Abstract
BackgroundPerifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. In this study, we investigated the effect of the combined treatment of perifosine and radiation (CTPR) on prostate cancer cells in vitro and on prostate cancer xenografts in vivo.MethodsHuman prostate cancer cell line, CWR22RV1, was treated with perifosine, radiation, or CTPR. Clonogenic survival assays, sulforhodamine B cytotoxity assays and cell density assays were used to assess the effectiveness of each therapy in vitro. Measurements of apoptosis, cell cycle analysis by flow cytometry and Western blots were used to evaluate mechanisms of action in vitro. Tumor growth delay assays were used to evaluate radiation induced tumor responses in vivo.ResultsIn vitro, CTPR had greater inhibitory effects on prostate cancer cell viability and clonogenic survival than either perifosine or radiation treatment alone. A marked increase in prostate cancer cell apoptosis was noted in CTPR. Phosphorylation of AKT-T308 AKT and S473 were decreased when using perifosine treatment or CTPR. Cleaved caspase 3 was significantly increased in the CTPR group. In vivo, CTPR had greater inhibitory effects on the growth of xenografts when compared with perifosine or radiation treatment alone groups.ConclusionsPerifosine enhances prostate cancer radiosensitivity in vitro and in vivo. These data provide strong support for further development of this combination therapy in clinical studies.
Highlights
Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy
Perifosine increases sensitivity of human CWR22RV1 cells to radiation In order to assess the effect of perifosine on prostate cancer radiosensitivity, we first tested various doses of perifosine exposure in combination with radiation treatment in CWR22RV1 cells using the proliferation assay (MTS assay) and the colony formation assay
We found that the combination of perifosine and radiation had a greater inhibitory effect on cell viability compared to perifosine or radiation alone (Figure 1A)
Summary
Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. Prostate cancer cells can become radioresistant, resulting in poor long term prognosis for many prostate cancer patients. It is essential to clarify and target underlying mechanisms involved in the development of radioresistant cells to improve and optimize radiotherapy strategies for prostate cancer patients. Deregulation of the PI3K/Akt pathway is often associated with tumorigenesis [4,5] and poor prognosis in cancer patients [6,7,8]. The PI3K/Akt pathway has been implicated extensively as a contributor to radioresistance [9]. These insights present the PI3K/Akt pathway as an attractive target for anticancer therapy, and more importantly, for combined treatment therapy
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