Telomerase inhibitor imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells

Katrina M. Burchett, Ying Yan, Michel M Ouellette

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Telomerase is required for the unlimited lifespan of cancer cells. The vast majority of pancreatic adenocarcinomas overexpress telomerase activity and blocking telomerase could limit their lifespan. GRN163L (Imetelstat) is a lipidconjugated N39RP59 thio-phosphoramidate oligonucleotide that blocks the template region of telomerase. The aim of this study was to define the effects of long-term GRN163L exposure on the maintenance of telomeres and lifespan of pancreatic cancer cells. Telomere size, telomerase activity, and telomerase inhibition response to GRN163L were measured in a panel of 10 pancreatic cancer cell lines. The cell lines exhibited large differences in levels of telomerase activity (46-fold variation), but most lines had very short telomeres (2-3 kb in size). GRN163L inhibited telomerase in all 10 pancreatic cancer cell lines, with IC50 ranging from 50 nM to 200 nM. Continuous GRN163L exposure of CAPAN1 (IC50 = 75 nM) and CD18 cells (IC50 = 204 nM) resulted in an initial rapid shortening of the telomeres followed by the maintenance of extremely short but stable telomeres. Continuous exposure to the drug eventually led to crisis and to a complete loss of viability after 47 (CAPAN1) and 69 (CD18) doublings. Crisis In these cells was accompanied by activation of a DNA damage response (c-H2AX) and evidence of both senescence (SA-b-galactosidase activity) and apoptosis (sub-G1 DNA content, PARP cleavage). Removal of the drug after long-term GRN163L exposure led to a reactivation of telomerase and re-elongation of telomeres in the third week of cultivation without GRN163L. These findings show that the lifespan of pancreatic cancer cells can be limited by continuous telomerase inhibition. These results should facilitate the design of future clinical trials of GRN163L in patients with pancreatic cancer. Copyright:

Original languageEnglish (US)
Article numbere85155
JournalPloS one
Volume9
Issue number1
DOIs
StatePublished - Jan 7 2014

Fingerprint

pancreatic neoplasms
telomerase
Telomerase
Pancreatic Neoplasms
Cells
telomeres
Telomere
Inhibitory Concentration 50
inhibitory concentration 50
cell lines
chronic exposure
Cell Line
Maintenance
neoplasm cells
imetelstat
Galactosidases
Telomere Shortening
galactosidases
drugs
DNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Telomerase inhibitor imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells. / Burchett, Katrina M.; Yan, Ying; Ouellette, Michel M.

In: PloS one, Vol. 9, No. 1, e85155, 07.01.2014.

Research output: Contribution to journalArticle

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