G-quadruplex compounds and cisplatin act synergistically to inhibit cancer cell growth in vitro and in vivo

Mekala Gunaratnam , Colin Green , João Bruno Moreira , Adam D. Moorhouse , Lloyd R. Kelland , John E. Moses , Stephen Neidle

The ability of two structurally diverse telomeric G-quadruplex binding compounds to synergise the action of cis-platin has been investigated in two cancer cell lines. One compound is a trisubstututed acridine compound AS1410, a close analogue of BRACO-19, and the other is a non-polycyclic compound synthesised using click chemistry and containing two triazole rings. Both compounds produce growth arrest at sub-cytotoxic concentrations in the two cell lines (MCF7 and A549), with behaviour consistent with telomere targeting mechanisms. Synergistic behaviour was observed in both cell lines with both compounds in combination with cis-platin, but only when the ratio of AS1410:cis-platin is >1. In vivo tumour xenograft studies with the A549 lung cancer model and the trisubstituted acridine compound AS1410 showed only a modest antitumour effect when administered alone, but produced rapid and highly significant decreases in tumour volume when administered in combination with cis-platin.

Mots clés: G-quadruplex; ligand; telomere; cis-platin; synergy

Mekala Gunaratnam, Colin Green, João Bruno Moreira, Adam D. Moorhouse, Lloyd R. Kelland, et al.. G-quadruplex compounds and cisplatin act synergistically to inhibit cancer cell growth in vitro and in vivo. Biochemical Pharmacology, 2009, 78 (2), pp.115. ⟨10.1016/j.bcp.2009.03.018⟩. ⟨hal-00493508⟩