A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition.

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)](2+) (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest.

γH2AX expression in cytological specimens as a biomarker of response to radiotherapy in solid malignancies.

Many anticancer treatments, including radiotherapy, act by damaging DNA and hindering cell function and proliferation. H2AX is a histone protein directly associated with DNA that is phosphorylated to produce γH2AX that accumulates in foci in an early response to DNA double-strand breaks, the most deleterious lesion caused by anticancer therapy. This study reports a γH2AX detection assay that has the potential to be used as a biomarker of response to guide cancer treatment.