title: Effect of PI3K/Akt pathway inhibition-mediated G1 arrest on chemosensitization in ovarian cancer cells.
abstract: BACKGROUND
  Pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway prevents G(1) cell cycle progression into S, resulting in G(1) accumulation. The hypothesis that this arrest might negatively impact on chemotherapeutic agents primarily effective in S, G(2) or M-phase was investigated.
  
  
  METHODS
  Inhibition of PI3K/Akt pathway signaling via LY294002 and Akti-1/2 was demonstrated by immunoblotting. Cell cycle progression was determined by flow cytometric analysis. Cell proliferation was assayed using the XTT cell viability assay. The Chou and Talalay median effect principal was used to evaluate drug interaction.
  
  
  RESULTS
  In SKOV3 and IGROV1 human ovarian cancer cells, LY294002 and Akti-1/2 increased the percentage of cells in G(1) and reversed the cell cycle effects of cisplatin, paclitaxel, gemcitabine and topotecan. Pathway blockade synergistically enhanced the cytotoxicity of cisplatin and paclitaxel, but antagonized gemcitabine and topotecan effects.
  
  
  CONCLUSIONS
  Pharmacological PI3K/Akt inhibition antagonizes the efficacy of chemotherapeutic agents primarily effective in the S or G(2)-phase of the cell cycle.
authors.affiliation: UCLA David Geffen School of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Los Angeles, CA 90095-1740, USA.
authors.forename: Mirela
authors.initials: M
authors.lastname: Fekete
authors.forename: Chintda
authors.initials: C
authors.lastname: Santiskulvong
authors.forename: Carol
authors.initials: C
authors.lastname: Eng
authors.forename: Oliver
authors.initials: O
authors.lastname: Dorigo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001596:Benzylamines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage; D015398:Signal Transduction; D019772:Topotecan / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D001596:Benzylamines; D002867:Chromones; D002945:Cisplatin; D003841:Deoxycytidine; D009025:Morpholines; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines; D019772:Topotecan; D000093542:Gemcitabine; C501521:Akt-I-1,2 compound; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one