Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer cell lines

Murakami, Junko; Nagai, Nobuo; Shigemasa, Kazushi; Ohama, Koso

doi:10.1016/s0959-8049(99)00037-4

Cited by 63 publications

(46 citation statements)

References 26 publications

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“…Azydothymidine (AZT), an antiviral compound currently being used as a treatment for AIDS, produces effective inhibition of telomerase activity in multiple cell lines along with progressive telomere shortening and cytotoxic effects, both of which seem to be cell line dependent. When delivered to ovarian mucinous cystadenocarcinoma and uterine endometrial carcinoma cells, antiproliferative effects were observed after only 3 days, despite a reported lack of telomerase activity inhibition [41]. In contrast, when administered to various breast cancer cell lines, antiproliferative effects were not observed until much later, but were accompanied by inhibition of telomerase activity [42].…”

Section: Htert Inhibition By Nucleoside Analogs and Small Moleculesmentioning

confidence: 99%

Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity

2008

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Telomeres, the specialized structures that comprise the ends of chromosomes, form a closed structure, or t-loop, that is important in preventing genomic instability. Forced modulation of this structure, via overexpression of a dominant-negative form of telomere repeat binding factor 2, a protein critical for maintaining t-loop structure, for example, can result in the activation of DNA-damage responses, and ultimately cellular senescence or apoptosis. This response is also seen in normal somatic cells, where telomeres steadily decrease in length as cellular proliferation occurs owing to inefficient replication of terminal telomeric DNA. When telomere length becomes critically short, t-loop structure is compromised, and the cell undergoes senescence. Telomerase, the enzyme responsible for telomere length maintenance, is overexpressed in a majority of cancers. Its lack of expression in most normal somatic cells makes it an attractive target in designing cancer therapeutics. Compounds currently under development that seek to inhibit hTERT, the reverse transcriptase component of telomerase, include nucleoside analogs and the small molecule BIBR1532. Compounds inhibiting the RNA component of telomerase, hTERC, include peptide nucleic acids, 2-5A antisense oligonucleotides, and N3'-P5' thio-phosphoramidates. Recently, an oligonucleotide sharing sequence homology with terminal telomeric DNA, termed 'T-oligo', has shown cytotoxic effects in multiple cancers in culture and animal models. Independent of telomerase function, T-oligo is thought to mimic the DNA-damage response a cell normally experiences when the telomere t-loop structure becomes dysfunctional. In this review, the molecular mechanisms attributed to telomerase inhibitors and T-oligo, as well as their potential as cancer therapeutics, are discussed.

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Section: Htert Inhibition By Nucleoside Analogs and Small Moleculesmentioning

confidence: 99%

Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity

2008

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“…Second, AZT works as a reverse transcriptase inhibitor and affects telomerase activity (which has reverse transcriptase activity). Telomerase activity is not detected in normal cells, but is active in germ cells, stem cells, and cancer cells and correlates with the increased cell growth malign cells compared with benign cells [17][18][19]. Third, epidemiological research on AIDS patients treated with antiretroviral drugs showed that antiretroviral therapy correlates with a reduced incidence of AIDS-related tumors, for example, Kaposi sarcoma, Kaposi sarcoma-associated primary effusion lymphoma, Epstein-Barr virus-associated lymphoma or primary central nervous system lymphoma [20][21][22][23][24][25][26][27].…”

Section: Azidothymidine Inhibits Melanoma Cell Growth In Vitro and Inmentioning

confidence: 99%

Azidothymidine inhibits melanoma cell growth in vitro and in vivo

Humer¹,

Ferko²,

Waltenberger³

et al. 2008

Melanoma Research

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Azidothymidine (AZT), currently used for HIV treatment, was also shown to induce cell growth inhibition and apoptosis in different human tumors. The objective of this study was to investigate the ability of AZT to inhibit the growth of human melanoma cells in vitro and in vivo. In cytotoxicity assays, treatment of cells with varying concentrations of AZT-induced inhibition of cell growth and apoptosis in three human melanoma cell lines without affecting the growth of nontumorigenic cells. AZT-dependent inhibition of proliferation was accompanied by a significant S-phase arrest of the cell cycle. Coexposure of cells to AZT during cisplatin treatment showed a synergistic effect on cytotoxicity. Moreover, AZT monotreatment of melanoma in a severe combined immunodeficiency-mouse xenotransplantation model resulted in significant tumor reduction. These results demonstrate for the first time the antimelanoma activity of AZT, suggesting its clinical utilization either as a sole agent or in combination with other chemotherapeutic agents.

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“…Antisense-EGFR transfected cells, which expressed low telomerase activity, exhibited shorter peak TRF length than control cells, this result is in keeping with the role of telomerase for maintenance of telomere. Murakami et al (1999) used reverse transcriptase inhibitors, dideoxyinosine (ddI) and AZT-5' triphosphate (AZT-TP), to inhibit telomerase activity of gynaecological cancer cells. They found that ddI and AZT-TP treatment of tumour cells reduced telomerase activity, shortened the length of the telomere and increased p53 expression.…”

Section: Discussionmentioning

confidence: 99%

Antisense epidermal growth factor receptor RNA transfection in human glioblastoma cells down-regulates telomerase activity and telomere length

et al. 2002

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Epidermal growth factor receptor is overexpressed and/or amplified in up to 50% of glioblastomas, suggesting an important role of this gene in glial tumorigenesis and progression. In the present study we demonstrated that epidermal growth factor receptor is involved in regulation of telomerase activity in glioblastoma. Antisense-epidermal growth factor receptor approach was used to inhibit epidermal growth factor receptor expression of glioblastoma U87MG cells. Telomerase activity in antisense-epidermal growth factor receptor cells decreased by up to 54 folds compared with control cells. Moreover, the telomere lengths of antisense-epidermal growth factor receptor cells were shortened. In addition, the tumorigenicity of antisense-epidermal growth factor receptor cells was significantly inhibited. Taken together, there were strong correlations between tumorigenicity and epidermal growth factor receptor expression levels, and between tumorigenicity and telomerase activity. These results provide evidence that epidermal growth factor receptor plays an important role in the regulation of telomerase activity of glioma cells. Our findings provide new insights into both the biological functions of epidermal growth factor receptor and the regulation of telomerase activity. The inhibition of telomerase activity triggered by antisense-epidermal growth factor receptor treatment may reflect yet another mechanism of antisense-epidermal growth factor receptor approach in tumour suppression.

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Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer cell lines

Cited by 63 publications

References 26 publications

Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity

Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity

Azidothymidine inhibits melanoma cell growth in vitro and in vivo

Antisense epidermal growth factor receptor RNA transfection in human glioblastoma cells down-regulates telomerase activity and telomere length

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