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

Pchejetski, Dmitry, Doumerc, Nicolas, Golzio, Muriel, Naymark, Maria, Teissié, Justin, Kohama, Takafumi, Waxman, Jonathan, Malavaud, Bernard and Cuvillier, Olivier (2008) Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models. Molecular Cancer Therapeutics, 7 (7). pp. 1836-45. ISSN 1535-7163

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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.

Item Type: Article
Uncontrolled Keywords: 4-aminobenzoic acid,animals,antineoplastic agents,apoptosis,camptothecin,caspases,cell line, tumor,cell survival,ceramides,drug therapy, combination,green fluorescent proteins,humans,lysophospholipids,male,mice,neoplasm metastasis,phosphotransferases (alcohol group acceptor),prostatic neoplasms,sphingosine,treatment outcome,xenograft model antitumor assays,para-aminobenzoates
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 16 Dec 2014 10:06
Last Modified: 25 Jul 2018 10:20
URI: https://ueaeprints.uea.ac.uk/id/eprint/51541
DOI: 10.1158/1535-7163.MCT-07-2322

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