G-quadruplex compounds and cis-platin act synergistically to inhibit cancer cell growth in vitro and in vivo.
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 trisubstituted 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 anti-tumour effect when administered alone, but produced rapid and highly significant decreases in tumour volume when administered in combination with cis-platin.
Gunaratnam
Mekala
M
CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
Green
Colin
C
Moreira
João Bruno
JB
Moorhouse
Adam D
AD
Kelland
Lloyd R
LR
Moses
John E
JE
Neidle
Stephen
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D054856:G-Quadruplexes; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D002945:Cisplatin