Amphiphilic Cationic Triscyclometalated Iridium(III) Complex-Peptide Hybrids Induce Paraptosis-like Cell Death of Cancer Cells via an Intracellular Ca2+-Dependent Pathway.

Abstract

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 Ca2+ concentrations via direct Ca2+ transfer from ER to mitochondria, the loss of mitochondrial membrane potential (ΔΨm), 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 Ca2+, as evidenced by costaining experiments using a specific probe. These results will be presented and discussed.

• Authors: Kenta Yokoi, Chandrasekar Balachandran, Masakazu Umezawa, Koji Tsuchiya, Aleksandra Mitrić, Shin Aoki
• Journal: ACS omega (ACS Omega) Vol. 5 Issue 12 Pg. 6983-7001 (Mar 31 2020) ISSN: 2470-1343 [Electronic] United States
• PMID: 32258934 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 American Chemical Society.