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

  • Herbert B
  • Pitts A
  • Baker S
 et al. 
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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-supplied keywords

  • Antineoplastic Agents
  • Biology
  • Cell Division
  • Drug Effects
  • Enzyme Inhibitors
  • Epithelial Cells
  • Human
  • Peptide Nucleic Acids
  • Pharmacology
  • Support,Non-U.S.Gov't
  • Support,U.S.Gov't,P.H.S.
  • antagonists & inhibitors
  • apoptosis
  • breast
  • cell death
  • cells
  • frequencies
  • frequency
  • growth
  • human-cells
  • inhibition
  • inhibitors
  • oligonucleotide
  • oligonucleotides
  • peptide nucleic acid
  • pharmacokinetics
  • physiology
  • strategy
  • telomerase
  • telomerase activity
  • telomerase inhibitors
  • telomere
  • telomere shortening
  • telomeres

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Authors

  • B Herbert

  • A E Pitts

  • S I Baker

  • S E Hamilton

  • W E Wright

  • J W Shay

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