title: Inhibitory effects of the HDAC inhibitor valproic acid on prostate cancer growth are enhanced by simultaneous application of the mTOR inhibitor RAD001.
abstract: OBJECTIVE
  To analyze the combined impact of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell growth.
  
  
  METHODS
  PC-3, DU-145 and LNCaP cells were treated with RAD001, VPA or with an RAD001-VPA combination for 3 or 5 days. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT assay, flow cytometry and Western blotting, respectively. Effects of drug treatment on cell signaling pathways were determined.
  
  
  RESULTS
  Separate application of RAD001 or VPA distinctly reduced tumor cell growth and impaired cell cycle progression. Significant additive effects were evoked when both drugs were used in concert. Particularly, the cell cycle regulating proteins cdk1, cdk2, cdk4 and cyclin B were reduced, whereas p21 and p27 were enhanced by the RAD001-VPA combination. Signaling analysis revealed deactivation of EGFr, ERK1/2 and p70S6k. Phosphorylation of Akt was diminished in DU-145 but elevated in PC-3 and LNCaP cells.
  
  
  CONCLUSIONS
  The RAD001-VPA combination exerted profound antitumor properties on a panel of prostate cancer cell lines. Therefore, simultaneous blockage of HDAC and mTOR related pathways should be considered when designing novel therapeutic strategies for treating prostate carcinoma.
authors.affiliation: Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wedel
authors.forename: Lukasz
authors.initials: L
authors.lastname: Hudak
authors.forename: Jens-Michael
authors.initials: JM
authors.lastname: Seibel
authors.forename: Eva
authors.initials: E
authors.lastname: Juengel
authors.forename: Igor
authors.initials: I
authors.lastname: Tsaur
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiesner
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.forename: Roman A
authors.initials: RA
authors.lastname: Blaheta
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000378:metabolism; D000068338:Everolimus; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D000068338:Everolimus; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020123:Sirolimus