Author:
Choi Eun Jung,Cho Bong Jun,Lee David J,Hwang Yeo Hyeon,Chun Sun Ha,Kim Hans H,Kim In Ah
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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Cited by
94 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献