Resveratrol Dimers Are Novel Sphingosine Kinase 1 Inhibitors and Affect Sphingosine Kinase 1 Expression and Cancer Cell Growth and Survival

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2012 Jan 19

PMID 22251058

Citations 28

Authors

Keng Gat Lim

Alexander I Gray

Susan Pyne

Nigel J Pyne

Affiliations

Soon will be listed here.

Abstract

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, [(3)H] 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 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 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.

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