Amphiphilic Cationic Triscyclometalated Iridium(III) Complex-Peptide Hybrids Induce Paraptosis-like Cell Death of Cancer Cells via an Intracellular Ca-Dependent Pathway.

We report on the design and synthesis of a green-emitting iridium complex-peptide hybrid (IPH) , which has an electron-donating hydroxyacetic acid (glycolic acid) moiety between the Ir core and the peptide part. It was found that is selectively cytotoxic against cancer cells, and the dead cells showed a green emission. Mechanistic studies of cell death indicate that induces a paraptosis-like cell death through the increase in mitochondrial Ca concentrations via direct Ca transfer from ER to mitochondria, the loss of mitochondrial membrane potential (ΔΨ), and the vacuolization of cytoplasm and intracellular organelle. Although typical paraptosis and/or autophagy markers were upregulated by through the mitogen-activated protein kinase (MAPK) signaling pathway, as confirmed by Western blot analysis, autophagy is not the main pathway in -induced cell death. The degradation of actin, which consists of a cytoskeleton, is also induced by high concentrations of Ca, as evidenced by costaining experiments using a specific probe. These results will be presented and discussed.