Research article summary (published 29 Nov 2009):

Sphingosine kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel.

Full Abstract

It has recently been shown that docetaxel chemotherapy is effective in prolonging life in patients with prostate cancer (PCa). We have investigated potential ways of increasing the effectiveness of chemotherapy in this disease. We have previously reported that sphingosine kinase 1 (SphK1) inhibition is a key step in docetaxel-induced apoptosis in the PC-3 PCa cell line and that pharmacologicalSphK1 inhibition is chemosensitizing in the docetaxel-resistant PCa LNCaP cell line. In this study we have addressed the mechanism of docetaxel-induced apoptosis of PC-3 cells and identified SphK1-dependent and -independent components. We have shown that SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Using hormoneresistant PC-3 and DU145 PCa cells we have demonstrated that both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose. This work points out to potential ways of increasing the effectiveness of chemotherapy for PCa by SphK1 inhibition.

Author information

Author/s: Sauer, Lysann (L); Nunes, Joao (J); Salunkhe, Vishal (V); Skalska, Lenka (L); Kohama, Takafumi (T); Cuvillier, Olivier (O); Waxman, Jonathan (J); Pchejetski, Dmitry (D);

Affiliation: Department of Oncology, Imperial College London, London, United Kingdom.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Dec; vol 125 (issue 11) : pp 2728-36

Dates: Created 2009/10/05; Completed 2009/11/06;

PMID: 19521959, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Antineoplastic Agents - therapeutic use Apoptosis - drug effects Blotting, Western Caspases - metabolism Cell Cycle - drug effects Cell Line, Tumor Cell Proliferation - drug effects Drug Resistance, Neoplasm Flow Cytometry

Humans Male Neoplasms, Hormone-Dependent - drug therapy; enzymology; genetics Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; genetics; metabolism Prostatic Neoplasms - drug therapy; enzymology; genetics RNA, Messenger - genetics; metabolism RNA, Small Interfering - pharmacology Reverse Transcriptase Polymerase Chain Reaction Taxoids - therapeutic use

Associated Chemicals: Antineoplastic Agents (0) ; RNA, Messenger (0) ; RNA, Small Interfering (0) ; Taxoids (0) ; docetaxel (114977-28-5) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Caspases (EC 3.4.22.-)

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