title: The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  Human 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  Perifosine enhances prostate cancer radiosensitivity in vitro and in vivo. These data provide strong support for further development of this combination therapy in clinical studies.
authors.affiliation: Department of Radiation Oncology, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Gao
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ishiyama
authors.forename: Mianen
authors.initials: M
authors.lastname: Sun
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Brinkman
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Wang
authors.forename: Julie
authors.initials: J
authors.lastname: Zhu
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Mai
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Daniel
authors.initials: D
authors.lastname: Floryk
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.forename: E Brian
authors.initials: EB
authors.lastname: Butler
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Bin S
authors.initials: BS
authors.lastname: Teh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010767:Phosphorylcholine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D011838:Radiation-Sensitizing Agents; D010767:Phosphorylcholine