Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential

In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanisti...

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Autores principales:	Chandrasekar Balachandran, Kenta Yokoi, Kana Naito, Jebiti Haribabu, Yuichi Tamura, Masakazu Umezawa, Koji Tsuchiya, Toshitada Yoshihara, Seiji Tobita, Shin Aoki
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cyclometalated iridium complex peptide hybrid anticancer agents paraptosis cytoplasmic vacuolization Ca<sup>2+</sup> Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/e56603c0095a4cdfba9e31644617f6d3
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spelling	oai:doaj.org-article:e56603c0095a4cdfba9e31644617f6d32021-11-25T18:29:18ZCyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential10.3390/molecules262270281420-3049https://doaj.org/article/e56603c0095a4cdfba9e31644617f6d32021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/7028https://doaj.org/toc/1420-3049In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca<sup>2+</sup>)–calmodulin (CaM) complex and induce an overload of intracellular Ca<sup>2+</sup>, resulting in the induction of non-apoptotic programmed cell death. In this work, we conduct a detailed mechanistic study of cell death induced by ASb-2, a typical example of IPHs, and describe how ASb-2 induces paraptotic programmed cell death in a manner similar to that of celastrol, a naturally occurring triterpenoid that is known to function as a paraptosis inducer in cancer cells. It is suggested that ASb-2 (50 µM) induces ER stress and decreases the mitochondrial membrane potential (Δ<i>Ψ<sub>m</sub></i>), thus triggering intracellular signaling pathways and resulting in cytoplasmic vacuolization in Jurkat cells (which is a typical phenomenon of paraptosis), while the change in Δ<i>Ψ<sub>m</sub></i> values is negligibly induced by celastrol and curcumin. Other experimental data imply that both ASb-2 and celastrol induce paraptotic cell death in Jurkat cells, but this induction occurs via different signaling pathways.Chandrasekar BalachandranKenta YokoiKana NaitoJebiti HaribabuYuichi TamuraMasakazu UmezawaKoji TsuchiyaToshitada YoshiharaSeiji TobitaShin AokiMDPI AGarticlecyclometalated iridium complexpeptide hybridanticancer agentsparaptosiscytoplasmic vacuolizationCa<sup>2+</sup>Organic chemistryQD241-441ENMolecules, Vol 26, Iss 7028, p 7028 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cyclometalated iridium complex peptide hybrid anticancer agents paraptosis cytoplasmic vacuolization Ca<sup>2+</sup> Organic chemistry QD241-441
spellingShingle	cyclometalated iridium complex peptide hybrid anticancer agents paraptosis cytoplasmic vacuolization Ca<sup>2+</sup> Organic chemistry QD241-441 Chandrasekar Balachandran Kenta Yokoi Kana Naito Jebiti Haribabu Yuichi Tamura Masakazu Umezawa Koji Tsuchiya Toshitada Yoshihara Seiji Tobita Shin Aoki Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential
description	In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca<sup>2+</sup>)–calmodulin (CaM) complex and induce an overload of intracellular Ca<sup>2+</sup>, resulting in the induction of non-apoptotic programmed cell death. In this work, we conduct a detailed mechanistic study of cell death induced by ASb-2, a typical example of IPHs, and describe how ASb-2 induces paraptotic programmed cell death in a manner similar to that of celastrol, a naturally occurring triterpenoid that is known to function as a paraptosis inducer in cancer cells. It is suggested that ASb-2 (50 µM) induces ER stress and decreases the mitochondrial membrane potential (Δ<i>Ψ<sub>m</sub></i>), thus triggering intracellular signaling pathways and resulting in cytoplasmic vacuolization in Jurkat cells (which is a typical phenomenon of paraptosis), while the change in Δ<i>Ψ<sub>m</sub></i> values is negligibly induced by celastrol and curcumin. Other experimental data imply that both ASb-2 and celastrol induce paraptotic cell death in Jurkat cells, but this induction occurs via different signaling pathways.
format	article
author	Chandrasekar Balachandran Kenta Yokoi Kana Naito Jebiti Haribabu Yuichi Tamura Masakazu Umezawa Koji Tsuchiya Toshitada Yoshihara Seiji Tobita Shin Aoki
author_facet	Chandrasekar Balachandran Kenta Yokoi Kana Naito Jebiti Haribabu Yuichi Tamura Masakazu Umezawa Koji Tsuchiya Toshitada Yoshihara Seiji Tobita Shin Aoki
author_sort	Chandrasekar Balachandran
title	Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential
title_short	Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential
title_full	Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential
title_fullStr	Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential
title_full_unstemmed	Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential
title_sort	cyclometalated iridium(iii) complex–cationic peptide hybrids trigger paraptosis in cancer cells via an intracellular ca<sup>2+</sup> overload from the endoplasmic reticulum and a decrease in mitochondrial membrane potential
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e56603c0095a4cdfba9e31644617f6d3
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Cyclometalated Iridium(III) Complex–Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca<sup>2+</sup> Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential

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