Apoferritin‐Cu(II) Nanoparticles Induce Oncosis in Multidrug‐Resistant Colon Cancer Cells

Abstract

Multidrug resistance (MDR) limits the application of clinical chemotherapeutic drugs. There is an urgent need to develop non‐apoptosis‐inducing agents that circumvent drug resistance. Herein, four therapeutic copper complexes encapsulated in natural nanocarrier apoferritin (AFt‐Cu1‐4) are reported. Although they are isomers, they exhibit significantly different organelle distributions and cell death mechanisms. AFt‐Cu1 and AFt‐Cu3 accumulate in the cytoplasm and induce autophagy, whereas AFt‐Cu2 and AFt‐Cu4 can quickly enter the nucleus and trigger oncosis. Excitedly, AFt‐Cu2 and AFt‐Cu4 show a strong tumor growth inhibition effect in mice models bearing multidrug‐resistant colon xenograft via intravenous injection. To the best of the authors’ knowledge, this is the first example of metal‐based nucleus‐targeted oncosis inducers overcoming multidrug resistance in vivo.

Two-Photon Photodegradation of E3 Ubiquitin Ligase Cereblon by a Ru(II) Complex: Inducing Ferroptosis in Cisplatin-Resistant Tumor Cells

“…In contrast, the other cell death mode inhibitors, including apoptosis inhibitor Z-VAD-FMK (Z-V), lysosomal proteasemediated cell death inhibitor leupeptin (Leu), necrosis/ necroptosis inhibitor necrostain-1 (Nec-1), paraptosis inhibitor cycloheximide (Cyc), autophagic inhibitor 3-methyladenine (3-MA), and oncosis inhibitor DPQ, were ineffective. 5,8 Lipid peroxide upregulation is a characteristic of ferroptosis. 48 The degree of lipid peroxidation was detected using confocal luminescence imaging with a lipid peroxidationspecific sensor C11-BODIPY.…”

“…As shown in Figure B, after co-incubating with ferroptosis inhibitor ferrostatin-1 (Fer-1), the cell viability of Ru-Poma -PDT increased from 36.13 ± 0.77% to 88.57 ± 15.40%. In contrast, the other cell death mode inhibitors, including apoptosis inhibitor Z-VAD-FMK (Z-V), lysosomal protease-mediated cell death inhibitor leupeptin (Leu), necrosis/necroptosis inhibitor necrostain-1 (Nec-1), paraptosis inhibitor cycloheximide (Cyc), autophagic inhibitor 3-methyladenine (3-MA), and oncosis inhibitor DPQ, were ineffective. , …”

“…Cancers can develop resistance by dysregulation of apoptotic machinery, and the increasing prevalence of these drug-resistant cancers necessitates further research and treatment development . In contrast to apoptosis, other programmed cell death, for example, ferroptosis, pyroptosis, and necroptosis, are different in terms of signaling pathways and critical proteins executing death, providing a theoretical basis for circumventing apoptosis resistance. , Recently, Gaiddon reported two Ru(II) complexes triggering nonapoptotic programmed cell death through endoplasmic reticulum (ER) stress pathways and were more effective against apoptosis-resistant cells than the clinical drug oxaliplatin . Su et al reported an Ir(III) complex that induced mitophagy in cisplatin-resistant cancer cells .…”