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Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component
1The Center for Surgery Research, The Cleveland Clinic Foundation, OH 44195, USA.
Abstract:
Prostate cancer is the most common malignancy of elderly men in the United States. Since there is no curative treatment for advanced prostate cancer, exploration of novel modalities of treatment is essential. Telomerase, a ribonucleoprotein, is detected in the vast majority of prostate cancer, but not in normal or benign prostatic hyperplasia tissues. Thus, telomerase is expected to be a very strong candidate for targeted therapy of prostate cancer. In this study, we synthesized a 19-mer antisense oligonucleotide against the RNA component of human telomerase (hTR) linked to a 2-5A molecule (2-5A-anti-hTR) and examined its cytotoxic effect on prostate cancer cells. The 2-5A antisense strategy relies on the recruitment and activation of RNase L at the site of targeted RNA sequence. We here show that treatment with 2-5A-anti-hTR in the presence of a cationic liposome reduced cell viability of tumor cell lines tested to 9-18% within 6 days. In contrast, normal fibroblast cells were resistant to the treatment. Its effect was mainly due to induction of apoptosis by activated caspase family members. Furthermore, treatment of subcutaneous tumors in nude mice with 2-5A-anti-hTR significantly suppressed the tumor growth through induction of apoptosis (P<0.001). The treatment with 2-5A-anti-hTR may be a promising strategy for the treatment modality of prostate cancer with telomerase activity.
Insights
A novel antisense oligonucleotide targeting human telomerase RNA (hTR) effectively reduced prostate cancer cell viability and suppressed tumor growth in mice by inducing apoptosis. This targeted therapy shows promise for advanced prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer is a prevalent malignancy in elderly men, lacking curative treatments for advanced stages.
- Telomerase is highly expressed in prostate cancer but not in normal tissues, making it a potential therapeutic target.
- Antisense oligonucleotide strategies offer targeted approaches for cancer therapy.
Purpose of the Study:
- To synthesize and evaluate the efficacy of a novel 2-5A-anti-hTR antisense oligonucleotide for prostate cancer treatment.
- To investigate the cytotoxic effects and mechanism of action of 2-5A-anti-hTR on prostate cancer cells and tumors.
Main Methods:
- Synthesis of a 19-mer antisense oligonucleotide targeting human telomerase RNA (hTR), linked to a 2-5A molecule (2-5A-anti-hTR).
- Assessment of cytotoxic effects on prostate cancer cell lines and normal fibroblasts using cationic liposomes for delivery.
- Evaluation of tumor growth suppression and apoptosis induction in subcutaneous mouse xenograft models.
Main Results:
- 2-5A-anti-hTR treatment significantly reduced prostate cancer cell viability to 9-18% within 6 days.
- Normal fibroblast cells exhibited resistance to the treatment.
- Significant tumor growth suppression (P<0.001) was observed in vivo, primarily through the induction of apoptosis via activated caspase family members.
Conclusions:
- The 2-5A-anti-hTR compound demonstrates potent and selective cytotoxic effects against prostate cancer cells.
- This novel therapeutic strategy effectively suppresses tumor growth in vivo by inducing apoptosis.
- 2-5A-anti-hTR represents a promising targeted therapy for prostate cancer exhibiting telomerase activity.
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