Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands

Abstract

Telomerase represents a relevant target for cancer therapy. Molecules able to stabilize the G-quadruplex (G4), a structure adopted by the 3 0 -overhang of telomeres, are thought to inhibit telomerase by blocking its access to telomeres. We investigated the cellular effects of four new 2,6-pyridine-dicarboxamide derivatives displaying strong selectivity for G4 structures and strong inhibition of telomerase in in vitro assays. These compounds inhibited cell proliferation at very low concentrations and then induced a massive apoptosis within a few days in a dosedependent manner in cultures of three telomerase-positive glioma cell lines, T98G, CB193 and U118-MG. They had also antiproliferative effects in SAOS-2, a cell line in which telomere maintenance involves an alternative lengthening of telomeres (ALT) mechanism. We show that apoptosis was preceded by multiple alterations of the cell cycle: activation of S-phase checkpoints, dramatic increase of metaphase duration and cytokinesis defects. These effects were not associated with telomere shortening, but they were directly related to telomere instability involving telomere end fusion and anaphase bridge formation. Pyridine-based G-quadruplex ligands are therefore promising agents for the treatment of various tumors including malignant gliomas.

Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action

“…These experiments unambiguously demonstrate that inhibition determined by TRAP in the presence of G-quadruplex ligands was not due to telomerase inhibition. For ligands such as telomestatin (15), Phen-DC3 (16), and 360A (17), the amplification of telomeric products was inhibited but amplification of the internal control that does not form a quadruplex was not.…”

G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells

“…These compounds were first evaluated as telomerase inhibitors and induced telomere shortening and senescence. Recently, it was observed that G-quadruplex ligands induced a short-term response (cell death) that cannot be explained merely by telomerase inhibition (26,29,41). Thus, these ligands probably have special biological activities as potential antitumor agents (42).…”

“…Several classes of small molecules have been identified to interact with and stabilize G-quadruplexes, including tricyclic anthraquinones (20), fluorenones (21), substituted acridines (22,23), cationic porphyrins (24,25), telomestatin (SOT-095; ref. 26), a perylenetetracarboxylic diimide derivative (27), indoloquinolines (28), pyridinedicarboxamide derivatives (29), and a benzonaphthofurandione tetracyclic compound (30). Cryptolepine is a naturally occurring quindoline alkaloid.…”

DNA architecture: from G to Z

“…Stabilizing intramolecular telomeric G-quadruplexes and the G-quadruplexes formed by sequences in oncogenic promoters is an attractive strategy for the development of anticancer drugs [37,38]. Indeed, some G-quadruplex ligands exhibit anticancer activities [38,[56][57][58].…”