FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1.
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.
Pchejetski
Dmitri
D
Department of Surgery and Cancer, Imperial College London, London, United Kingdom. d.pshezhetskiy@imperial.ac.uk
Bohler
Torsten
T
Brizuela
Leyre
L
Sauer
Lysann
L
Doumerc
Nicolas
N
Golzio
Muriel
M
Salunkhe
Vishal
V
Teissié
Justin
J
Malavaud
Bernard
B
Waxman
Jonathan
J
Cuvillier
Olivier
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D005720:Gamma Rays; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013110:Sphingosine; D000099157:Sphingosine Kinase