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Published on: March 6, 2012
Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA
1Department of Neurosurgery, Brain Tumor Center/Cancer Center, The Cleveland Clinic Foundation, Ohio 44195, USA.
Abstract:
Telomerase is the RNA-protein complex which elongates telomeric DNA (TTAGGG)n and appears to play an important role in cellular immortalization. The almost exclusive expression of telomerase in tumor cells, and not in most normal cells, offers an exciting opportunity for therapy by inhibiting its function. Here, we have investigated the effect of inhibition of telomerase on the growth and survival of human malignant glioma cells in vitro and in vivo by using a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-5A). 2-5A antisense functions by activating the endoribonuclease, RNase L, resulting in the degradation of single stranded, targeted RNA. We have shown that the 2-5A antisense treatment effectively suppressed tumor cell growth and survival in vitro. Furthermore, treatment of tumors grown in nude mice with the antisense oligonucleotide inhibited survival of the tumor cells. TUNEL assays suggest that this effect is mediated through the induction of apoptosis. Targeting telomerase RNA with 2-5A antisense, therefore, may represent an effective and novel approach for treatment of a broad range of cancers.
Insights
This study shows that a novel 2-5A antisense oligonucleotide targeting telomerase RNA effectively suppressed malignant glioma cell growth and survival. This approach may offer a new cancer therapy by inducing apoptosis in tumor cells.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Telomerase is crucial for cellular immortalization and is highly expressed in tumor cells.
- Inhibiting telomerase presents a promising therapeutic strategy for cancer treatment.
- Human malignant glioma cells are characterized by uncontrolled proliferation.
Purpose of the Study:
- To investigate the efficacy of a 2-5A antisense oligonucleotide targeting human telomerase RNA.
- To evaluate the impact of telomerase inhibition on malignant glioma cell growth and survival in vitro and in vivo.
- To explore the mechanism of action, including apoptosis induction.
Main Methods:
- Utilized a 19-mer antisense oligonucleotide against human telomerase RNA linked to 2',5'-oligoadenylate (2-5A).
- Assessed tumor cell growth and survival in vitro.
- Evaluated the effect on tumors grown in nude mice.
- Performed TUNEL assays to detect apoptosis.
Main Results:
- The 2-5A antisense treatment significantly suppressed malignant glioma cell growth and survival in vitro.
- Inhibition of tumor cell survival was observed in vivo in nude mice.
- TUNEL assays indicated that apoptosis induction is the primary mechanism behind the observed effects.
Conclusions:
- Targeting telomerase RNA with 2-5A antisense oligonucleotides is an effective strategy for inhibiting malignant glioma cell proliferation.
- This approach demonstrates potential as a novel therapeutic strategy for various cancers.
- The induction of apoptosis is a key factor in the anti-cancer effects of this treatment.
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