title: Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition.
abstract: OBJECTIVE
  Histone deacetylase inhibitors (HDACIs) can enhance the sensitivity of cells to photon radiation treatment (XRT) by altering numerous molecular pathways. We investigated the effect of pan-HDACIs such as suberoylanilide hydroxamic acid (SAHA) on radiation response in two osteosarcoma (OS) and two rhabdomyosarcoma (RMS) cell lines.
  
  
  METHODS
  Clonogenic survival, cell cycle analysis, and apoptosis were examined in OS (KHOS-24OS, SAOS2) and RMS (A-204, RD) cell lines treated with HDACI and HDACI plus XRT, respectively. Protein expression was investigated via immunoblot analysis, and cell cycle analysis and measurement of apoptosis were performed using flow cytometry.
  
  
  RESULTS
  SAHA induced an inhibition of cell proliferation and clonogenic survival in OS and RMS cell lines and led to a significant radiosensitization of all tumor cell lines. Other HDACI such as M344 and valproate showed similar effects as investigated in one OS cell line. Furthermore, SAHA significantly increased radiation-induced apoptosis in the OS cell lines, whereas in the RMS cell lines radiation-induced apoptosis was insignificant with and without SAHA. In all investigated sarcoma cell lines, SAHA attenuated radiation-induced DNA repair protein expression (Rad51, Ku80).
  
  
  CONCLUSIONS
  Our results show that HDACIs enhance radiation action in OS and RMS cell lines. Inhibition of DNA repair, as well as increased apoptosis induction after exposure to HDACIs, can be mechanisms of radiosensitization by HDACIs.
authors.affiliation: Department of Pediatric Oncology, University of Heidelberg, Heidelberg, Germany. claudia.blattmann@med.uni-heidelberg.de
authors.forename: Claudia
authors.initials: C
authors.lastname: Blattmann
authors.forename: Susanne
authors.initials: S
authors.lastname: Oertel
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Markus
authors.initials: M
authors.lastname: Thiemann
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.forename: Marc
authors.initials: M
authors.lastname: Bischof
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Klaus-J
authors.initials: KJ
authors.lastname: Weber
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D000072200:Ku Autoantigen; D012516:Osteosarcoma / Q000532:radiotherapy*; D017785:Photons / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D012208:Rhabdomyosarcoma / Q000532:radiotherapy*; D014410:Tumor Stem Cell Assay / Q000379:methods; D014635:Valproic Acid / Q000627:therapeutic use; D000077337:Vorinostat
chemical_list: D034961:Antigens, Nuclear; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C515554:RAD51 associated protein 2, human; D011838:Radiation-Sensitizing Agents; D000077337:Vorinostat; D014635:Valproic Acid; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen