Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer |
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Authors: | Ginelle C Gellert Z Gunnur Dikmen Woodring E Wright Sergei Gryaznov Jerry W Shay |
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Institution: | (1) Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA;(2) Geron Corporation, Menlo Park, CA, USA;(3) Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, 75390-9039 Dallas, Texas, USA |
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Abstract: | Summary Telomerase activity is undetectable in most normal tissues but the vast majorities of cancers express active telomerase. Therefore,
telomerase serves as an attractive target for the treatment of cancers. GRN163L is a lipid-modified oligonucleotide N3′→P5′
thio-phosphoramidate complementary to the RNA template region of human telomerase. The anti-telomerase activity of GRN163L
was evaluated using MDA-MB-231 and MDA-MB-435 human breast adenocarcinoma cell lines. Twice weekly administration of GRN163L
resulted in the inhibition of telomerase activity and progressive telomere shortening. Cells treated with GRN163L did not
demonstrate decreased cell proliferation for up to 2 weeks. However, after additional treatment, cell proliferation gradually
decreased in GRN163L-treated cells compared to untreated or mismatch control oligoncleotide treated cells. Furthermore, anti-tumorigenic
effects were seen in cells treated with GRN163L, as cells lose their ability to form colonies in soft agar and were unable
to form colonies in the clonal efficiency assay upon incubation with GRN163L. Moreover, breast cancer cells that were treated
with GRN163L for only 1 week prior to plating in invasion chambers, and when bulk telomere are still long, exhibit significantly
diminished invasive potential. These results reveal critical information regarding the effectiveness of GRN163L as a potential
therapeutic agent for the treatment of human breast cancer. |
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Keywords: | breast cancer oligonucleotide telomerase inhibitor therapeutics |
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