2-5A Antisense Directed against Telomerase RNA Produces Apoptosis in Ovarian Cancer Cells

Kushner, David M.; Paranjape, Jayashree M.; Bandyopadhyay, Bhaswati; Cramer, H.; Leaman, Douglas W.; Kennedy, Alexander W.; Silverman, Robert H.; Cowell, John K.

doi:10.1006/gyno.1999.5668

Cited by 72 publications

(33 citation statements)

References 29 publications

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“…Taken together, these findings suggest that the combined effect of antisense and 2 -5A actions is required for effective telomerase inhibition. Similar observations using this 2 -5A -linked anti -hTR strategy have been reported by our group and others in different types of cancers, including gliomas, 22 prostate cancer, 25 and ovarian cancer cells, 26 although these studies have not examined the telomere length before and after the treatments.…”

Section: Discussionsupporting

confidence: 83%

2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells

et al. 2002

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Human telomerase RNA ( hTR ), an important component of telomerase, is a possible target of telomerase -based cancer gene therapy. The present study was undertaken to assess the efficacy of antisense hTR therapy using newly developed 2 -5A ( 5 0 -phosphorylated 2 0 -5 0 -linked oligoadenylate ) -linked oligonucleotides against cervical cancer cells. ME180 and SiHa cells were treated with 2 -5A -linked antisense hTR designed to complement the region of hTR between residues 76 and 94. The hTR expression, telomerase activity, cell viability, and apoptosis were then examined. The 2 -5A anti -hTR effectively degraded hTR and inhibited telomerase activity. The 2 -5A mutant anti -hTR and the anti -hTR without 2 -5A were not capable of inhibiting telomerase activity. Inhibition of telomerase by 2 -5A anti -hTR rapidly decreased cell viability only in telomerase -positive cells within 3 -6 days after the treatment, when telomere length has not yet been shortened. This inhibition was associated with apoptosis, possibly through activation of caspase family members. These findings suggest that 2 -5A -linked antisense -hTR therapy has a potent telomeraseinhibitory effect associated with a cytocidal effect from caspase -induced apoptosis, and may therefore be a potential tool in telomerase -based gene therapy against cervical cancers.

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Section: Discussionsupporting

confidence: 83%

2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells

et al. 2002

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“…An antisense construct expressing 185 nucleotides of hTERC was able to shorten telomeres in HeLa cells over 23-26 population doublings via the reduction of telomerase activity and induced apoptosis (Feng et al, 1995). ODNs tagged with 2 0 -5 0 -oligoadenylate (2-5A) to bind and cleave hTERC caused apoptosis in glioma, prostate, cervical, bladder and ovarian cancer cells within 4-5 days (Kondo et al, 1998;Kushner et al, 2000;Koga et al, 2001;Yatabe et al, 2002). To enhance the binding properties to hTERC sequences and stability, 2 0 -O-methyl-RNA oligomers were developed (Herbert et al, 1999).…”

Section: Agents Targeting Htercmentioning

confidence: 99%

Telomerase and its potential for therapeutic intervention

Phatak

Burger

2007

British J Pharmacology

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Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation -a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed.

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“…An antisense oligonucleotide against hTER linked to 2 ± 5A (2 ± 5A-anti-hTER) in the presence of cationic liposome reduced the viability of human malignant glioma cells to 20 ± 43% within 4 days through induction of caspase-dependent apoptosis (Mukai et al, 2000;Komata et al, 2000). Similar antitumor e ects of 2 ± 5A-anti-hTER were demonstrated in prostate cancer, ovarian cancer, and bladder cancer cells Kushner et al, 2000;Koga et al, 2001a). In contrast, cultured astrocytes, endothelial cells, or ®broblasts lacking telomerase were resistant to the 2 ± 5A-anti-hTER treatment.…”

Section: -5a Antisense Systemmentioning

confidence: 92%

Telomerase as a therapeutic target for malignant gliomas

et al. 2002

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Telomerase, a ribonucleoprotein enzyme, is considered as a potential target of cancer therapy because of its preferential expression in tumors. In particular, malignant gliomas are one of the best candidates for telomerasetargeted therapy. It is because malignant gliomas are predominantly telomerase-positive, while normal brain tissues do not express telomerase. In theory, there are two telomerase-associated therapeutic approaches for telomerase-positive tumors. One approach is the antitelomerase cancer therapy to directly inhibit telomerase activity, resulting in apoptotic cell death or growth arrest. Two major components of the telomerase holoenzyme complex, the RNA template (hTER) and catalytic subunit (reverse transcriptase, hTERT) are well considered as therapeutic targets. The other approach is the telomerasespeci®c cancer therapy by targeting telomerase-expressing tumor cells as a means to directly kill the cells. Strategies using the transfer of therapeutic gene under the hTERT promoter system as well as immunotherapy directed against telomerase-positive cells are generally included. These telomerase-associated therapies are very promising for the treatment of malignant gliomas.

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2-5A Antisense Directed against Telomerase RNA Produces Apoptosis in Ovarian Cancer Cells

Cited by 72 publications

References 29 publications

2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells

2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells

Telomerase and its potential for therapeutic intervention

Telomerase as a therapeutic target for malignant gliomas

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