Telomerase targeted oligonucleotide thio-phosphoramidates in t24-luc bladder cancer cells

Z. Gunnur Dikmen, Woodring E. Wright, Jerry W. Shay, Sergei M. Gryaznov

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Bladder carcinoma is the second most common genitourinary malignancy. Treatment options for bladder cancer include surgery, combined with chemotherapy, radiation, and/or immunotherapy. The adjuvant chemotherapy and immunotherapy regimen have been widely used in locally invasive as well as metastatic disease. The evaluation of new active agents with improved tolerability has been the focus of investigations over the past decade with minimal overall improvements in outcomes. Telomerase activity has been found in ∼85-90% of all human tumors, but not in the majority of adjacent normal tissues. This suggests that telomerase may bean attractive target for the development of novel anticancer therapeutic agents. GRN163L is a lipid conjugated oligonucleotide N3′ → P5′ thio-phosphoramidate, and is a potent telomerase RNA (hTR) template antagonist. In the present study, we show that the telomerase activity of T24-luc bladder cancer cells is inhibited by 1 μM GRN163L within 24 h of incubation. After two weeks of exposure to GRN163L, T24-luc cells became "clustered" whereas non-cancerous normal human uroepithelial cells were not morphologically affected. Moreover, in vitro GRN163L treated T24-luc bladder cancer cells entered G0/G 1 arrest following 2 weeks of continuous exposure and stopped dividing. Mismatch control compound had no effect on normal bladder epithelial cells or T24-luc cells. Additionally, a new generation of thio-phosphoramidate oligonucleotides were designed and tested in T24-luc cells and compared with GRN163L. The obtained results warrant further in vivo evaluation of GRN163L as a potential treatment for bladder cancer.

Original languageEnglish (US)
Pages (from-to)444-452
Number of pages9
JournalJournal of Cellular Biochemistry
Volume104
Issue number2
DOIs
StatePublished - May 15 2008

Keywords

  • Bladder cancer
  • GRN163L
  • Telomerase
  • Thio-phosphoramidate oligonucleotide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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