The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index; none of the 49 sources its claims cite is checked for support yet.
Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death
Open accessAbstract
The correlation between telomerase activity and human tumors has led to the hypothesis that tumor growth requires reactivation of telomerase and that telomerase inhibitors represent a class of chemotherapeutic agents. Herein, we examine the effects of inhibition of telomerase inside human cells. Peptide nucleic acid and 2′ -O- MeRNA oligomers inhibit telomerase, leading to progressive telomere shortening and causing immortal human breast epithelial cells to undergo apoptosis with increasing frequency until no cells remain. Telomere shortening is reversible: if inhibitor addition is terminated, telomeres regain their initial lengths. Our results validate telomerase as a target for the discovery of anticancer drugs and supply general insights into the properties that successful agents will require regardless of chemical type. Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics, making the inhibitors we describe practical lead compounds for testing for an antitelomerase chemotherapeutic strategy.
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TL;DR
Inhibiting telomerase in immortal human cells with 2′-O-MeRNA or PNA oligonucleotides caused progressive telomere shortening, apoptosis, and eventual loss of proliferation. Telomere shortening and growth arrest were reversible when inhibitor treatment was stopped.
Key findings
- Complementary 2′-O-MeRNA inhibited >95% of telomerase activity 1 day after transfection and >70% at 3 days. HME50-5E proliferation slowed after 15–25 days, and no treated cells remained after 110 days; apoptosis rose from <5% during the first 60 days to 14% at 80 days and 56% at 100 days, versus 2–3% in controls.
- DU145 cells began slowing after 60 days and had undergone 20 fewer population doublings than mismatch-treated cells by 120 days. HME50-hTERT cells, with longer telomeres, showed no significant growth reduction over 120 days.
- Mean telomere restriction fragment length decreased from 2,000 to 1,700 bp in HME50-5E cells by 60 days, from 3,600 to 2,200 bp in DU145 cells by 76 days, and from 7,600 to 6,800 bp in HME50-hTERT cells after 75 days. A template-directed PNA inhibited >90% of telomerase activity at 1 day and shortened telomeres, whereas a nontemplate PNA inhibited only 50% and did not shorten telomeres.
- After inhibitor withdrawal at 76 days, eroded telomeres returned to approximately initial lengths within 3 weeks, and previously static HME50-5E cells regained growth within 3 weeks. No evidence for an ALT pathway was observed.
Methods
- Immortal human cell lines HME50-5E, DU145, and HME50-hTERT were transfected with 2′-O-MeRNA or PNA/DNA complexes using cationic lipids; treatment was repeated every 3–4 days for 120 days, with mismatch oligomers, lipid alone, or nontemplate PNA as controls.
- Telomerase activity was measured by TRAP, mean telomere length by telomere restriction fragment Southern analysis, apoptosis by Annexin V flow cytometry, and proliferation by cell counts/population doublings.
- Effects of matched versus mismatched or nontemplate inhibitors were compared over time to test sequence-specific, telomerase-dependent mechanisms.
Limitations
- Stated in the paper: the TRF assay does not monitor subtelomeric erosion and may underestimate total telomeric DNA loss; 5–30% of telomerase activity remained after treatment; systemic telomerase inhibition would also affect normal stem cells; the long lag before phenotypic effects complicates drug development; and no ALT pathway was observed in these cell types, leaving applicability to ALT-positive tumors uncertain.
- Evident from the text: findings are in vitro in a small number of immortal cell lines, including p53-mutant lines, with no animal or human efficacy/toxicity data; the 120-day culture experiments required stringent precautions against contamination but remain vulnerable to long-term culture artifacts.
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31 Not checked yet · 31 Own result · 28 Own interpretation · 5 No basis given · 2 Own method · 1 Check pending
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“and this percentage increased to 56% after 100 days”
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“Within 60 days of treatment, the mean telomere length of HME50-5E cells treated with 2′-O-MeRNA complementary to hTR was reduced from 2,000 to 1,700 bp (Fig. 4a).”
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“leading to progressive telomere shortening”
- Also stated in: § Abstract · plain
“cause telomeres to shorten”
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“The growth of cells treated with the control oligomer containing mismatch bases was not affected.”
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“By 80 days, however, 14% of cells treated with the match oligomer were observed to undergo apoptosis”
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In the paper
“Peptide nucleic acid and 2′-O-MeRNA oligomers inhibit telomerase”
- Also stated in: § Abstract · plain
“We observe that 2′-O-MeRNA and peptide nucleic acid (PNA) oligomers complementary to the template region of hTR inhibit telomerase”
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“By the end of the experiment (after 120 days), these cells had undergone 20 fewer population doublings than had cells treated with mismatch-containing oligomer.”
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“By contrast, cells treated with lipid alone or the 2′-O-MeRNA oligomer containing mismatched bases underwent apoptosis at a rate of 2–3% throughout the entire experiment.”
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“HME50-hTERT cells have a much longer mean TRF length (7.6 kilobases) than either HME50-5E or DU145 cells”
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“Telomere shortening is reversible: if inhibitor addition is terminated, telomeres regain their initial lengths.”
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- Probably not a substantial claim. 23
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In the paper
“The TRF length of cells treated with 2-O-MeRNA containing mismatches relative to hTR remained at 2,000 bp, and the signal intensity of probe hybridization was undiminished.”
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In the paper
“We observe telomere shortening and decreased cell proliferation, even though between 5% and 30% of telomerase activity remained after treatment with inhibitor.”
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In the paper
“Telomerase activity has been found in almost all human tumors but not in adjacent normal cells (3, 4).”
What the sources say
- Not checked yetcites [3] Kim N W, Piatyszek M A, Prowse K R, Harley C B, West M D, Ho P L C, Coviello G M, Wright W E, Weinrich S L, Shay J W. Science. 1994;266:2011–2015. doi: 10.1126/science.7605428. [DOI] [PubMed] [Google Scholar] source
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In the paper
“Human telomerase is a ribonucleoprotein that adds repeated units of TTAGGG to the ends of telomeres (1, 2).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The levels of telomerase activity were within the linear range of the TRAP assay (40).”
What the sources say
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plain- Asserted: passes — The authors put it forward as true.
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In the paper
“or tumor aggressiveness (11, 12).”
What the sources say
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“recent reports of the effect of the mTR deletion in different genetic backgrounds (17, 18) suggest that the role of telomerase in cancer development could be highly context dependent (19).”
What the sources say
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hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The cells divide normally until telomeres shorten sufficiently to affect proliferation. At this stage, most cells die”
What the sources say
- Not checked yetcites [31] Lunblad V, Blackburn E H. Cell. 1993;73:347–360. doi: 10.1016/0092-8674(93)90234-h. [DOI] [PubMed] [Google Scholar] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“expression of telomerase in conjunction with expression of simian virus 40 large T oncoprotein and an oncogenic allele of H-ras has been shown to promote tumorigenic conversion of normal human cells (28).”
What the sources say
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In the paper
“whereas the late-stage disease has high telomerase activity and correlates with a poor outcome (6).”
What the sources say
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This decrease in measured TRF length may be an underestimate of the total loss of chromosomal DNA, because the TRF assay does not monitor erosion of subtelomeric regions and because relatively little telomeric DNA remained to hybridize with radiolabeled probe.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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“The 2′-O-MeRNA inhibitor contained four phosphorothioate linkages, a chemical moiety noted for its propensity to produce misleading cellular effects that seem sequence-specific but are actually unrelated to binding to the intended target (42).”
What the sources say
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plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, the lack of telomerase expression seems to curb growth of rapidly proliferating cells eventually, whereas an increase in telomerase permits indefinite proliferation.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Mutation of the RNA component of telomerase of Tetrahymena (20), Kluyveromyces lactis (21), Saccharomyces cerevisiae (22)”
What the sources say
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plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, although telomerase activity can confer extended life span to cells, other mechanisms may also exist.”
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In the paper
“Telomerase will be an unusually challenging target for drug development because of the long lag period expected before telomeres would shorten sufficiently to produce detrimental effects on cell growth and because of the possibility of alternate mechanisms for maintenance of telomeres.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“other studies have suggested that telomerase activity is correlated with the pathologic stage (8–11)”
What the sources say
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In the paper
“but some rare survivors continue to proliferate through a recombination mechanism to maintain telomere length.”
What the sources say
- Not checked yetcites [31] Lunblad V, Blackburn E H. Cell. 1993;73:347–360. doi: 10.1016/0092-8674(93)90234-h. [DOI] [PubMed] [Google Scholar] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“a few rare tumors (29) and some experimentally immortalized cell lines (30) lack detectable telomerase activity.”
What the sources say
- Not checked yetcites [29] Gupta J, Han L P, Wang P, Bacchetti S. J Natl Cancer Inst. 1996;88:1152–1157. doi: 10.1093/jnci/88.16.1152. [DOI] [PubMed] [Google Scholar] source
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In the paper
“To confirm that the effects of inhibitor addition were reproducible, treatment of HME50-5E cells with 2′-O-MeRNA was repeated, and a similar decrease in proliferation was observed.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Because of the extreme length of these experiments, stringent precautions were taken to avoid contamination of cultured cells, and all experiments were completed successfully without interruption.”
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In the paper
“Recent work with PNAs introduced into cells by electroporation has shown decreased cell viability, supporting our findings (49).”
What the sources say
- Not checked yetcites [49] Shammas M A, Simmons C S, Corey D R, Shmookler-Reis R J. Oncogene. 1999;18:6191–6200. doi: 10.1038/sj.onc.1203069. [DOI] [PubMed] [Google Scholar] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This inhibition may result in few side effects, because the relatively short telomeres of tumors may erode to a critical length before irreversible harm is done to other cells.”
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In the paper
“Telomerase is an ideal target for oligonucleotides, because its RNA template is essential for activity and is intrinsically accessible to binding by nucleic acids.”
- Also stated in: § Discussion · plain
“The exposed RNA template of hTR makes telomerase an ideal target for oligonucleotides”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, 2′-O-MeRNA and other 2′-O-alkyl-derivatized oligomers bind more tightly to complementary RNA sequences than do analogous DNA oligomers”
What the sources say
- Not checked yetcites [45] Agrawal S, Jiang Z, Zhao Q, Shaw D, Cai Q, Roskey A, Channavajjala L, Saxinger C, Zhang R. Proc Natl Acad Sci USA. 1997;94:2620–2625. doi: 10.1073/pnas.94.6.2620. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Systemic administration of telomerase inhibitors will also inhibit telomerase in normal stem cells.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Oligonucleotides are being tested in 13 ongoing clinical trials (43)”
What the sources say
- Not checked yetcites [43] Hogrefe R I. Antisense Nucleic Acid Drug Dev. 1999;9:351–357. doi: 10.1089/oli.1.1999.9.351. [DOI] [PubMed] [Google Scholar] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Tu et al. (47) have performed a comprehensive survey of the literature, leading Stein (48) to estimate that non-sequence-selective effects may be at least partially implicated in results reported in 94% of the 2,026 studies published through 1997.”
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“and have improved resistance to degradation by nucleases, reducing the need for phosphorothioate linkages and improving the selectivity of antisense effects (45, 46)”
What the sources say
- Not checked yetcites [45] Agrawal S, Jiang Z, Zhao Q, Shaw D, Cai Q, Roskey A, Channavajjala L, Saxinger C, Zhang R. Proc Natl Acad Sci USA. 1997;94:2620–2625. doi: 10.1073/pnas.94.6.2620. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Indeed, we have previously observed that oligonucleotides that contain uniform phosphorothioate oligonucleotides inhibit telomerase in a non-sequence-specific fashion, presumably through binding to hTERT (38).”
What the sources say
- Not checked yetcites [38] Pitts A E, Corey D R. Proc Natl Acad Sci USA. 1998;95:11549–11554. doi: 10.1073/pnas.95.20.11549. [DOI] [PMC free article] [PubMed] [Google Scholar] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“one oligonucleotide, Fomivirsen, has been approved for the treatment of cytomegalovirus retinitis (44).”
What the sources say
- Not checked yetcites [44] Marwick C. J Am Med Assoc. 1998;280:871. [Google Scholar] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The mice used in these experiments possessed much longer telomeres than those found in cancerous human cells.
“the mice used in these experiments possessed much longer telomeres than those found in cancerous human cells”
The paper relies on this without support.
Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics.
“Chemically similar oligonucleotides are in clinical trials and have well characterized pharmacokinetics”
The paper relies on this without support.
HME50-5E cells were derived from HME50 preimmortal cells that had one mutant p53 allele and lost the second allele during spontaneous immortalization.
“HME50-5E cells were derived from HME50 preimmortal cells that had one mutant p53 allele and lost the second allele during spontaneous immortalization”
The paper relies on this without support.
DU145 cells have two mutant p53 alleles.
“whereas DU145 cells have two mutant alleles”
The paper relies on this without support.
The genetic background of HME50-hTERT cells is similar to that of HME50-5E cells.
“even though the genetic background of HME50-hTERT cells is similar to that of HME50-5E cells”
The paper relies on this without support.
HME50-5E cells have shorter telomeres than DU145 cells.
“which have shorter telomeres than DU145 cells”
The paper relies on this without support.
HME50-hTERT cells have an initial telomere length approximately 4,000 bp longer than that of HME50-5E cells.
“their initial telomere length of HME50-hTERT cells is approximately 4,000 bp longer.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Induction of ALT has also never been reported in previous publications using other means of telomerase inhibition (Hahn et al., 1999b;Herbert et al., 1999;Zhang et al., 1999).”
From A highly selective telomerase inhibitor limiting human cancer cell proliferation (2001) · cites this paper as Herbert et al., 1999
In the citing paper
“Several strategies to inhibit telomerase activity have been reported.These include peptide nucleic acids and 2¢-O-MeRNA oligonucleotides directed towards the telomerase RNA template (Herbert et al., 1999), compounds that target telomeric DNA such as cationic porphyrins or anthraquinones (Sun et al., 1997) and nucleosidic reverse transcriptase inhibitors (Strahl and Blackburn, 1996).”
From A highly selective telomerase inhibitor limiting human cancer cell proliferation (2001) · cites this paper as Herbert et al., 1999
In the citing paper
“In contrast to previous results employing anti-sense oligonucleotides or the expression of dominant-negative hTERT alleles (Hahn et al., 1999b;Herbert et al., 1999;Zhang et al., 1999) we saw no evidence for an increased rate of apoptosis in the inhibitor-treated cells.”
From A highly selective telomerase inhibitor limiting human cancer cell proliferation (2001) · cites this paper as Herbert et al., 1999
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Telomerase, mitochondria and oxidative stress
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Self-citationTelomeres and telomerases as drug targets
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Therapeutic Targeting of Telomerase
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Telomerase activation, cellular immortalization and cancer
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Telomeres and Telomerase: Implications for Cancer and Aging
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Analysis of Telomerase Processivity
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Metadata
- Authors
- Herbert, B.-S., Pitts, A. E., Baker, S. I., Hamilton, S. E., Wright, W. E., Shay, J. W., & Corey, D. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-12-07
- Volume
- 96
- Issue
- 25
- Pages
- 14276-14281
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC24427
- OpenAlex
- W2118228848
- Cited by
- 539
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 11 · 2018: 9 · 2017: 9 · 2016: 5 · 2015: 18 · 2014: 7 · 2013: 12 · 2012: 13
- FWCI
- 27.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- National Institutes of Health
- National Cancer Institute (CA 74908, R01CA074908, CA-85143)
- National Institute of General Medical Sciences (T32GM007062, T32GM07062-23)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- telomerase inhibition, telomere shortening, apoptosis, peptide nucleic acid, 2'-O-methyl RNA, breast epithelial cells, cell immortalization, anticancer drug targets
- MeSH terms
- Antineoplastic Agents, Cell Division, Enzyme Inhibitors, Humans, Oligonucleotides, Telomere, Cell Death, Telomerase, Peptide Nucleic Acids
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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