Inhibition of human telomerase by oligonucleotide chimeras, composed of an antisense moiety and a chemically modified homo‐oligonucleotide

Tárkányi, Ilona; Horváth, András; Szatmári, István; Eizert, Helga; Vámosi, György; Damjanovich, Sándor; Ségal-Bendirdjian, Évelyne; Aradi, J.

doi:10.1016/j.febslet.2005.01.041

Cited by 22 publications

(18 citation statements)

References 20 publications

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“…A lot of reports have confirmed that antisense oligonucleotides can bind start location of mRNA translation inside cells, block translation of target RNA into target protein, and finally suppress cellular proliferation (14)(15)(16). However, antisense therapy is still restricted in application of clinical therapy because of two existing problems, such as rapid degradation by exonuclease or endonuclease and poor diffusion across the cell membrane (17)(18)(19). Although some methods, such as chemically modified oligonucleotides, oligonucleotides bound to virus and synthetic carriers, and small interfering RNA, have been explored to solve these problems (20,21), so far no optimal solution is established.…”

Section: Introductionmentioning

confidence: 99%

Dendrimer-Modified Magnetic Nanoparticles Enhance Efficiency of Gene Delivery System

Pan

Cui²,

Sheng³

et al. 2007

Cancer Research

295

165

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Magnetic nanoparticles (MNP) with a diameter of 8 nm were modified with different generations of polyamidoamine (PAMAM) dendrimers and mixed with antisense survivin oligodeoxynucleotide (asODN). The MNP then formed asODNdendrimer-MNP composites, which we incubated with human tumor cell lines such as human breast cancer MCF-7, MDA-MB-435, and liver cancer HepG2 and then analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, quantitative reverse transcription-PCR, Western blotting, laser confocal microscopy, and high-resolution transmission electron microscopy. Results showed that the asODN-dendrimer-MNP composites were successfully synthesized, can enter into tumor cells within 15 min, caused marked down-regulation of the survivin gene and protein, and inhibited cell growth in dose-and time-dependent means. No.5 generation of asODN-dendrimer-MNP composites exhibits the highest efficiency for cellular transfection and inhibition. These results show that PAMAM dendrimer-modified MNPs may be a good gene delivery system and have potential applications in cancer therapy and molecular imaging diagnosis.

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Section: Introductionmentioning

confidence: 99%

Dendrimer-Modified Magnetic Nanoparticles Enhance Efficiency of Gene Delivery System

Pan

Cui²,

Sheng³

et al. 2007

Cancer Research

295

165

View full text Add to dashboard Cite

show abstract

“…It must be noted that UD29 is a mononucleotide, however, its deoxyoligonucleotide derivatives are also active biologically inhibiting the HIV entry and the telomerase enzyme [18,29,30]. Preliminary results on the activity of some other derivatives of the thiolated nucleotide and polynucleotide have also been reported [31].…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Kanizsai

Ghidán

Ongrádi

et al. 2012

Acta Microbiologica Et Immunologica Hungarica

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Antiretroviral effect of thiolated nucleotide 4-thio-uridylate (S 4 UMP, designated as UD29) against human immunodeficiency virus type 1 (HIV-1) have been quantitatively determined in cell-based viral infectivity assays. In syntitium inhibition assay on MT-2 human T-cell line UD29 prevented cell fusion and formation of syntitia induced by HIV-1 IIIB with IC 50 values of 11.7 µg/ml. In a single-cycle viral infection assay (MAGI assay) UD29 proved to have a potent inhibitory effect against HIV-1 IIIB on HeLaCD4-LTR/b-gal cells, which was dose dependent with IC 50 values of 4.75 µg/ml and IC 90 of 39.7 µg/ml. UD29 showed a most prominent antiviral effect when administered 30 min prior HIV-1 infection. As HIV entry requires thiol/disulfide exchange process, results suggest that reactive -SH group of enol-form of the thiolated nucleotide may interfere with the function of cell surface proteins. UD29 cannot penetrate into cells and may have an interactive role in redox processes active in viral entry.

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“…3 In eukaryotic chromosomal DNA, telomeres are shortened each time a cell divides until they reach critical lengths that trigger cell death. 4 On the other hand, most cancer cells demonstrate high telomerase expression and the majority of human cancers prevent telomere erosion by telomerase. Telomerase activation by human telomerase reverse transcriptase (hTERT) has been described as a critical step during cancer progression, and the telomerase activation is also related to tumor cell radioresistance.…”

Section: Introductionmentioning

confidence: 99%

Complementary treatment of siTERT for improving the antitumor effect of TERT-specific I-131 therapy

et al. 2012

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Sodium iodide symporter (NIS)-based radionuclide therapy provides an effective means of treating malignant tumors. However, it is sometimes inadequate because of limited effects on radio-resistant tumors, and thus, combination therapies with other therapeutic options have been requested to enhance its efficacy. Human telomerase reverse transcriptase (hTERT) has been reported to be involved in the progression of most cancers and also been viewed as a good candidate for targeting tumor. Application of TERTspecific radionuclide therapies using NIS gene transfer have been reported to treat TERT-positive tumors, but this approach only demonstrated tumor regression rather than eradication. As inhibiting TERT expression by introducing the hTERT-specific shRNA (siTERT) has been suggested as a therapeutic option, we investigated the complementary role of siTERT treatment after the TERTspecific I-131 therapy and its possibility as a novel anticancer therapeutic strategy. Retroviruses containing TERT promoter/NIS for TERT specific Radionuclide therapy and siTERT for TERT targeting antisense therapy were produced. Hep3B cells expressing TERT specific NIS (Hep3B-TERT/NIS) were xenografted into nude mouse and visualized with micro-SPECT/CT for monitoring NIS activity. The levels of hTERT mRNA, protein and its activity were confirmed by RT-PCR, Western blotting and Telomerase repeat amplification protocol assay. Cell proliferation was monitored by MTT assay and induced apoptosis was confirmed by Annexin-V-PI staining. Therapeutic effects of I-131 and/or siTERT were evaluated by clonogenic assay and mouse tumor model. Reduction of hTERT mRNA, protein and TERT activity by siTERT were observed in Hep3B-TERT/NIS cells. The viabilities of the infected cells were significantly decreased to 50% versus siScramble treated controls. The early apoptotic cell population was increased by siTERT. The survival rates of cells treated with siTERT or I-131 alone were 72.4 ± 7.6% and 56.2 ± 5.2%, respectively. However, the survival rate of cells treated with I-131 and siTERT were decreased to 22.1 ± 2.8%. From mouse xenograft model, we also found that the siTERT gene therapy showed synergism to the radioiodine therapy for reducing tumor growth in vivo. Our Results suggested that complementary siTERT gene therapy offers a novel strategy of cancer therapy to improve the therapeutic efficacy of TERT-specific I-131.

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Inhibition of human telomerase by oligonucleotide chimeras, composed of an antisense moiety and a chemically modified homo‐oligonucleotide

Cited by 22 publications

References 20 publications

Dendrimer-Modified Magnetic Nanoparticles Enhance Efficiency of Gene Delivery System

Dendrimer-Modified Magnetic Nanoparticles Enhance Efficiency of Gene Delivery System

Antiretroviral effect of 4-thio-uridylate against human immunodeficiency virus type 1

Complementary treatment of siTERT for improving the antitumor effect of TERT-specific I-131 therapy

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