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Angewandte Chemie (International Ed. in... May 2024An optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor-immune responses. Research has shown that...
An optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor-immune responses. Research has shown that non-apoptotic cell death, such as pyroptosis and ferroptosis, can enhance the immune response. Despite this, there has been limited investigation and reporting on the mechanisms of oncosis and its correlation with immune response. Herein, we designed and synthesized a Ru(II) complex that targeted the nucleus and mitochondria to induce cell oncosis. Briefly, the Ru(II) complex disrupts the nucleus and mitochondria DNA, which active polyADP-ribose polymerase 1, accompanied by ATP consumption and porimin activation. Concurrently, mitochondrial damage and endoplasmic reticulum stress result in the release of Ca2+ ions and increased expression of Calpain 1. Subsequently, specific pore proteins porimin and Calpain 1 promote cristae destruction or vacuolation, ultimately leading to cell membrane rupture. The analysis of RNA sequencing demonstrates that Ru(II) complex can initiate the oncosis-associated pathway and activate both innate and adaptive immunity. In vivo experiments have confirmed that oncosis facilitates the maturation of dendritic cells and the awakening of adaptive cytotoxic T lymphocytes but also induces the polarization of tumor-associated macrophages (TAMs) towards an M1 phenotype and activates the innate immune response of TAMs.
PubMed: 38771671
DOI: 10.1002/anie.202405679 -
Cell Death Discovery Mar 2024Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular...
Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is reactive oxygen species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD's ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD's therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.
PubMed: 38472168
DOI: 10.1038/s41420-024-01911-w -
ACS Nano Feb 2024The design of bio-responsive functional molecular materials that can undergo self-assembly to form nanostructures within cells in response to cellular endogenous stimuli...
The design of bio-responsive functional molecular materials that can undergo self-assembly to form nanostructures within cells in response to cellular endogenous stimuli and the clarification of their prospective reaction mechanisms are of paramount significance. This work aims to elucidate the spatiotemporal generation of subcellular nanostructures and their influence on cellular functionality. Three sets of cyclometalated platinum complexes have been designed and synthesized as near-infrared phosphorescent turn-on probes for specific anions based on dynamic self-assembly in aqueous solution. The augmentation of the quantity of aromatic rings in the NN bidentate ligand of the complex modifies both the intensity of the intermolecular Pt-Pt interaction and the capacity to generate self-assembled nanowires with near-infrared emission. Besides, we explored the impact of the CN ligand's substituent effect on anion recognition, which revealed that complexes with electron-absorbing F atom substitution exhibit superior selectivity for Br. These complexes display vivid green turn-on luminescence upon interaction with cellular biomolecules, enabling dynamic monitoring of their subcellular distribution and their interaction on diverse conditions. Furthermore, our complexes were observed to induce oncosis in cancer cells, underscoring the potential of our work in facilitating in vitro diagnosis and developing effective theranostic agents for cancer therapy.
PubMed: 38345022
DOI: 10.1021/acsnano.3c11366 -
Journal of Biological Inorganic... Mar 2024Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to...
Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.
Topics: Humans; Poloxamer; Lysosomes; A549 Cells; Antineoplastic Agents; Ruthenium; Coordination Complexes; Membrane Potential, Mitochondrial; Drug Screening Assays, Antitumor; Oxidative Stress
PubMed: 38189962
DOI: 10.1007/s00775-023-02039-5 -
Bioorganic Chemistry Feb 2024Abnormally high levels of copper in tumors stimulate malignant proliferation and migration of cancer cells, which proposes a formidable challenge for the thorough...
Abnormally high levels of copper in tumors stimulate malignant proliferation and migration of cancer cells, which proposes a formidable challenge for the thorough therapy of malignant tumors. In this work, we developed a reliable, mitochondria-targeted near-infrared aggregation-induced emission fluorescent probe, TTQ-Th, whose thiourea moiety specifically could recognize mitochondria even both upon loss of mitochondrial membrane potential or in fixated cells, and can capture copper overexpressed by tumor cells, leading to severe copper deficiency. In parallel, TTQ-Th can generate sufficient reactive oxygen species (ROS) upon photoexcitation, while copper deficiency inhibits expression of related copper-based enzymes, resulting in a decline in ATP production. Such energy deficiency, combined with reduced MMP and elevated oxidative stress can lead to critical cell oncosis. Both in vitro and intracellular experiments can illustrate that the elevated ROS has remarkable damage to tumor cells and contributes to the elimination of the primary tumor, while copper deficiency further hinder tumor cell migration and induces G0/G1 cell cycle arrest in a dose-dependent manner, which is an efficacious strategy for the treatment of malignant tumors.
Topics: Humans; Photosensitizing Agents; Copper; Photochemotherapy; Reactive Oxygen Species; Mitochondria; Neoplasms
PubMed: 38176374
DOI: 10.1016/j.bioorg.2023.107020 -
Journal of Medicinal Chemistry Jan 2024A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)(dppz)], -, were rationally designed...
A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)(dppz)], -, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was -CFCH or -MeNCH. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives ( and ) were the best performers, being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate O and/or OH in cell-free media.
Topics: Humans; Coordination Complexes; Iridium; Photosensitizing Agents; Dermatitis, Phototoxic; Lysosomes; Benzothiazoles; Antineoplastic Agents; Cell Line, Tumor; Neoplasms
PubMed: 38141031
DOI: 10.1021/acs.jmedchem.3c01978 -
Advanced Healthcare Materials Feb 2024Multidrug resistance (MDR) limits the application of clinical chemotherapeutic drugs. There is an urgent need to develop non-apoptosis-inducing agents that circumvent...
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.
Topics: Humans; Mice; Animals; Copper; Apoferritins; Drug Resistance, Multiple; Cell Line, Tumor; Nanoparticles; Colonic Neoplasms; Drug Resistance, Neoplasm; Antineoplastic Agents
PubMed: 38073257
DOI: 10.1002/adhm.202302564 -
Burns & Trauma 2023Globally, ischemic stroke causes millions of deaths per year. The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and... (Review)
Review
Globally, ischemic stroke causes millions of deaths per year. The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region. In the infarct region, cell injuries follow either the regulated pathway involving precise signaling cascades, such as apoptosis and autophagy, or the nonregulated pathway, which is uncontrolled by any molecularly defined effector mechanisms such as necrosis. However, numerous studies have recently found that a certain type of necrosis can be regulated and potentially modified by drugs and is nonapoptotic; this type of necrosis is referred to as regulated necrosis. Depending on the signaling pathway, various elements of regulated necrosis contribute to the development of ischemic stroke, such as necroptosis, pyroptosis, ferroptosis, pathanatos, mitochondrial permeability transition pore-mediated necrosis and oncosis. In this review, we aim to summarize the underlying molecular mechanisms of regulated necrosis in ischemic stroke and explore the crosstalk and interplay among the diverse types of regulated necrosis. We believe that targeting these regulated necrosis pathways both pharmacologically and genetically in ischemia-induced neuronal death and protection could be an efficient strategy to increase neuronal survival and regeneration in ischemic stroke.
PubMed: 38026442
DOI: 10.1093/burnst/tkad016 -
Lasers in Medical Science Oct 2023Quantitative phase imaging (QPI) has emerged as an indispensable tool in the field of biomedicine, offering the ability to obtain quantitative maps of phase changes due... (Review)
Review
Quantitative phase imaging (QPI) has emerged as an indispensable tool in the field of biomedicine, offering the ability to obtain quantitative maps of phase changes due to optical path length delays without the need for contrast agents. These maps provide valuable information about cellular morphology and dynamics, unperturbed by the introduction of exogenous substances. In this review, a summary of recent studies that have focused on elucidating the growth dynamics of individual cells using QPI is presented. Specifically, investigations into cellular changes occurring during mitosis, the differentiation of cellular organelles, the assessment of distinct cell death processes (i.e., apoptosis, necrosis, and oncosis) and the precise measurement of live cell temperature are explored. Furthermore, the captivating applications of QPI in theragnostics, where its potential for transformative impact is prominently showcased, are highlighted. Finally, the challenges that need to be overcome for its wider adoption and successful integration into biomedical research are outlined.
Topics: Apoptosis; Cell Death; Cell Proliferation
PubMed: 37851109
DOI: 10.1007/s10103-023-03902-2 -
Frontiers in Bioengineering and... 2023Chips-based platforms intended for single-cell manipulation are considered powerful tools to analyze intercellular interactions and cellular functions. Although the...
Chips-based platforms intended for single-cell manipulation are considered powerful tools to analyze intercellular interactions and cellular functions. Although the conventional cell co-culture models could investigate cell communication to some extent, the role of a single cell requires further analysis. In this study, a precise intercellular interaction model was built using a microelectrode array [microelectrode array (MEA)]-based and dielectrophoresis-driven single-cell manipulation chip. The integrated platform enabled precise manipulation of single cells, which were either trapped on or transferred between electrodes. Each electrode was controlled independently to record the corresponding cellular electrophysiology. Multiple parameters were explored to investigate their effects on cell manipulation including the diameter and depth of microwells, the geometry of cells, and the voltage amplitude of the control signal. Under the optimized microenvironment, the chip was further evaluated using 293T and neural cells to investigate the influence of electric field on cells. An examination of the inappropriate use of electric fields on cells revealed the occurrence of oncosis. In the end of the study, electrophysiology of single neurons and network of neurons, both differentiated from human induced pluripotent stem cells (iPSC), was recorded and compared to demonstrate the functionality of the chip. The obtained preliminary results extended the nature growing model to the controllable level, satisfying the expectation of introducing more elaborated intercellular interaction models.
PubMed: 37829565
DOI: 10.3389/fbioe.2023.1258626