Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor

被引:32
作者
Arivazhagan, A. [2 ]
Kumar, Durairaj Mohan [1 ]
Sagar, Vinay [3 ]
Patric, Irene Rosita Pia [1 ]
Sridevi, S. [1 ]
Thota, Balaram
Srividya, Mallavarapu R.
Prasanna, K. [4 ]
Thennarasu, K.
Mondal, Neelima [3 ]
Hegde, A. S. [4 ]
Chandramouli, B. A. [2 ]
Santosh, V.
Rao, M. R. S. [5 ]
Kondaiah, P.
Somasundaram, K. [1 ]
机构
[1] Indian Inst Sci, Dept Microbiol & Cell Biol, Bangalore 560012, Karnataka, India
[2] Natl Inst Mental Hlth & Neurosci, Dept Neurosurg, Bangalore 560029, Karnataka, India
[3] Jawaharlal Nehru Univ, Sch Life Sci, New Delhi 110067, India
[4] Sri Satya Sai Inst Higher Med Sci, Bangalore 560066, Karnataka, India
[5] Jawaharlal Nehru Ctr Adv Sci Res, Bangalore 560064, Karnataka, India
关键词
Glioma; Astrocytoma; Glioblastoma; Prognosis; TOP2A; Temozolomide chemotherapy; II-ALPHA; BREAST-CANCER; PROLIFERATION MARKER; DNA TOPOISOMERASES; MALIGNANT GLIOMA; CELL-LINES; ETOPOSIDE; EXPRESSION; SENSITIVITY; RESISTANT;
D O I
10.1007/s11060-011-0758-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
The search for molecular markers which predict response to chemotherapy is an important aspect of current neuro-oncology research. MGMT promoter methylation is the only proved marker of glioblastoma. The purpose of this study was to assess the effect of topoisomerase expression on glioblastoma survival and study the mechanisms involved. The transcript levels of all isoforms of the topoisomerase family in all grades of diffuse astrocytoma were assessed. A prospective study of patients with glioblastoma treated by a uniform treatment procedure was performed with the objective of correlating outcome with gene expression. The ability of TOP2A enzyme to relax the super coiled plasmid DNA in the presence of temozolomide was evaluated to assess its effect on TOP2A. The temozolomide cyctotoxicity of TOP2A-silenced U251 cells was assessed. The transcript levels of TOP2A, TOP2B, and TOP3A are upregulated significantly in GBM in comparison with lower grades of astrocytoma and normal brain samples. mRNA levels of TOP2A correlated significantly with survival of the patients. Higher TOP2A transcript levels in GBM patients predicted better prognosis (P = 0.043; HR = 0.889). Interestingly, we noted that temozolomide inhibited TOP2A activity in in-vitro enzyme assays. We also noted that siRNA knock down of TOP2A rendered a glioma cell line resistant to temozolomide chemotherapy. We demonstrated for the first time that temozolomide is also a TOP2A inhibitor and established that TOP2A transcript levels determine the chemosensitivity of glioblastoma to temozolomide therapy. Very high levels of TOP2A are a good prognostic indicator in GBM patients receiving temozolomide chemotherapy.
引用
收藏
页码:289 / 297
页数:9
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