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

Kenta Yokoi; Chandrasekar Balachandran; Masakazu Umezawa; Koji Tsuchiya; Aleksandra Mitrić; Shin Aoki

doi:10.1021/acsomega.0c00337

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

ACS Omega. 2020 Mar 17;5(12):6983-7001. doi: 10.1021/acsomega.0c00337. eCollection 2020 Mar 31.

Authors

Kenta Yokoi¹, Chandrasekar Balachandran¹, Masakazu Umezawa², Koji Tsuchiya², Aleksandra Mitrić^{1

3}, Shin Aoki^{1

2}

Affiliations

¹ Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
² Research Institute for Science and Technology (RIST), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
³ Faculty of Technology and Metallurgy, University of Belgrade, 4 Karnegijeva Street, Belgrade 11000, Serbia.

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 (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 Ca²⁺, as evidenced by costaining experiments using a specific probe. These results will be presented and discussed.