Specific telomere dysfunction induced by GRN163L increases radiation sensitivity in breast cancer cells.
OBJECTIVE
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
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.
Gomez-Millan
Jaime
J
Department of Radiation Oncology, Radiation and Cancer Biology Laboratory, Indiana University School of Medicine, Indianapolis, IN 46202-5251, USA.
Goldblatt
Erin M
EM
Gryaznov
Sergei M
SM
Mendonca
Marc S
MS
Herbert
Brittney-Shea
BS
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009841:Oligonucleotides; D009842:Oligopeptides / Q000627:therapeutic use*; D011836:Radiation Tolerance; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; C505952:GRN163L peptide; D009841:Oligonucleotides; D009842:Oligopeptides; D019098:Telomerase