title: Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway.
abstract: OBJECTIVE
  Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo.
  
  
  METHODS
  In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method.
  
  
  RESULTS
  The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone.
  
  
  CONCLUSIONS
  Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China.|Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Nan
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China.|Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, People's Republic of China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China.|Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, People's Republic of China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China. zhongyue2457@sina.com.|Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, People's Republic of China. zhongyue2457@sina.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002867:Chromones / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D015316:Genetic Therapy; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage*; D051058:Oncogene Protein v-akt / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase
keywords: AKT; Combinatorial therapy; Glioma; LY294002; PI3K; PTEN