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Amphiphilic Cationic Triscyclometalated Iridium(III) Complex–Peptide Hybrids Induce Paraptosis-like Cell Death of Cancer Cells via an Intracellular Ca2+-Dependent Pathway
journal contribution
posted on 2020-03-17, 08:33 authored by Kenta Yokoi, Chandrasekar Balachandran, Masakazu Umezawa, Koji Tsuchiya, Aleksandra Mitrić, Shin AokiWe
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.