Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks.
Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1 week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Short-term imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1h of repair whereas the increase of foci size was prominent later on. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.
Department of Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Sweden. xuping_wu@yahoo.com
Xuping
X
Wu
Shirin
S
Smavadati
Katarina
K
Nordfjäll
Krister
K
Karlsson
Fredrik
F
Qvarnström
Martin
M
Simonsson
Michael
M
Bergqvist
Sergei
S
Gryaznov
Simon
S
Ekman
Ylva
Y
Paulsson-Karlsson
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects* / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; C509186:TERT protein, human; D019098:Telomerase; C519562:imetelstat