PMID- 24678590
OWN - NLM
STAT- MEDLINE
DCOM- 20141203
LR  - 20211021
IS  - 1748-717X (Electronic)
IS  - 1748-717X (Linking)
VI  - 9
IP  - 1
DP  - 2014 Mar 30
TI  - Fractionated radiotherapy is the main stimulus for the induction of cell death 
      and of Hsp70 release of p53 mutated glioblastoma cell lines.
PG  - 89
LID - 10.1186/1748-717X-9-89 [doi]
AB  - BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary brain tumor 
      in adults. Despite a multimodal therapy consisting of resection followed by 
      fractionated radiotherapy (RT) combined with the chemotherapeutic agent (CT) 
      temozolomide (TMZ), its recurrence is almost inevitable. Since the immune system 
      is capable of eliminating small tumor masses, a therapy should also aim to 
      stimulate anti-tumor immune responses by induction of immunogenic cell death 
      forms. The histone deacetylase inhibitor valproic acid (VPA) might foster this. 
      METHODS: Reflecting therapy standards, we applied in our in vitro model 
      fractionated RT with a single dose of 2Gy and clinically relevant concentrations 
      of CT. Not only the impact of RT and/or CT with TMZ and/or VPA on the clonogenic 
      potential and cell cycle of the glioblastoma cell lines T98G, U251MG, and U87MG 
      was analyzed, but also the resulting cell death forms and release of danger 
      signals such as heat-shock protein70 (Hsp70) and high-mobility group protein B1 
      (HMGB1). RESULTS: The clonogenic assays revealed that T98G and U251MG, having 
      mutated tumor suppressor protein p53, are more resistant to RT and CT than U87MG 
      with wild type (WT) p53. In all glioblastoma cells lines, fractionated RT induced 
      a G2 cell cycle arrest, but only in the case of U87MG, TMZ and/or VPA alone 
      resulted in this cell cycle block. Further, fractionated RT significantly 
      increased the number of apoptotic and necrotic tumor cells in all three cell 
      lines. However, only in U87MG, the treatment with TMZ and/or VPA alone, or in 
      combination with fractionated RT, induced significantly more cell death compared 
      to untreated or irradiated controls. While necrotic glioblastoma cells were 
      present after VPA, TMZ especially led to significantly increased amounts of U87MG 
      cells in the radiosensitive G2 cell cycle phase. While CT did not impact on the 
      release of Hsp70, fractionated RT resulted in significantly increased 
      extracellular concentrations of Hsp70 in p53 mutated and WT glioblastoma cells. 
      CONCLUSIONS: Our results indicate that fractionated RT is the main stimulus for 
      induction of glioblastoma cell death forms with immunogenic potential. The 
      generated tumor cell microenvironment might be beneficial to include immune 
      therapies for GBM in the future.
FAU - Rubner, Yvonne
AU  - Rubner Y
FAU - Muth, Carolin
AU  - Muth C
FAU - Strnad, Annedore
AU  - Strnad A
FAU - Derer, Anja
AU  - Derer A
FAU - Sieber, Renate
AU  - Sieber R
FAU - Buslei, Rolf
AU  - Buslei R
FAU - Frey, Benjamin
AU  - Frey B
FAU - Fietkau, Rainer
AU  - Fietkau R
FAU - Gaipl, Udo S
AU  - Gaipl US
AD  - Department of Radiation Oncology, University Hospital Erlangen, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany. 
      udo.gaipl@uk-erlangen.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140330
PL  - England
TA  - Radiat Oncol
JT  - Radiation oncology (London, England)
JID - 101265111
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HMGB1 Protein)
RN  - 0 (HMGB1 protein, human)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Antineoplastic Agents/administration & dosage
MH  - Apoptosis
MH  - Brain Neoplasms/*radiotherapy
MH  - Cell Cycle
MH  - Cell Death
MH  - Cell Line, Tumor
MH  - Dacarbazine/administration & dosage/analogs & derivatives
MH  - *Dose Fractionation, Radiation
MH  - G2 Phase
MH  - Glioblastoma/*drug therapy/*genetics/*radiotherapy
MH  - HMGB1 Protein/metabolism
MH  - HSP70 Heat-Shock Proteins/*metabolism
MH  - Humans
MH  - Mutation
MH  - Necrosis
MH  - Temozolomide
MH  - Tumor Suppressor Protein p53/*genetics
MH  - Valproic Acid/chemistry
PMC - PMC3994240
EDAT- 2014/04/01 06:00
MHDA- 2014/12/15 06:00
PMCR- 2014/03/30
CRDT- 2014/04/01 06:00
PHST- 2014/01/13 00:00 [received]
PHST- 2014/03/27 00:00 [accepted]
PHST- 2014/04/01 06:00 [entrez]
PHST- 2014/04/01 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
PHST- 2014/03/30 00:00 [pmc-release]
AID - 1748-717X-9-89 [pii]
AID - 10.1186/1748-717X-9-89 [doi]
PST - epublish
SO  - Radiat Oncol. 2014 Mar 30;9(1):89. doi: 10.1186/1748-717X-9-89.