Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death

B. S. Herbert, A. E. Pitts, S. I. Baker, S. E. Hamilton, W. E. Wright, J. W. Shay, D. R. Corey

Research output: Contribution to journalArticle

478 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14276-14281
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number25
DOIs
StatePublished - Dec 7 1999

Fingerprint

Telomere Shortening
Telomerase
Cell Death
Peptide Nucleic Acids
Telomere
Drug Discovery
Human Activities
Oligonucleotides
Neoplasms
Breast
Pharmacokinetics
Epithelial Cells
Clinical Trials
Apoptosis
Growth

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. / Herbert, B. S.; Pitts, A. E.; Baker, S. I.; Hamilton, S. E.; Wright, W. E.; Shay, J. W.; Corey, D. R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 25, 07.12.1999, p. 14276-14281.

Research output: Contribution to journalArticle

@article{cb02c2d9bbc1427bbe33cee7b75647ca,
title = "Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death",
abstract = "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.",
author = "Herbert, {B. S.} and Pitts, {A. E.} and Baker, {S. I.} and Hamilton, {S. E.} and Wright, {W. E.} and Shay, {J. W.} and Corey, {D. R.}",
year = "1999",
month = "12",
day = "7",
doi = "10.1073/pnas.96.25.14276",
language = "English (US)",
volume = "96",
pages = "14276--14281",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "25",

}

TY - JOUR

T1 - Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death

AU - Herbert, B. S.

AU - Pitts, A. E.

AU - Baker, S. I.

AU - Hamilton, S. E.

AU - Wright, W. E.

AU - Shay, J. W.

AU - Corey, D. R.

PY - 1999/12/7

Y1 - 1999/12/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033455559&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033455559&partnerID=8YFLogxK

U2 - 10.1073/pnas.96.25.14276

DO - 10.1073/pnas.96.25.14276

M3 - Article

C2 - 10588696

AN - SCOPUS:0033455559

VL - 96

SP - 14276

EP - 14281

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 25

ER -