Antiadhesive effects of GRN163L - An oligonucleotide N3′→ P5′ thio-phosphoramidate targeting telomerase

Shalmica R. Jackson, Chun Hong Zhu, Vera Paulson, Linda Watkins, Z. Gunnur Dikmen, Sergei M. Gryaznov, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

We determined previously that a novel human telomeraee RNA (hTR) antagonist, GRN163L, inhibited the tumorigenic potential of A549-luciferase (A549-luc) lung cancer cells in vitro and in vivo. Further studies revealed that A549-luc cells were also morphologically altered by GRN163L. A549-luc cells treated before cell attachment with a single dose of GRN163L only weakly attached to the substrate and remained rounded, whereas control mismatch-treated cells exhibited typical epitheloid appearance and adhesion properties. These morphologic changes were independent of hTR expression and telomerase inhibition and were unrelated to telomere length. This effect is dependent on the molecular properties of the lipid moiety, the phosphorothioate backbone, and the presence of triplet-G sequences within the GRN163L structure. Altered adhesion was manifested by a 50% reduction in rapid cellular attachment and a 3-fold decrease in total cell spreading surface area. Administration of a single dose of GRN163L (15 mg/kg) at the time of cell inoculation, using an in vivo model of lung cancer metastasis, resulted in significant reductions in tumor burden at days 13, 20, and 27 of tumor progression. Thus, the potent antimetastatic effects of GRN163L may be related, in part, to the antiadhesive effects of this novel cancer therapeutic conferred via specific structural determinants and that these effects are independent of telomerase inhibition or telomere shortening.

Original languageEnglish (US)
Pages (from-to)1121-1129
Number of pages9
JournalCancer Research
Volume67
Issue number3
DOIs
StatePublished - Feb 1 2007

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Telomerase
Oligonucleotides
Lung Neoplasms
Telomere Shortening
Telomere
Tumor Burden
Luciferases
Neoplasms
phosphoramidic acid
RNA
Neoplasm Metastasis
Lipids
A549 Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antiadhesive effects of GRN163L - An oligonucleotide N3′→ P5′ thio-phosphoramidate targeting telomerase. / Jackson, Shalmica R.; Zhu, Chun Hong; Paulson, Vera; Watkins, Linda; Dikmen, Z. Gunnur; Gryaznov, Sergei M.; Wright, Woodring E.; Shay, Jerry W.

In: Cancer Research, Vol. 67, No. 3, 01.02.2007, p. 1121-1129.

Research output: Contribution to journalArticle

Jackson, SR, Zhu, CH, Paulson, V, Watkins, L, Dikmen, ZG, Gryaznov, SM, Wright, WE & Shay, JW 2007, 'Antiadhesive effects of GRN163L - An oligonucleotide N3′→ P5′ thio-phosphoramidate targeting telomerase', Cancer Research, vol. 67, no. 3, pp. 1121-1129. https://doi.org/10.1158/0008-5472.CAN-06-2306
Jackson, Shalmica R. ; Zhu, Chun Hong ; Paulson, Vera ; Watkins, Linda ; Dikmen, Z. Gunnur ; Gryaznov, Sergei M. ; Wright, Woodring E. ; Shay, Jerry W. / Antiadhesive effects of GRN163L - An oligonucleotide N3′→ P5′ thio-phosphoramidate targeting telomerase. In: Cancer Research. 2007 ; Vol. 67, No. 3. pp. 1121-1129.
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