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 telomer ase-interactive agents on proliferation rates and chromosome stability in a novel in vivo model, developing sea urchin embryos. We studied two porphyr ins: (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, A ZT and TAG6 (but not TMPyP2 or ODN) decreased the rates of cell proliferati on and increased the percentage of cells trapped in mitosis. Nuclear locali zation of TAG6, but not of ODN, was demonstrated with 5'-fluoresceinated an alogs of TAG6 and ODN, Formation of elongated chromosomes incapable of sepa rating in anaphase, induced by TMPyP4, AZT and TAG6, closely resembled phen otypes resulting from telomerase template mutation or dominant negative TRF 2 allele, Our data suggest that G4-interactive agents exert their antiproli ferative effects via chromosomal destabilization and warrant their further development as valuable anticancer tools.