Potent Apoptotic Response Induced by Chloroacetamidine Anthrathiophenediones in Bladder Cancer Cells

We previously found that two neighboring
G-quadruplexes behave
as a molecular switch controlling the expression of HRAS (Cogoi, S.; Schekotikhin, A. E.; Xodo, L. E. Nucl.
Acids Res. 2014, DOI: 10.1093/nar/gku574). In this study we have designed anthrathiophenediones
with two chloroacetamidine-containing side chains (CATDs) as G-quadruplex
binders and have examined their anticancer activity in T24 bladder
cancer cells bearing mutant HRAS and in T24 xenografts.
The designed CATDs (3a–e), bearing
alkyl side chains of different length, penetrate T24 cancer cells
more than their analogues with guanidine-containing side chains. The
lead compounds 3a and 3c inhibit HRAS expression, metabolic activity, and colony formation
in T24 cancer cells. They also activate a strong apoptotic response,
as indicated by PARP-1, caspases 3/7, and annexin V/propidium iodide
assays. Apoptosis occurs under conditions where cyclin D1 is down-regulated
and the cell cycle arrested in G2 phase. Finally, compound 3a inhibits the growth of T24 xenografts and increases the median survival
time of nude mice.