Mitochondria are the primary target in the induction of apoptosis by chiral ruthenium(II) polypyridyl complexes in cancer cells

A series of novel chiral ruthenium(II) polypyridyl complexes (Delta-Ru1, Lambda-Ru1, Delta-Ru2, Lambda-Ru2, Delta-Ru3, Lambda-Ru3) were synthesized and evaluated to determine their antiproliferative activities. Colocalization, inductively coupled plasma mass spectrometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay studies showed that these ruthenium(II) complexes accumulated preferentially in the mitochondria and exhibited cytotoxicity against various cancer cells in vitro. The complex Delta-Ru1 is of particular interest because it was found to have half-maximal inhibitory concentrations comparable to those of cisplatin and better activity than cisplatin against a cisplatin-resistant cell line, A549-CP/R. Delta-Ru1 induced alterations in the mitochondrial membrane potential and triggered intrinsic mitochondria-mediated apoptosis in HeLa cells, which involved the regulation of Bcl-2 family members and the activation of caspases. Taken together, these data suggest that Delta-Ru1 may be a novel mitochondria-targeting anticancer agent.