This Article Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Pchejetski, D. Articles by Cuvillier, O. PubMed PubMed Citation Articles by Pchejetski, D. Articles by Cuvillier, O.

Research Articles: Therapeutics, Targets, and Development

Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models

¹ Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, UMR 5089; ² Université Toulouse III Paul Sabatier; ³ CHU Toulouse, Hôpital Rangueil, Service d'Urologie et de Transplantation Rénale, Toulouse, France; ⁴ Imperial College London, London, United Kingdom; and ⁵ Daiichi Sankyo Co. Ltd., Tokyo, Japan

Requests for reprints: Olivier Cuvillier, Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, UMR 5089, 31077 Toulouse Cedex 4, France. Phone: 33-561-17-55-13; Fax: 33-561-17-58-71. E-mail: olivier.cuvillier{at}ipbs.fr

Abstract

We have previously reported that, in prostate cancer, inhibition of the oncogenic sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway is a key element in chemotherapy-induced apoptosis. Here, we show that selective pharmacologic inhibition of SphK1 triggers apoptosis in LNCaP and PC-3 prostate cancer cells, an effect that is reversed by SphK1 enforced expression. More importantly, we show for the first time that the up-regulation of the SphK1/S1P pathway plays a crucial role in the resistance of prostate cancer cells to chemotherapy. Importantly, pharmacologic SphK1 inhibition with the B-5354c compound sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to S1P sphingolipid ratio. To conclude, our study highlights the notion that drugs specifically designed to inhibit SphK1 could provide a means of enhancing the effects of conventional treatment through the prosurvival antiapoptotic SphK1/S1P pathway. [Mol Cancer Ther 2008;7(7):1836–45]

Grant support: Institut National de la Santé et de la Recherche Médicale Interface Program, Centre National de la Recherche Scientifique, Institut National du Cancer, Association pour la Recherche sur le Cancer, and Fondation pour la Recherche Médicale (O. Cuvillier). D. Pchejetski is a recipient of Association Etudes et Recherches Urologiques.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁷ O. Cuvillier, personal data.

Received 11/26/07; revised 3/ 3/08; accepted 4/ 2/08.