{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:48:50Z","timestamp":1784641730701,"version":"3.55.0"},"reference-count":77,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,21]],"date-time":"2021-11-21T00:00:00Z","timestamp":1637452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In our previous paper, we reported that amphiphilic Ir complex\u2013peptide 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 (Ca2+)\u2013calmodulin (CaM) complex and induce an overload of intracellular Ca2+, 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 \u00b5M) induces ER stress and decreases the mitochondrial membrane potential (\u0394\u03a8m), thus triggering intracellular signaling pathways and resulting in cytoplasmic vacuolization in Jurkat cells (which is a typical phenomenon of paraptosis), while the change in \u0394\u03a8m 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.<\/jats:p>","DOI":"10.3390\/molecules26227028","type":"journal-article","created":{"date-parts":[[2021,11,21]],"date-time":"2021-11-21T21:00:50Z","timestamp":1637528450000},"page":"7028","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Cyclometalated Iridium(III) Complex\u2013Cationic Peptide Hybrids Trigger Paraptosis in Cancer Cells via an Intracellular Ca2+ Overload from the Endoplasmic Reticulum and a Decrease in Mitochondrial Membrane Potential"],"prefix":"10.3390","volume":"26","author":[{"given":"Chandrasekar","family":"Balachandran","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"},{"name":"Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3437-4567","authenticated-orcid":false,"given":"Kenta","family":"Yokoi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Naito","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jebiti","family":"Haribabu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Tamura","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3398-3993","authenticated-orcid":false,"given":"Masakazu","family":"Umezawa","sequence":"additional","affiliation":[{"name":"Research Institute for Science and Technology (RIST), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"Research Institute for Science and Technology (RIST), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshitada","family":"Yoshihara","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Graduate School of Science and Technology, Gunma University, 1-5-1 Tenjin-cho, Kiryu 376-8515, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4287-6487","authenticated-orcid":false,"given":"Seiji","family":"Tobita","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Graduate School of Science and Technology, Gunma University, 1-5-1 Tenjin-cho, Kiryu 376-8515, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Aoki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"},{"name":"Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"},{"name":"Research Institute for Science and Technology (RIST), Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","first-page":"e01935-15","article-title":"A single-amino-acid substitution in obg activates a new programmed cell death pathway in Escherichia coli","volume":"6","author":"Dewachter","year":"2015","journal-title":"ASM"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1007\/s11095-009-9895-1","article-title":"Programmed cell death pathways and current antitumor targets","volume":"26","author":"Tan","year":"2009","journal-title":"Pharmacol. 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