Specific telomere dysfunction induced by GRN163L increases radiation sensitivity in breast cancer cells

Jaime Gomez-Millan, Erin M. Goldblatt, Sergei M. Gryaznov, Marc S. Mendonca, Brittney Shea Herbert

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Purpose: Telomerase is expressed in 80-90% of tumor cells, but is absent in most somatic cells. The absence of telomerase activity results in progressive telomere shortening, leading to cellular senescence or death through deoxyribonucleic acid (DNA) damage signals. In addition, a role for telomerase in DNA damage repair has also been suggested. A specific telomerase inhibitor, GRN163L that is complementary to the template region of the telomerase ribonucleic acid component (hTR). We hypothesized that exposure to GRN163L, either through immediate inhibition of telomerase activity or through eventual telomere shortening and dysfunction, may enhance radiation sensitivity. Our goal was to test whether the treatment with GRN163L enhances sensitivity to irradiation (IR) in MDA-MB-231 breast cancer cells. Methods and Materials: The MDA-MB-231 breast cancer cells were treated with or without GRN163L for 2-42 days. Inhibition of telomerase activity and shortening of telomeres were confirmed. Cells were then irradiated and clonogenic assays were performed to show cell survival differences. In vivo studies using MDA-MB-231 xenografts were performed to corroborate the in vitro results. Results: We show that cells with shortened telomeres due to GRN163L enhance the effect on IR reducing survival by an additional 30% (p < 0.01). These results are confirmed in vivo, with a significant decrease in tumor growth in mice exposed to GRN163L. Conclusions: We found that GRN163L is a promising adjuvant treatment in combination with radiation therapy that may improve the therapeutic index by enhancing the radiation sensitivity. These studies prompt further investigation as to whether this combination can be applied to other cancers and the clinic.

Original languageEnglish (US)
Pages (from-to)897-905
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume67
Issue number3
DOIs
StatePublished - Mar 1 2007

Keywords

  • Breast cancer
  • Irradiation
  • Telomerase inhibitors
  • Thio-phosphoramidates

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

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