Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer.
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.
Gellert
Ginelle C
GC
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
Dikmen
Z Gunnur
ZG
Wright
Woodring E
WE
Gryaznov
Sergei
S
Shay
Jerry W
JW
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003114:Colony-Forming Units Assay; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007797:Laminin / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009841:Oligonucleotides; D009842:Oligopeptides / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism
D004338:Drug Combinations; C505952:GRN163L peptide; D007797:Laminin; D009841:Oligonucleotides; D009842:Oligopeptides; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D019098:Telomerase