Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640

James W. Antoon, Martin D. White, William D. Meacham, Evelyn M. Slaughter, Shannon E. Muir, Steven Elliott, Lyndsay V. Rhodes, Hasina B. Ashe, Thomas E. Wiese, Charles Smith, Matthew E. Burow, Barbara S. Beckman

Research output: Contribution to journalArticle

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Abstract

Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study,we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P < 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.

Original languageEnglish (US)
Pages (from-to)5124-5135
Number of pages12
JournalEndocrinology
Volume151
Issue number11
DOIs
StatePublished - Nov 1 2010

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Breast Neoplasms
Endocrine Gland Neoplasms
Sphingolipids
Competitive Binding
sphingosine kinase
3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
HEK293 Cells
Progesterone Receptors
Tamoxifen
Tumor Burden
Luciferases
Estrogen Receptors
Weight Loss
Ligands
Pharmaceutical Preparations
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Antoon, J. W., White, M. D., Meacham, W. D., Slaughter, E. M., Muir, S. E., Elliott, S., ... Beckman, B. S. (2010). Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology, 151(11), 5124-5135. https://doi.org/10.1210/en.2010-0420
Antoon, James W. ; White, Martin D. ; Meacham, William D. ; Slaughter, Evelyn M. ; Muir, Shannon E. ; Elliott, Steven ; Rhodes, Lyndsay V. ; Ashe, Hasina B. ; Wiese, Thomas E. ; Smith, Charles ; Burow, Matthew E. ; Beckman, Barbara S. / Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. In: Endocrinology. 2010 ; Vol. 151, No. 11. pp. 5124-5135.
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Antoon, JW, White, MD, Meacham, WD, Slaughter, EM, Muir, SE, Elliott, S, Rhodes, LV, Ashe, HB, Wiese, TE, Smith, C, Burow, ME & Beckman, BS 2010, 'Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640', Endocrinology, vol. 151, no. 11, pp. 5124-5135. https://doi.org/10.1210/en.2010-0420

Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. / Antoon, James W.; White, Martin D.; Meacham, William D.; Slaughter, Evelyn M.; Muir, Shannon E.; Elliott, Steven; Rhodes, Lyndsay V.; Ashe, Hasina B.; Wiese, Thomas E.; Smith, Charles; Burow, Matthew E.; Beckman, Barbara S.

In: Endocrinology, Vol. 151, No. 11, 01.11.2010, p. 5124-5135.

Research output: Contribution to journalArticle

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AU - Antoon, James W.

AU - White, Martin D.

AU - Meacham, William D.

AU - Slaughter, Evelyn M.

AU - Muir, Shannon E.

AU - Elliott, Steven

AU - Rhodes, Lyndsay V.

AU - Ashe, Hasina B.

AU - Wiese, Thomas E.

AU - Smith, Charles

AU - Burow, Matthew E.

AU - Beckman, Barbara S.

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Y1 - 2010/11/1

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Antoon JW, White MD, Meacham WD, Slaughter EM, Muir SE, Elliott S et al. Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology. 2010 Nov 1;151(11):5124-5135. https://doi.org/10.1210/en.2010-0420