Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos

Elzbieta Izbicka, David Nishioka, Vanessa Marcell, Eric Raymond, Karen K. Davidson, Richard A. Lawrence, Richard T. Wheelhouse, Laurence H. Hurley, Roy S. Wu, Daniel D. Von Hoff

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)355-365
Number of pages11
JournalAnti-Cancer Drug Design
Volume14
Issue number4
StatePublished - Aug 1999
Externally publishedYes

Keywords

  • G quadruplex
  • Porphyrin
  • Sea urchin
  • Telomerase
  • Telomere

ASJC Scopus subject areas

  • Biochemistry
  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Telomere-interactive agents affect proliferation rates and induce chromosomal destabilization in sea urchin embryos'. Together they form a unique fingerprint.

Cite this