title: High linear-energy-transfer radiation can overcome radioresistance of glioma stem-like cells to low linear-energy-transfer radiation.
abstract: Ionizing radiation is applied as the standard treatment for glioblastoma multiforme (GBM). However, radiotherapy remains merely palliative, not curative, because of the existence of glioma stem cells (GSCs), which are regarded as highly radioresistant to low linear-energy-transfer (LET) photons. Here we analyzed whether or not high-LET particles can overcome the radioresistance of GSCs. Glioma stem-like cells (GSLCs) were induced from the GBM cell line A172 in stem cell culture medium. The phenotypes of GSLCs and wild-type cells were confirmed using stem cell markers. These cells were irradiated with (60)Co gamma rays or reactor neutron beams. Under neutron-beam irradiation, high-LET proton particles can be produced through elastic scattering or nitrogen capture reaction. Radiosensitivity was assessed by a colony-forming assay, and the DNA double-strand breaks (DSBs) were assessed by a histone gamma-H2AX focus detection assay. In stem cell culture medium, GSLCs could form neurosphere-like cells and express neural stem cell markers (Sox2 and Musashi) abundantly in comparison with their parental cells. GSLCs were significantly more radioresistant to gamma rays than their parental cells, but neutron beams overcame this resistance. There were significantly fewer gamma-H2AX foci in the A172 GSLCs 24 h after irradiation with gamma rays than in their parental cultured cells, while there was no apparent difference following neutron-beam irradiation. High-LET radiation can overcome the radioresistance of GSLCs by producing unrepairable DNA DSBs. High-LET radiation therapy might have the potential to overcome GBM's resistance to X-rays in a clinical setting.
authors: Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
authors: Yuki
authors: Y
authors: Hirota
authors: Shin-Ichiro
authors: S
authors: Masunaga
authors: Natsuko
authors: N
authors: Kondo
authors: Shinji
authors: S
authors: Kawabata
authors: Hirokazu
authors: H
authors: Hirakawa
authors: Hirohiko
authors: H
authors: Yajima
authors: Akira
authors: A
authors: Fujimori
authors: Koji
authors: K
authors: Ono
authors: Toshihiko
authors: T
authors: Kuroiwa
authors: Shin-Ichi
authors: S
authors: Miyatake
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005909:Glioblastoma / Q000473:pathology / Q000503:physiopathology* / Q000532:radiotherapy*; D006801:Humans; D018499:Linear Energy Transfer / Q000528:radiation effects*; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology* / Q000528:radiation effects*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000528:radiation effects*
keywords: gamma rays; glioblastoma multiforme; glioma stem cells; linear energy transfer; neutron beams
references: J Neurooncol. 2009 Jan;91(2):199-206
references: 18813875
references: Int J Radiat Biol. 2006 Feb;82(2):111-8
references: 16546909
references: Mutat Res. 2009 Oct 2;669(1-2):8-12
references: 19576233
references: Cancer Res. 2003 Sep 15;63(18):5821-8
references: 14522905
references: J Neurosurg. 2005 Dec;103(6):1000-9
references: 16381186
references: Neurosurgery. 2007 Jul;61(1):82-90; discussion 90-1
references: 17621022
references: Int J Radiat Biol. 2009 May;85(5):391-402
references: 19382020
references: Oncogene. 2004 Dec 16;23(58):9392-400
references: 15558011
references: Nat Rev Cancer. 2006 Jun;6(6):425-36
references: 16723989
references: Int J Radiat Biol. 2010 Aug;86(8):682-91
references: 20569192
references: Nat Rev Cancer. 2008 Jul;8(7):545-54
references: 18511937
references: Neurosurgery. 2008 Feb;62(2):505-14; discussion 514-5
references: 18382330
references: Nature. 2006 Dec 7;444(7120):756-60
references: 17051156
references: Cancer Res. 2008 Jul 15;68(14):5915-23
references: 18632646
references: Radiat Oncol. 2011 Sep 05;6:106
references: 21888676
references: Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):390-6
references: 17459607
references: Nature. 2004 Nov 18;432(7015):396-401
references: 15549107
references: Biochem Biophys Res Commun. 2009 Mar 6;380(2):236-42
references: 19166820
references: Radiat Res. 1982 Jul;91(1):77-94
references: 7100396
references: Cancer Lett. 2009 Jun 28;279(1):13-21
references: 19232461
references: Radiat Res. 1975 Feb;61(2):304-15
references: 803317
references: Oncogenesis. 2012 Jun 04;1:e12
references: 23552696
references: Cancer Lett. 2010 May 28;291(2):150-7
references: 19913993
references: Nat Rev Genet. 2001 Mar;2(3):196-206
references: 11256071
references: J Radiat Res. 2009 Jan;50(1):51-60
references: 18957828
references: DNA Repair (Amst). 2008 Mar 1;7(3):405-17
references: 18248856
references: Radiat Res. 2006 Jan;165(1):59-67
references: 16392963
references: N Engl J Med. 2005 Mar 10;352(10):987-96
references: 15758009
references: Cancer Res. 2011 May 15;71(10):3676-87
references: 21454414
references: Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1226-35
references: 19545788