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BMC Cancer

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Open Access 01-12-2014 | Research article

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

Authors: Eun Jung Choi, Bong Jun Cho, David J Lee, Yeo Hyeon Hwang, Sun Ha Chun, Hans H Kim, In Ah Kim

Published in: BMC Cancer | Issue 1/2014

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.

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/17/prepub

Title: Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases
Authors: Eun Jung Choi
Bong Jun Cho
David J Lee
Yeo Hyeon Hwang
Sun Ha Chun
Hans H Kim
In Ah Kim
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-14-17

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