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
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 language | English |
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Pages (from-to) | 1605-1616 |
Number of pages | 12 |
Journal | British Journal of Pharmacology |
Volume | 166 |
Issue number | 5 |
Early online date | 21 Jun 2012 |
DOIs | |
Publication status | Published - 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