FTY720 Radiosensitizes Prostate
- Ko de
- Cancer www.a Published OnlineFirst October
Downloa iotherapy is widely used as a radical treatment for prostate cancer, but curative treatments are elusive orly differentiated tumors where survival is just 15% at 15 years. Dose escalation improves local response ut is limited by tolerance in normal tissues. A sphingosine analogue, FTY720 (fingolimod), a drug curin phase III studies for treatment of multiple sclerosis, has been found to be a potent apoptosis inducer state cancer cells. Using in vitro and in vivo approaches, we analyzed the impact of FTY720 on sphingoetabolism in hormone-refractory metastatic prostate cancer cells and evaluated its potential as a radioizer on cell lines and prostate tumor xenografts. In prostate cancer cell lines, FTY720 acted as a osine kinase 1 (SphK1) inhibitor that induced prostate cancer cell apoptosis in a manner independent ingosine-1-phosphate receptors. In contrast, γ irradiation did not affect SphK1 activity in prostate cells yet synergized with FTY720 to inhibit SphK1. In mice bearing orthotopic or s.c. prostate cancer s, we show that FTY720 dramatically increased radiotherapeutic sensitivity, reducing tumor growth and tumor 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. Cancer Res; 70(21); 8651–61. ©2010 AACR.