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Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases

Cited 76 time in Web of Science Cited 77 time in Scopus
Authors
Choi, Eun Jung; Cho, Bong Jun; Lee, David J; Hwang, Yeo Hyeon; Chun, Sun Ha; Kim, Hans H; Kim, In Ah
Issue Date
2014-01-13
Publisher
BioMed Central
Citation
BMC Cancer, 14(1):17
Keywords
GlioblastomaRadiosensitizationTemozolomidePro-survival signaling
Description
This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Abstract
Abstract

Background
Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR).


Methods
Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined.


Results
U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition).


Conclusions
Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas.
Language
English
URI
https://hdl.handle.net/10371/100514
DOI
https://doi.org/10.1186/1471-2407-14-17
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College of Medicine/School of Medicine (의과대학/대학원)Radiation Oncology (방사선종양학전공)Journal Papers (저널논문_방사선종양학전공)
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