Abstract
Human telomerase, the reverse transcriptase which extends the life span of a cell by adding telomeric repeats to chromosome ends, is expressed in most cancer cells but not in the majority of normal somatic cells. Inhibition of telomerase therefore holds great promise as anticancer therapy. We have synthesized a novel telomerase inhibitor GRN163L, a lipid—attached phosphoramidate oligonucleotide complementary to template region of the RNA subunit of telomerase. Here, we report that GRN163L is efficiently taken up by human myeloma cells without any need of transfection and is resistant to nucleolytic degradation. The exposure of myeloma cells to GRN163L led to an effective inhibition of telomerase activity, reduction of telomere length and apoptotic cell death after a lag period of 2–3 weeks. Mismatch control oligonucleotides had no effect on growth of myeloma cells. The in vivo efficacy of GRN163L was confirmed in two murine models of human multiple myeloma. In three independent experiments, significant reduction in tumor cell growth and better survival than control mice was observed. Furthermore, GRN163L-induced myeloma cell death could be significantly enhanced by Hsp90 inhibitor 17AAG. These data provide the preclinical rationale for clinical evaluation of GRN163L in myeloma and in combination with 17AAG.
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Acknowledgements
This work was supported in part by NIH-P50-100007 Developmental Research Award to MAS, and Merit Review Award from the Department of Veterans Affairs and NIH—RO1-CA124929 (NCM); NIH-P050-100007and NIH-PO1-78378 (NCM and KCA). NCM is a Leukemia Society Scholar in Translational Research.
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Shammas, M., Koley, H., Bertheau, R. et al. Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo. Leukemia 22, 1410–1418 (2008). https://doi.org/10.1038/leu.2008.81
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DOI: https://doi.org/10.1038/leu.2008.81
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