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The effect of the telomerase antagonist Imetelstat in esophageal carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Department of Medical Biosciences, pathology, Umeå University.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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 one 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. Cell cycle analysis demonstrated that short-term treatment with Imetelstat resulted in increased percentage of cells in G1 phase. 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 1 h 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.

Identifiers
URN: urn:nbn:se:uu:diva-152761OAI: oai:DiVA.org:uu-152761DiVA: diva2:413970
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2011-07-01
In thesis
1. Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase
Open this publication in new window or tab >>Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oesophageal cancer is a malignant and aggressive disease with very poor survival. The aim of this thesis was to evaluate novel therapeutic targets in oesophageal cancer.

In paper I, Hsp90 was expressed in all 81 oesophageal cancer tissues and also in nine oesophageal cancer cell lines. A specific Hsp90 inhibitor, 17-AAG, could efficiently inhibit cell proliferation, cell survival and sensitise oesophageal cancer cells to gamma photon irradiation. By inhibition of Hsp90 using 17-AAG, EGFR- and IGF-1R-mediated signalling was downregulated.

In paper II, tumour samples from 80 oesophageal cancer patients were investigated for the expression of EGFR and LRIG1-3. Based on a total score of intensity and expression fraction a trend towards survival differences was found for LRIG2 (p=0.18) and EGFR (p=0.09). Correlation analysis revealed a correlation between expression of EGFR and LRIG3 (p=0.0007). Significant correlations were found between LRIG1 mRNA expression levels and sensitivity to cisplatin (r = –0.74), docetaxel (r = –0.69), and vinorelbine (r = –0.82).

In paper III, microtubule targeting drugs podophyllotoxin (PPT), vincristine and docetaxel inhibited survival and proliferation of oesophageal cancer cells. Unexpectedly, experiments showed that microtubule destabilising agents inhibited EGFR phosphorylation and signalling. A tyrosine phosphatase inhibitor, sodium orthovanadate, was able to reverse the EGFR dephosphorylation.

In paper IV, imetelstat, a telomerase antagonist, inhibited telomerase activity, colony formation ability and decreased proliferation of oesophageal cancer cells. Inhibition of telomerase activity by imetelstat led to an increase of 53BP1 foci indicating induction of DSBs. Furthermore, the fraction and size of radiation-induced 53BP1 foci were increased by imetelstat pre-treatment.

In conclusion, Hsp90 and telomerase represent potential therapeutic targets in oesophageal cancer. And, the implication of EGFR and LRIG as prognostic factors is limited. Furthermore, disruption of the microtubule network may activate a protein tyrosine phosphatase that can regulate EGFR phosphorylation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 680
Keyword
Hsp90, EGFR, LRIG, microtubule, telomerase, oesophageal cancer, imetelstat, DNA double-strand break, 17-AAG, radiation, prognosis, radiosensitisation, microtubule targeting agents
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-152614 (URN)978-91-554-8100-1 (ISBN)
Public defence
2011-06-14, Auditorium Minus, Gustavianum, Akademigatan 3, 75310, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-05-24 Created: 2011-04-28 Last updated: 2011-07-01Bibliographically approved

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