Targeting telomerase for cancer therapeutics

Shay, Jerry W.; Keith, W. Nicol

doi:10.1038/sj.bjc.6604209

Cited by 151 publications

(132 citation statements)

References 31 publications

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“…The upregulation of telomerase in most human cancers and its requirement for proliferation makes anti-telomerase compounds a potential means to induce telomere shortening and initiation of a senescence program in tumor cells 64 . For example, treatment of HT1080 fibrosarcoma cell lines with the telomerase inhibitor BIBR1532 results in progressive telomere shortening, induction of a senescence phenotype and inhibition of tumor growth when transplanted into recipient mice 65 .…”

Section: Future Anti-cancer Therapy: Therapeutic Strategies That Targmentioning

confidence: 99%

Telomere dysfunction and tumour suppression: the senescence connection

2008

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Long lived organisms such as humans have evolved several intrinsic tumor suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem cell compartments. One of these anti-cancer barriers is the telomere, a specialized nucleoprotein that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.More than 40 years ago, Hayflick and Moorhead discovered that normal human diploid fibroblasts (HDFs) cannot grow indefinitely in culture 1 . Rather, their proliferative capacities are intrinsically limited. After 60-80 population doublings in culture, HDFs stop dividing and adopt a phenotype characterized by large, flat cell size, a vacuolated morphology, inability to synthesize DNA, and the presence of the senescence-associated β-galactosidase (SA-β-gal) marker 2 . We now know that the endpoint of this proliferative limit, termed replicative senescence, is due largely to erosion of telomeres, protective structures that cap the end of all eukaryotic chromosomes. Confirmation of this came from studies in which telomerase, the enzyme that maintains telomeres, was ectopically expressed in normal human somatic cells 3,4 . Activation of telomerase results in telomere elongation, abrogation of replicative senescence, a normal karyotype and cellular immortalization. These results clearly demonstrate that telomere length determines the proliferative lifespan of HDFs, and that upregulation of telomerase activity (hence telomere length) restores proliferative capacity.A large body of experimental evidence has demonstrated that telomere attrition contributes to tumorigenesis by promoting genome instability 5 . However, in the setting of a competent p53 pathway, mouse models have recently shown that telomere shortening is also tumor suppressive by promoting replicative senescence to inhibit tumor formation. In this Perspective, we will discuss how telomeres shorten with cell replication and how this might initiate a DNA damage response to induce replicative senescence (and cell death) and ultimately prevent tumorigenesis.

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Section: Future Anti-cancer Therapy: Therapeutic Strategies That Targmentioning

confidence: 99%

Telomere dysfunction and tumour suppression: the senescence connection

2008

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“…However, after radiation therapy, some radiation-resistant cells can appear, and these can cause tumor recurrence and poor outcomes. 3 We tried to inhibit telomerase activity after radionuclide gene therapy, because previously we found that radionuclide gene therapy had an inadequate effect on tumor growth. 10 One recent study found that hTERT promoter activity was increased in radiation-resistant laryngeal squamous cell carcinoma, and examined the effects of suicidal gene (hTERTp-HRP/IAA) therapy using hTERT promoter plus radiotherapy and they showed efficient tumor specific cytotoxicity of prodrug IAA in radiation-resistant human squamous cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Telomeres are chromosomal regions that consist of long 5 0 -TTAGGG-3 0 nucleotide repeats and telomere binding protein complex. 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.…”

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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“…Therefore, it is of critical importance to understand the roles of telomerase and telomeres in cancer development in order to design these new anti-cancer strategies. Some telomerasebased approaches have been developed in the recent years such as gene therapy, immunotherapy and small-molecule inhibitors of telomerase (Keith et al, 2007;Shay and Keith, 2008). Some of these promising candidates for telomerase-based therapies are now in different phases of clinical trials (Harley, 2008;Ouellette et al, 2011;Shay and Wright, 2011).…”

Section: Telomeres Dysfunctions and Relationship To Diseasesmentioning

confidence: 99%

Extra-Telomeric Effects of Telomerase (hTERT) in Cell Death

Bellot¹

2013

Apoptosis

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Targeting telomerase for cancer therapeutics

Cited by 151 publications

References 31 publications

Telomere dysfunction and tumour suppression: the senescence connection

Telomere dysfunction and tumour suppression: the senescence connection

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

Extra-Telomeric Effects of Telomerase (hTERT) in Cell Death

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