Telomerase inhibition by peptide nucleic acids reverses `immortality' of transformed human cells

Shammas, Masood A.; Simmons, Carla G.; Corey, David R.; Reis, Robert J. Shmookler

doi:10.1038/sj.onc.1203069

Cited by 134 publications

(92 citation statements)

References 47 publications

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“…Although in some malignancies such as cervical cancer the inhibition of telomerase induces apoptotic cell death within a few days, without inducing significant telomere shortening, 30 cell death in most cancer cells occurs after a lag period of 3À5 weeks, probably required for reduction in telomere length below critical limit. 18,[24][25][26][27]29,31 Moreover, we observed a marked reduction in telomere length, leading to complete erosion of telomeres on a subset of chromosomes in myeloma cells following GRN163L treatment. These data along with minimal change in gene expression confirm that GRN163L induces myeloma cell death through specific inhibition of telomerase and that it does not have significant nontelomeric effects on myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

“…This is quite consistent with our previous observations data showing that treatment with chemical, antisense and siRNA-based telomerase inhibitors does not affect the proliferation of normal cells. 29,31,32 Cancer cells vary in genetic and epigenetic factors, including intracellular levels of nucleases. Therefore, the loss of telomeric DNA following inhibition of telomerase activity may not be predictable and the efficacy of the inhibitor may not necessarily correlate with median telomere length.…”

Section: Discussionmentioning

confidence: 99%

“…Although a variety of telomerase inhibitors have been shown to inhibit proliferation of cancer cells, [18][19][20][21][22][23][24][25][27][28][29] there has been a need of agents which are specific enough and suited for in vivo utilization in human clinical trials. Our telomerase inhibitor (GRN163L) is phosphoramidate oligonucleotide complementary to the template region of the RNA subunit of telomerase (hTR) and has a lipid moiety attached, which facilitates uptake in human cells without any need of a transfection reagent or procedure.…”

Section: Discussionmentioning

confidence: 99%

“…[29][30][31][32][33][34][35] Approximately 8 weeks following bone implantation, 5 Â 10 6 human IL-6-dependent INA6 cells were injected directly into human bone in SCID-hu host. Production of human paraprotein in mouse serum was monitored as an indicator of myeloma cell growth.…”

Section: Scid-hu Mouse Modelmentioning

confidence: 99%

“…A number of telomerase inhibitors have been evaluated in a variety of cancer types. [19][20][21][22][23] We have demonstrated that telomerase inhibitors including G-quadruplex interacting agents, 18,24,25 peptide nucleic acids and antisense oligonucleotides targeting RNA component of telomerase, [26][27][28] and siRNAs targetinghTERT, 29 can induce apoptosis and/or senescence in a variety of human immortal and cancer cells including multiple myeloma cells, in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo

et al. 2008

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Human telomerase, the reverse transcriptase which extends the life span of a cell by adding telomeric repeats to chromosome ends, is expressed in most cancer cells but not in the majority of normal somatic cells. Inhibition of telomerase therefore holds great promise as anticancer therapy. We have synthesized a novel telomerase inhibitor GRN163L, a lipidFattached phosphoramidate oligonucleotide complementary to template region of the RNA subunit of telomerase. Here, we report that GRN163L is efficiently taken up by human myeloma cells without any need of transfection and is resistant to nucleolytic degradation. The exposure of myeloma cells to GRN163L led to an effective inhibition of telomerase activity, reduction of telomere length and apoptotic cell death after a lag period of 2-3 weeks. Mismatch control oligonucleotides had no effect on growth of myeloma cells. The in vivo efficacy of GRN163L was confirmed in two murine models of human multiple myeloma. In three independent experiments, significant reduction in tumor cell growth and better survival than control mice was observed. Furthermore, GRN163L-induced myeloma cell death could be significantly enhanced by Hsp90 inhibitor 17AAG. These data provide the preclinical rationale for clinical evaluation of GRN163L in myeloma and in combination with 17AAG.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Scid-hu Mouse Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo

et al. 2008

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Inhibition of telomerase activity and induction of apoptosis by Rhodospirillum rubrum L‐asparaginase in cancer Jurkat cell line and normal human CD4+ T lymphocytes

et al. 2017

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Rhodospirillum rubrum L‐asparaginase mutant E149R, V150P, F151T (RrA) down‐regulates telomerase activity due to its ability to inhibit the expression of telomerase catalytic subunit hTERT. The aim of this study was to define the effect of short‐term and long‐term RrA exposure on proliferation of cancer Jurkat cell line and normal human CD4+ T lymphocytes. RrA could inhibit telomerase activity in dose‐ and time‐dependent manner in both Jurkat and normal CD4+ T cells. Continuous RrA exposure of these cells resulted in shortening of telomeres followed by cell cycle inhibition, replicative senescence, and development of apoptosis. Complete death of Jurkat cells was observed at the day 25 of RrA exposure while normal CD4+ T cells died at the day 50 due to the initial longer length of telomeres. Removal of RrA from senescent cells led to a reactivation of hTERT expression, restoration telomerase activity, re‐elongation of telomeres after 48 h of cultivation, and survival of cells. These findings demonstrate that proliferation of cancer and normal telomerase‐positive cells can be limited by continuous telomerase inhibition with RrA. Longer telomeres of normal CD4+ T lymphocytes make such cells more sustainable to RrA exposure that could give them an advantage during anti‐telomerase therapy. These results should facilitate further investigations of RrA as a potent anti‐telomerase therapeutic protein.

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