Low dose ionizing radiation responses and knockdown of ATM kinase activity in glioma stem cells

Lim, Yi Chieh, Roberts, Tara, Harding, Angus, Day, Bryan, Kozlov, Sergei, Walker, David and Lavin, Martin (2008) Low dose ionizing radiation responses and knockdown of ATM kinase activity in glioma stem cells. Acta Medica Nagasakiensia, 53 Suppl.: 37-43.


Author Lim, Yi Chieh
Roberts, Tara
Harding, Angus
Day, Bryan
Kozlov, Sergei
Walker, David
Lavin, Martin
Title Low dose ionizing radiation responses and knockdown of ATM kinase activity in glioma stem cells
Journal name Acta Medica Nagasakiensia   Check publisher's open access policy
ISSN 0001-6055
Publication date 2008
Year available 2008
Sub-type Article (original research)
Open Access Status
Volume 53
Issue Suppl.
Start page 37
End page 43
Total pages 7
Place of publication Nagasaki-ken, Japan
Publisher Nagasaki Daigaku * Igakubu
Collection year 2009
Language eng
Subject 2700 Medicine
Formatted abstract
Genesis of new cells in the mammalian brain has previously been regarded as a negligible event; an assumption that long prevented our understanding in the development of neoplasias. The recent discovery of perpetual lineages derived from neural stem cells has resulted in a new approach to studying the cellular behaviour of potential cancer stem cells in the brain. Glioblastoma multiforme (GBM), the most aggressive and lethal brain tumour is derived from such a group of cancerous stem cells known as glioma stem cells. GBM cells are impervious to conventional therapies such as surgical resection and ionizing radiation because of their pluripotent and radioresistant properties. Thus in our study, we aim to investigate whether a combination of chemo- and radio- therapies is an effective treatment for glioma stem cells. The study utilizes a specific kinase inhibitor (ATMi) of the ATM (Ataxia-telangiectasia mutated) protein which is an essential protein in DNA-damage responses. In the presence of both low dose radiation and ATMi, glioma stem cells have rapid onset of cell death and reduction in growth. Since DNA damage can be inherited through cell division, accumulated DNA breaks in later generations may also lead to cell death. The limitation of conventional radiation therapy is that administration of fractionated (low) doses to reduce any potential harm to the surrounding healthy cells in the brain outweighs the benefits of high radiation doses to induce actual arrest in the propagation of malignant cells. Our study demonstrates a benefit in using low dose radiation combined with chemotherapy resulting in a reduction in malignancy of glioma stem cells.

Genesis of new cells in the mammalian brain has previously been regarded as a negligible event; an assumption that long prevented our understanding in the development of neoplasias. The recent discovery of perpetual lineages derived from neural stem cells has resulted in a new approach to studying the cellular behaviour of potential cancer stem cells in the brain. Glioblastoma multiforme (GBM), the most aggressive and lethal brain tumour is derived from such a group of cancerous stem cells known as glioma stem cells. GBM cells are impervious to conventional therapies such as surgical resection and ionizing radiation because of their pluripotent and radioresistant properties. Thus in our study, we aim to investigate whether a combination of chemo- and radio- therapies is an effective treatment for glioma stem cells. The study utilizes a specific kinase inhibitor (ATMi) of the ATM (Ataxia-telangiectasia mutated) protein which is an essential protein in DNA-damage responses. In the presence of both low dose radiation and ATMi, glioma stem cells have rapid onset of cell death and reduction in growth. Since DNA damage can be inherited through cell division, accumulated DNA breaks in later generations may also lead to cell death. The limitation of conventional radiation therapy is that administration of fractionated (low) doses to reduce any potential harm to the surrounding healthy cells in the brain outweighs the benefits of high radiation doses to induce actual arrest in the propagation of malignant cells. Our study demonstrates a benefit in using low dose radiation combined with chemotherapy resulting in a reduction in malignancy of glioma stem cells. 
Keyword ATM inhibitor
DNA damage
Glioma stem cell
Ionizing radiation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
School of Medicine Publications
 
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