TY - JOUR
T1 - Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos
AU - Izbicka, Elzbieta
AU - Nishioka, David
AU - Marcell, Vanessa
AU - Raymond, Eric
AU - Davidson, Karen K.
AU - Lawrence, Richard A.
AU - Wheelhouse, Richard T.
AU - Hurley, Laurence H.
AU - Wu, Roy S.
AU - Von Hoff, Daniel D.
PY - 1999/8
Y1 - 1999/8
N2 - 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 viveo 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.
AB - 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 viveo 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.
KW - G quadruplex
KW - Porphyrin
KW - Sea urchin
KW - Telomerase
KW - Telomere
UR - http://www.scopus.com/inward/record.url?scp=0032742766&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032742766&partnerID=8YFLogxK
M3 - Article
C2 - 10625928
AN - SCOPUS:0032742766
SN - 0266-9536
VL - 14
SP - 355
EP - 365
JO - Anti-Cancer Drug Design
JF - Anti-Cancer Drug Design
IS - 4
ER -