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.
Highlights
In the western world prostate cancer is the most commonly diagnosed noncutaneous cancer in men and is the second leading cause of cancer-related death [1]
We report that FTY720 induced a rapid inhibition of sphingosine kinase 1 (SphK1) enzymatic activity in PC-3 and DU145 cells (-28 ± 5% and -40 ± 5% in PC-3 and DU145 cells, respectively, at 6 hours; Fig. 2)
We show for the first time that FTY720 is a strong inducer of apoptosis in hormone-refractory, metastatic prostate cancer PC-3 cells
Summary
In the western world prostate cancer is the most commonly diagnosed noncutaneous cancer in men and is the second leading cause of cancer-related death [1]. In the United States the lifetime probability of developing prostate cancer is 1 in 6, and it is estimated that 192,280 new cases of prostate cancer were diagnosed during 2009, and there were 27,360 deaths. The management of prostate cancer is complex, but for the majority of patients radiotherapy remains a definitive treatment for early-stage disease. Up to 85% of patients with poor histologic subtypes of localized prostate cancer relapse [2]. In radiotherapy research the current emphasis is on computerized planning to deliver increased dosage schedules. There is an opportunity to approach the Authors' Affiliations: 1Department of Surgery and Cancer, Imperial College London, London, United Kingdom; 2INSERM U858/I2MR EQ 10, CHU Rangueil, 3Hôpital Rangueil, Service d'Urologie et de Transplantation Rénale, 4CNRS, Institut de Pharmacologie et de Biologie Structurale; and 5Université de Toulouse, UPS, IPBS, Toulouse, France
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