The HIV protease and PI3K/Akt inhibitor nelfinavir does not improve the curative effect of fractionated irradiation in PC-3 prostate cancer in vitro and in vivo

BACKGROUND: Radiotherapy has a high curative potential in localized prostate cancer, however, there are still patients with locally advanced tumours who face a considerable risk of recurrence. Radiosensitization using molecular targeted drugs could help to optimize treatment for this high-risk group. The PI3K/Akt pathway is overexpressed in many prostate cancers and is correlated to radioresistance. Nelfinavir, an HIV protease inhibitor (HPI), was found to block this pathway and to radiosensitize cancer cells of different origin. This is the first study examining the effect of nelfinavir in combination with irradiation on prostate cancer cell survival in vitro as well as on growth time and local tumour control in vivo. METHODS: The in vitro effect of nelfinavir on radioresponse of PC-3 was tested by colony formation assay with 10 μM nelfinavir. In vivo, the effect of nelfinavir alone and in combination with irradiation was tested in nude mice carrying PC-3 xenografts. For evaluating tumour growth time, mice were treated with 80 mg nelfinavir/kg body weight, daily at 5 days per week over 6 weeks. Simultaneous irradiation with 30 fractions and total doses between 30 and 120 Gy was applied to calculate local tumour control for day 180 after treatment. RESULTS: Nelfinavir inhibited Akt phosphorylation at Ser473 and showed a minor but significant effect on clonogenic cell survival in vitro with slightly higher cell survival rates after combined treatment. The treatment of PC-3 xenografts with nelfinavir alone led to no significant increase of tumour growth time and no improvement of local tumour control. CONCLUSIONS: Despite promising growth delay effects of nelfinavir in other tumour models and first clinical applications of this drug as anti-cancer agent, PC-3 prostate cancer cells express no or only minor sensitivity to nelfinavir treatment alone and no radiosensitizing effect in vitro or in vivo.