Antiadhesive effects of GRN163L--an oligonucleotide N3'->P5' thio-phosphoramidate targeting telomerase.
We determined previously that a novel human telomerase RNA (hTR) antagonist, GRN163L, inhibited the tumorigenic potential of A549-luciferase (A549-luc) lung cancer cells in vitro and in vivo. Further studies revealed that A549-luc cells were also morphologically altered by GRN163L. A549-luc cells treated before cell attachment with a single dose of GRN163L only weakly attached to the substrate and remained rounded, whereas control mismatch-treated cells exhibited typical epitheloid appearance and adhesion properties. These morphologic changes were independent of hTR expression and telomerase inhibition and were unrelated to telomere length. This effect is dependent on the molecular properties of the lipid moiety, the phosphorothioate backbone, and the presence of triplet-G sequences within the GRN163L structure. Altered adhesion was manifested by a 50% reduction in rapid cellular attachment and a 3-fold decrease in total cell spreading surface area. Administration of a single dose of GRN163L (15 mg/kg) at the time of cell inoculation, using an in vivo model of lung cancer metastasis, resulted in significant reductions in tumor burden at days 13, 20, and 27 of tumor progression. Thus, the potent antimetastatic effects of GRN163L may be related, in part, to the antiadhesive effects of this novel cancer therapeutic conferred via specific structural determinants and that these effects are independent of telomerase inhibition or telomere shortening.
Jackson
Shalmica R
SR
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Zhu
Chun-Hong
CH
Paulson
Vera
V
Watkins
Linda
L
Dikmen
Z Gunnur
ZG
Gryaznov
Sergei M
SM
Wright
Woodring E
WE
Shay
Jerry W
JW
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology*; D009842:Oligopeptides / Q000235:genetics*; D010756:Phosphoric Acids / Q000494:pharmacology; D012313:RNA / Q000037:antagonists & inhibitors* / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D016615:Telomere / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000577:Amides; C505952:GRN163L peptide; D009841:Oligonucleotides; D009842:Oligopeptides; D010756:Phosphoric Acids; D012313:RNA; C011067:phosphoramidic acid; D019098:Telomerase