Telomerase antagonist imetelstat increases radiation sensitivity in esophageal squamous cell carcinoma

Abstract

The morbidity and mortality of esophageal cancer is one of the highest around the world and the principal therapeutic method is radiation. Thus, searching for sensitizers with lower toxicity and higher efficiency to improve the efficacy of radiation therapy is critical essential. Our research group has previously reported that imetelstat, the thio-phosphoramidate oligonucleotide inhibitor of telomerase, can decrease cell proliferation and colony formation ability as well as increase DNA breaks induced by radiation in esophageal cancer cells. Further study in this project showed that imetelstat significantly sensitized esophageal cancer cells to radiation in vitro. Later study showed that imetelstat leads to increased cell apoptosis. We also measured the expression level of several DNA repair and apoptosis signaling proteins. pS345 CHK1, γ-H2AX, p53 and caspase3 expression were up-regulated in imetelstat treated cells, identifying these factors as molecular markers. Mouse in vivo model using imetelstat at clinically achievable concentrations and fractionated irradiation scheme yielded results demonstrating radiosensitization effect. Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation. Our study supported imetelstat increase radiation sensitivity of esophageal squamous cell carcinoma through inducing cell apoptosis and the specific inhibitor of telomerase might serve as a potential novel therapeutic tool for esophageal squamous cell carcinoma therapy.

Telomeres and telomerase in oncogenesis (Review)

“…A change in mesenchymal stem cell morphology, loss of adhesion, and G1 phase arrest of the cell cycle have been demonstrated (99). Although the use of GRN163L alone is currently ineffective, it has been shown to have promising effects in combination with other molecularly targeted drugs or in the sensitization of cancer cells to radiation therapy (100)(101)(102). T-oligos homologous to the 3'-telomeric overhang are also promising oligonucleotides that have demonstrated anticancer activity.…”

Therapeutic Targeting of Gastrointestinal Cancer Stem Cells

“…In vivo, treatment with GRN163L decreased tumor volume in a mouse xenograft model [80]. Additionally, GRN163L increased radiation sensitivity in esophageal squamous cell carcinoma cell lines, leading to increased apoptosis [81,82]. Although these studies suggest promise for a potential GI cancer therapeutic, to date, 19 clinical trials have been opened utilizing GRN163L, yet none have been targeted at GI cancers [83].…”

Oligonucleotides Targeting Telomeres and Telomerase in Cancer

“…One study using esophageal cancer cells showed that cells treated with GRN163L underwent significantly higher levels of apoptosis than untreated cells after undergoing radiation therapy. Additionally, mouse esophageal cancer xenografts showed enhanced apoptosis and inhibition of proliferation following radiation treatment combined with GRN163L [ 31 ]. Another study in mouse orthotopic glioblastoma xenograft models also showed that after treatment with 30 mg/kg of GRN163L triweekly for a month followed by five days of radiation therapy, mice had an increased overall survival compared to those treated with radiation or GRN163L alone.…”