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Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor
- Source :
- Cancer genetics. 207(9)
- Publication Year :
- 2014
-
Abstract
- Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40–50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.
- Subjects :
- Niacinamide
Cancer Research
Telomerase
Indoles
DNA Repair
DNA damage
Chromosomal Proteins, Non-Histone
Drug Evaluation, Preclinical
Oligonucleotides
Apoptosis
Ataxia Telangiectasia Mutated Proteins
Mice, SCID
Biology
Histones
Imetelstat
chemistry.chemical_compound
Mice
Cell Line, Tumor
Genetics
Animals
Humans
DNA Breaks, Double-Stranded
Enzyme Inhibitors
Phosphorylation
Molecular Biology
Rhabdoid Tumor
Telomere Shortening
Cell Proliferation
Cell growth
Telomere Homeostasis
SMARCB1 Protein
Molecular biology
Xenograft Model Antitumor Assays
Telomere
DNA-Binding Proteins
Mice, Inbred C57BL
chemistry
Cell culture
Cancer cell
Cancer research
Female
Growth inhibition
Tumor Suppressor Protein p53
Transcription Factors
Subjects
Details
- ISSN :
- 22107762
- Volume :
- 207
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Cancer genetics
- Accession number :
- edsair.doi.dedup.....d0cd5acfafb80b9d679bccee81237658