Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models.
Mol Cancer Ther
; 7(7): 1836-45, 2008 Jul.
Article
en En
| MEDLINE
| ID: mdl-18644996
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
/
Fosfotransferasas (Aceptor de Grupo Alcohol)
/
Ensayos Antitumor por Modelo de Xenoinjerto
Límite:
Animals
/
Humans
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Male
Idioma:
En
Revista:
Mol Cancer Ther
Asunto de la revista:
ANTINEOPLASICOS
Año:
2008
Tipo del documento:
Article
País de afiliación:
Francia