Abstract
AS1411 binds nucleolin (NCL) and is the first oligodeoxynucleotide aptamer to reach phase I and II clinical trials for the treatment of several cancers. However, the mechanisms by which AS1411 targets and kills glioma cells and tissues remain unclear. Here we report that AS1411 induces cell apoptosis and cycle arrest, and inhibits cell viability by up-regulation of p53 and down-regulation of Bcl-2 and Akt1 in human glioma cells. NCL was overexpressed in both nucleus and cytoplasm in human glioma U87, U251 and SHG44 cells compared to normal human astrocytes (NHA). AS1411 bound NCL and inhibited the proliferation of glioma cells but not NHA, which was accompanied with up-regulation of p53 and down-regulation of Bcl-2 and Akt1. Moreover, AS1411 treatment resulted in the G2/M cell cycle arrest in glioma cells, which was however abolished by overexpression of NCL. Further, AS1411 induced cell apoptosis, which was prevented by silencing of p53 and overexpression of Bcl-2. In addition, AS1411 inhibited the migration and invasion of glioma cells in an Akt1-dependent manner. Importantly, AS1411 inhibited the growth of glioma xenograft and prolonged the survival time of glioma tumor-bearing mice. These results revealed a promising treatment of glioma by oligodeoxynucleotide aptamer.
Highlights
Glioblastoma (GBM) is one of the most common and devastating primary malignant intracranial tumors in human
The results showed that NCL was highly stained in both nucleus and cytoplasm in U87 cells but only stained in nucleus in normal human astrocytes (NHA) (Fig 1f)
We demonstrated that NCL was over-expressed in glioma cells and tissues
Summary
Glioblastoma (GBM) is one of the most common and devastating primary malignant intracranial tumors in human. The current therapy for newly diagnosed GBM is surgical resection followed by radiotherapy plus chemotherapy [1]. The prognosis is poor with a median overall survival of only 14.6 months, median progression free survival of 6.9 months and 5 year survival rate of only 9.8% after diagnosis [1, 2]. The treatment failure mainly results from the resistance of malignant glioma cells to current therapeutic modules [3], it is in urgent need to identify effective modalities for the management of glioma patients. Aptamers are designed as 12–30 bases oligonucleotides (ssDNA or RNA), or peptides. They were first identified from basic science studies with viruses in the 1980s and have been found
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