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

被引：97

作者：

Choi, Eun Jung ^{[1
]}

Cho, Bong Jun ^{[1
]}

Lee, David J. ^{[1
]}

Hwang, Yeo Hyeon ^{[1
]}

Chun, Sun Ha ^{[1
]}

Kim, Hans H. ^{[1
]}

Kim, In Ah ^{[1
,2
]}

机构：

[1] Seoul Natl Univ Bundang Hosp, Dept Radiat Oncol, Bundanggu, Seongnamsi Kyeo, South Korea

[2] Seoul Natl Univ, Canc Res Inst, Seoul 110779, South Korea

来源：

BMC CANCER | 2014年 / 14卷

基金：

新加坡国家研究基金会;

关键词：

Glioblastoma; Radiosensitization; Temozolomide; Pro-survival signaling; GROWTH-FACTOR RECEPTOR; MOLECULAR CHAPERONE; CANCER CELLS; TUMOR-CELLS; PHASE-II; GLIOBLASTOMA; INHIBITOR; EGFR; HEAT-SHOCK-PROTEIN-90; KINASE;

D O I：

10.1186/1471-2407-14-17

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页数：12

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