Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component.
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.
Kondo
Y
Y
The Center for Surgery Research, The Cleveland Clinic Foundation, OH 44195, USA.
Koga
S
S
Komata
T
T
Kondo
S
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D004337:Drug Carriers; D004789:Enzyme Activation; D006801:Humans; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D012313:RNA / Q000235:genetics / Q000627:therapeutic use*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D019098:Telomerase / Q000235:genetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; D020169:Caspases