FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1

Dmitri Pchejetski, Torsten Bohler, Leyre Brizuela, Lysann Sauer, Nicolas Doumerc, Muriel Golzio, Vishal Salunkhe, Justin Teissié, Bernard Malavaud, Jonathan Waxman, Olivier Cuvillier

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

Abstract

Radiotherapy is widely used as a radical treatment for prostate cancer, but curative treatments are elusive for poorly differentiated tumors where survival is just 15% at 15 years. Dose escalation improves local response rates but is limited by tolerance in normal tissues. A sphingosine analogue, FTY720 (fingolimod), a drug currently in phase III studies for treatment of multiple sclerosis, has been found to be a potent apoptosis inducer in prostate cancer cells. Using in vitro and in vivo approaches, we analyzed the impact of FTY720 on sphingolipid metabolism in hormone-refractory metastatic prostate cancer cells and evaluated its potential as a radiosensitizer on cell lines and prostate tumor xenografts. In prostate cancer cell lines, FTY720 acted as a sphingosine kinase 1 (SphK1) inhibitor that induced prostate cancer cell apoptosis in a manner independent of sphingosine-1-phosphate receptors. In contrast, γ irradiation did not affect SphK1 activity in prostate cancer cells yet synergized with FTY720 to inhibit SphK1. In mice bearing orthotopic or s.c. prostate cancer tumors, we show that FTY720 dramatically increased radiotherapeutic sensitivity, reducing tumor growth and metastasis without toxic side effects. Our findings suggest that low, well-tolerated doses of FTY720 could offer significant improvement to the clinical treatment of prostate cancer.
Original languageEnglish
Pages (from-to)8651-61
Number of pages11
JournalCancer Research
Volume70
Issue number21
DOIs
Publication statusPublished - 1 Nov 2010

Keywords

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Cycle
  • Cell Proliferation
  • Flow Cytometry
  • Gamma Rays
  • Humans
  • Immunosuppressive Agents
  • Male
  • Mice
  • Mice, Nude
  • Phosphotransferases (Alcohol Group Acceptor)
  • Propylene Glycols
  • Prostatic Neoplasms
  • RNA, Messenger
  • RNA, Small Interfering
  • Radiation Tolerance
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sphingosine
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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