Ruthenium(II) polypyridyl complexes: Cellular uptake, cell image and apoptosis of HeLa cancer cells induced by double targets

•We present two novel Ru(II) complexes with hydrophobic ancillary ligands RPD and RBD.•RPD enter the HeLa cells through non-endocytotic, but energy-dependent mechanism.•RPD induces HeLa cell apoptosis through mitochondria-mediated pathway.•RPD lock a telomeric DNA into a G-quadruplex conformation.

Studies have shown that ruthenium complexes have relatively strong anticancer activity, cell uptake of drugs have a crucial impact on the pharmacological activity, using autofluorescence of ruthenium complexes could effectively track cancer cells and drug distribution, transport accurately in real time. In this work, we present the synthesis and detailed characterization of two novel Ru(II) complexes with hydrophobic ancillary ligands, namely [Ru(bpy)2(5-idip)]2+ (RBD) and [Ru(phen)2(5-idip)]2+ (RPD) (5-idip = 2-indole-[4,5-f][1,10]phenanthroline). We have shown that RPD can enter the HeLa cells efficiently through non-endocytotic, but energy-dependent mechanism and first accumulated in lysosomes, and then escape from the lysosomes and localize within the nuclei, efficiently lead to the inhibition of DNA transcription and translation and induced cell apoptosis. Further studies on the mechanism of apoptosis in HeLa cells demonstrate that RPD is able to induce mitochondria-mediated apoptosis in HeLa cells through activation of initiator caspase-9 and down-stream effector caspase-3 and -7 and cleavage of PARP. We have also demonstrated that RPD bind to telomeric G-quadruplex DNA effectively and selectively, together with increased p21 and p16 expression. Our findings suggest that RPD induces HeLa cell apoptosis through mitochondria-mediated pathway and inhibition of telomerase activity. RPD may be a candidate for further evaluation as a chemotherapeutic agent for human cancers.

Graphical abstractTwo Ruthenium(II) polypyridyl complexes exhibit anticancer activity by mitochondria mediated apoptosis and telomerase inhibition.Figure optionsDownload full-size imageDownload as PowerPoint slide