Telomerase targeted oligonucleotide thio-phosphoramidates in T24-luc bladder cancer cells.
Bladder carcinoma is the second most common genitourinary malignancy. Treatment options for bladder cancer include surgery, combined with chemotherapy, radiation, and/or immunotherapy. The adjuvant chemotherapy and immunotherapy regimen have been widely used in locally invasive as well as metastatic disease. The evaluation of new active agents with improved tolerability has been the focus of investigations over the past decade with minimal overall improvements in outcomes. Telomerase activity has been found in approximately 85-90% of all human tumors, but not in the majority of adjacent normal tissues. This suggests that telomerase may be an attractive target for the development of novel anticancer therapeutic agents. GRN163L is a lipid conjugated oligonucleotide N3' --> P5' thio-phosphoramidate, and is a potent telomerase RNA (hTR) template antagonist. In the present study, we show that the telomerase activity of T24-luc bladder cancer cells is inhibited by 1 microM GRN163L within 24 h of incubation. After two weeks of exposure to GRN163L, T24-luc cells became "clustered" whereas non-cancerous normal human uroepithelial cells were not morphologically affected. Moreover, in vitro GRN163L treated T24-luc bladder cancer cells entered G(0)/G(1) arrest following 2 weeks of continuous exposure and stopped dividing. Mismatch control compound had no effect on normal bladder epithelial cells or T24-luc cells. Additionally, a new generation of thio-phosphoramidate oligonucleotides were designed and tested in T24-luc cells and compared with GRN163L. The obtained results warrant further in vivo evaluation of GRN163L as a potential treatment for bladder cancer.
Dikmen
Z Gunnur
ZG
Faculty of Medicine, Department of Biochemistry, University of Hacettepe, Ankara, Turkey. gunnur@hacettepe.edu.tr
Wright
Woodring E
WE
Shay
Jerry W
JW
Gryaznov
Sergei M
SM
D000577:Amides; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D009841:Oligonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010756:Phosphoric Acids; D012313:RNA / Q000037:antagonists & inhibitors; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000577:Amides; D000970:Antineoplastic Agents; C505952:GRN163L peptide; D009841:Oligonucleotides; D009842:Oligopeptides; D010756:Phosphoric Acids; C422952:telomerase RNA; D012313:RNA; C011067:phosphoramidic acid; D019098:Telomerase