The cytotoxic effects of single-stranded telomere mimics on OMA-BL1 cells.
Telomerase is a ribonucleoprotein that adds 5'-d(TTAGGG)-3' hexameric repeats onto the 3' ends of chromosomes. High telomerase activity has been associated with immortal cells, transformed cells, mitogenic stimulation, and proliferative diseases. It is not clear what phenotype would be observed by transient inhibition of telomerase. Studies were designed to inhibit telomerase activity using a series of S-ODN telomere sequence motifs. The studies evaluated the length, hydrogen bonding, and sequence requirements of telomerase inhibition using the TRAP assay and a bioassay measuring cell viability following exposure to the compounds. In addition, we have also studied the role of the 3' end and secondary structure of telomere mimics on telomerase inhibition. Observations reveal that sensitivity to the S-ODNs may not require hybridization to an antisense target but required guanine nucleotides on the 3' end for cells in culture and telomerase inhibition in vitro. The importance of H bonding and the requirement for a free 3' end for the activity of these compounds has also been demonstrated. However, transient inhibition of telomerase is not cytotoxic to all immortal cells and is not sufficient to explain the mechanism of cytotoxicity of these short oligonucleotides.
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T J
TJ
Department of Pharmacology, The Eppley Cancer Center, University of Nebraska Medical Center, 600 S. 42nd Street, Omaha, Nebraska 68198-6260, USA.
Mata
J E
JE
Bridge
J A
JA
Siebler
J C
JC
Neff
J R
JR
Iversen
P L
PL
D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006860:Hydrogen Bonding; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D013873:Thionucleotides / Q000235:genetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D019098:Telomerase