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

31 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
LanguageEnglish
Pages1605-1616
Number of pages12
JournalBritish Journal of Pharmacology
Volume166
Issue number5
Early online date21 Jun 2012
DOIs
Publication statusPublished - Jul 2012

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Cell Survival
Growth
Neoplasms
Sphingosine
MCF-7 Cells
Breast Neoplasms
Dipterocarpaceae
sphingosine kinase
resveratrol
Thymidine
Down-Regulation
Phosphorylation
ampelopsin
Apoptosis
Lipids
DNA

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

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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",
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Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival. / Lim, Keng Gat; Gray, Alexander I; Pyne, Susan; Pyne, Nigel J.

In: British Journal of Pharmacology, Vol. 166, No. 5, 07.2012, p. 1605-1616.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Resveratrol dimers are novel sphingosine kinase 1 inhibitors and affect sphingosine kinase 1 expression and cancer cell growth and survival

AU - Lim, Keng Gat

AU - Gray, Alexander I

AU - Pyne, Susan

AU - Pyne, Nigel J

N1 - © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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N2 - 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

AB - 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

KW - resveratrol dimers

KW - novel sphingosine kinase 1 inhibitors

KW - sphingosine kinase 1 expression

KW - cancer cell growth

KW - sphingosine 1-phosphate

KW - ampelopsin A

KW - balanocarpol

KW - inhibitor kinetics

KW - polyADP ribose polymerase

KW - extracellular signal-regulated kinase

KW - resveratrol

KW - proliferation

KW - cancer

KW - apoptosis

KW - sphingosine kinase 1

U2 - 10.1111/j.1476-5381.2012.01862.x

DO - 10.1111/j.1476-5381.2012.01862.x

M3 - Article

VL - 166

SP - 1605

EP - 1616

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -