Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos.
Cationic porphyrins, which interact with guanine quadruplex (G4) telomeric folds, inhibit telomerase activity in human tumor cells. In this study, we have further examined effects of porphyrins and other telomere- and telomerase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyrins: (i) TMPyP4, a potent telomerase inhibitor; and (ii) TMPyP2, an isomer of TMPyP4 and an inefficient telomerase inhibitor, azidothymine (AZT), the reverse transcriptase inhibitor, antisense phosphorothioate oligonucleotide to telomerase RNA (TAG6) and a control scrambled sequence (ODN). TMPyP4, AZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferation and increased the percentage of cells trapped in mitosis. Nuclear localization of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated analogs of TAG6 and ODN. Formation of elongated chromosomes incapable of separating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phenotypes resulting from telomerase template mutation or dominant negative TRF2 allele. Our data suggest that G4-interactive agents exert their antiproliferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.
Izbicka
E
E
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. eizbicka@saci.org
Nishioka
D
D
Marcell
V
V
Raymond
E
E
Davidson
K K
KK
Lawrence
R A
RA
Wheelhouse
R T
RT
Hurley
L H
LH
Wu
R S
RS
Von Hoff
D D
DD
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002875:Chromosomes / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology*; D012617:Sea Urchins / Q000196:embryology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D011166:Porphyrins; D015215:Zidovudine; D019098:Telomerase