Amphiphilic Cationic Triscyclometalated Iridium(III) Complex–Peptide Hybrids Induce Paraptosis-like Cell Death of Cancer Cells via an Intracellular Ca(2+)-Dependent Pathway

[Image: see text] We report on the design and synthesis of a green-emitting iridium complex–peptide hybrid (IPH) 4, which has an electron-donating hydroxyacetic acid (glycolic acid) moiety between the Ir core and the peptide part. It was found that 4 is selectively cytotoxic against cancer cells, and the dead cells showed a green emission. Mechanistic studies of cell death indicate that 4 induces a paraptosis-like cell death through the increase in mitochondrial Ca(2+) concentrations via direct Ca(2+) transfer from ER to mitochondria, the loss of mitochondrial membrane potential (ΔΨ(m)), and the vacuolization of cytoplasm and intracellular organelle. Although typical paraptosis and/or autophagy markers were upregulated by 4 through the mitogen-activated protein kinase (MAPK) signaling pathway, as confirmed by Western blot analysis, autophagy is not the main pathway in 4-induced cell death. The degradation of actin, which consists of a cytoskeleton, is also induced by high concentrations of Ca(2+), as evidenced by costaining experiments using a specific probe. These results will be presented and discussed.