657-4578;
CORE (COnnecting REpositories)