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Bioelectrochemistry (Amsterdam,... Apr 2023Irreversible electroporation (IRE) has been reported to variably cause apoptosis, necrosis, oncosis or pyroptosis. Intracellular ATP is a key substrate for apoptosis...
Irreversible electroporation (IRE) has been reported to variably cause apoptosis, necrosis, oncosis or pyroptosis. Intracellular ATP is a key substrate for apoptosis which is rapidly depleted during IRE, we sought to understand whether intracellular ATP levels is a determinant of the mode of cell death following IRE. A mouse bladder cancer cell line (MB49) was treated with electric fields while increasing the number of pulses at a fixed electric field strength, and pulse width. Cell proliferation and viability and ATP levels were measured at different timepoints post-treatment. Cell death was quantified with Annexin-V/Propidium Iodide staining. Caspase activity was measure with a fluorometric kit and western blotting. A pan-caspase (Z-VAD-FMK) inhibitor was used to assess the impact of signal inhibition. We found cell death following IRE was insensitive to caspase inhibition and was correlated with ATP loss. These findings were confirmed by cell death assays and measurement of changes in caspase expression on immunoblotting. This effect could not be rescued by ATP supplementation. Rapid and acute ATP loss during IRE interferes with caspase signaling, promoting necrosis. Cell necrosis from IRE is expected to be immunostimulatory and may be effective in cancer cells that carry mutated or defective apoptosis genes.
Topics: Mice; Animals; Apoptosis; Necrosis; Cell Death; Electroporation; Caspases; Adenosine Triphosphate; Caspase 3
PubMed: 36549173
DOI: 10.1016/j.bioelechem.2022.108355 -
Science China. Life Sciences Mar 2023Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species (ROS) generation and lipid peroxidation....
Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species (ROS) generation and lipid peroxidation. Here, we report a novel iron-dependent form of ferroptosis induced by labile iron and investigate the mechanism underlying this process. We find that labile iron-induced ferroptosis is distinct from canonical ferroptosis and is linked to the mitochondrial pathway. Specifically, the mitochondrial calcium uniporter mediates the ferroptosis induced by labile iron. Interestingly, cells undergoing labile iron-induced ferroptosis exhibit cytoplasmic features of oncosis and nuclear features of apoptosis. Furthermore, labile iron-induced ferroptosis involves a unique set of genes. Finally, labile iron-induced ferroptosis was observed in liver subjected to acute iron overload in vivo. Our study reveals a novel form of ferroptosis that may be implicated in diseases caused by acute injury.
Topics: Iron; Ferroptosis; Apoptosis; Reactive Oxygen Species; Lipid Peroxidation
PubMed: 36515861
DOI: 10.1007/s11427-022-2244-4 -
Molecules (Basel, Switzerland) Nov 2022The potentially therapeutic effects of the naturally abundant plant flavonoid quercetin have been extensively studied. An extensive body of literature suggests that... (Review)
Review
The potentially therapeutic effects of the naturally abundant plant flavonoid quercetin have been extensively studied. An extensive body of literature suggests that quercetin's powerful antioxidant effects may relate to its ability to treat disease. Glutamate excitotoxicity occurs when a neuron is overstimulated by the neurotransmitter glutamate and causes dysregulation of intracellular calcium concentrations. Quercetin has been shown to be preventative against many forms of neuronal cell death resulting from glutamate excitotoxicity, such as oncosis, intrinsic apoptosis, mitochondrial permeability transition, ferroptosis, phagoptosis, lysosomal cell death, parthanatos, and death by reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. The clinical importance for the attenuation of glutamate excitotoxicity arises from the need to deter the continuous formation of tissue infarction caused by various neurological diseases, such as ischemic stroke, seizures, neurodegenerative diseases, and trauma. This review aims to summarize what is known concerning glutamate physiology and glutamate excitotoxic pathophysiology and provide further insight into quercetin's potential to hinder neuronal death caused by cell death pathways activated by glutamate excitotoxicity. Quercetin's bioavailability may limit its use clinically, however. Thus, future research into ways to increase its bioavailability are warranted.
Topics: Humans; Glutamic Acid; Quercetin; Antioxidants; Reactive Oxygen Species; Neurodegenerative Diseases
PubMed: 36364448
DOI: 10.3390/molecules27217620 -
Acta Pharmaceutica Sinica. B Sep 2022As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer... (Review)
Review
As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance. A variety of anticancer drugs, synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects. Moreover, the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers, but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment. This review first introduces the main characteristics, the mechanism and various pharmacological modulators of different non-apoptotic cell death forms, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, lysosomal-dependent cell death, and oncosis. Second, we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components. Furthermore, the combination therapies of non-apoptotic cell death with photothermal therapy, photodynamic therapy, immunotherapy and other modalities are summarized. Finally, the challenges and future perspectives in this regard are also discussed.
PubMed: 36176912
DOI: 10.1016/j.apsb.2022.03.020 -
Cellular and Molecular Life Sciences :... Sep 2022Oncosis (from Greek ónkos, meaning "swelling") is a non-apoptotic cell death process related to energy depletion. In contrast to apoptosis, which is the main form of...
Oncosis (from Greek ónkos, meaning "swelling") is a non-apoptotic cell death process related to energy depletion. In contrast to apoptosis, which is the main form of cell death induced by anticancer drugs, oncosis has been relatively less explored but holds potential to overcome drug resistance phenomena. In this study, we report a novel rationally designed mitochondria-targeted iridium(III) complex (OncoIr3) with advantageous properties as a bioimaging agent. OncoIr3 exhibited potent anticancer activity in vitro against cancer cells and displayed low toxicity to normal dividing cells. Flow cytometry and fluorescence-based assays confirmed an apoptosis-independent mechanism involving energy depletion, mitochondrial dysfunction and cellular swelling that matched with the oncotic process. Furthermore, a Caenorhabditis elegans tumoral model was developed to test this compound in vivo, which allowed us to prove a strong oncosis-derived antitumor activity in animals (with a 41% reduction of tumor area). Indeed, OncoIr3 was non-toxic to the nematodes and extended their mean lifespan by 18%. Altogether, these findings might shed new light on the development of anticancer metallodrugs with non-conventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Death; Cell Line, Tumor; Iridium; Necrosis; Neoplasms
PubMed: 36066676
DOI: 10.1007/s00018-022-04526-5 -
Frontiers in Pharmacology 2022Change in the energy metabolism of cancer cells, which display significant differences compared to normal cells, is a rising phenomenon in developing new therapeutic...
Change in the energy metabolism of cancer cells, which display significant differences compared to normal cells, is a rising phenomenon in developing new therapeutic approaches against cancers. One of the metabolic enzymes, hexokinase-II (HK-II) is involved in glycolysis, and inhibiting the HK-II activity may be a potential metabolic target for cancer therapy as most of the drugs in clinical use act on DNA damage. Methyl jasmonate (MJ) is one of the compounds blocking HK-II activity in cancer cells. In a previous study, we showed that the novel MJ analogs inhibit HK-II activity through VDAC detachment from the mitochondria. In this study, to evaluate the potential of targeting HK-2 activity, through patient cohort analysis, we first determined HK-2 expression levels and prognostic significance in highly lethal glioblastoma (GBM) brain tumor. We then examined the therapeutic effects of the novel analogs in the GBM cells. Here, we report that, among all, compound-10 (C-10) showed significant therapeutic efficacy as compared to MJ which is in use for preclinical and clinical studies. Afterward, we analyzed cell death triggered by C-10 in two different GBM cell lines. We found that C-10 treatment increased the apoptotic/necrotic cells and autophagy in GBM cells. The newly developed analog, C-10, was found to be lethal against GBM by the activation of cell death authorities, mostly in a necrotic and autophagic fashion at the early stages of the treatment. Considering that possibly decreased intracellular ATP levels by C-10 mediated inhibition of HK-2 activity and disabled VDAC interaction, a more detailed analysis of HK-2 inhibition-mediated cell death can provide a deep understanding of the mechanism of action on the oncosis/necroptosis axis. These findings provide an option to design clinically relevant and effective novel HK-II inhibitors and suggest novel MJ analogs to further study them as potential anticancer agents against GBM.
PubMed: 35677429
DOI: 10.3389/fphar.2022.828400 -
Biochimica Et Biophysica Acta.... Sep 2022CD147/Basigin/EMMPRIN is overexpressed in several cancerous tissues and it has been shown to induce matrix metalloproteinases (MMPs) whose expression is associated with...
CD147/Basigin/EMMPRIN is overexpressed in several cancerous tissues and it has been shown to induce matrix metalloproteinases (MMPs) whose expression is associated with cancer metastasis. Thus, targeting CD147 with monoclonal antibodies (mAbs) potentially has therapeutic applications in cancer immunotherapy. Here, we report the use of anti-CD147 mAbs targeting domain 1 of CD147, namely M6-1D4 (IgM), M6-1F3 (IgM), M6-2F9 (IgM) and M6-1E9 (IgG2a), against several human cancer cell lines. Strikingly, IgM but not IgG mAbs against CD147, especially clone M6-1D4, induced acute cellular swelling, and this phenomenon appeared to be specifically found with hepatocellular carcinoma (HCC) cells. Furthermore, molecular investigation upon treating HepG2 cells with M6-1D4 showed unfolded protein response (UPR) activation, autophagosome accumulation, and cell cycle arrest, but without classic apoptosis related features. More interestingly, prolonged M6-1D4 treatment (24 h) resulted in irreversible oncosis leading to necroptosis. Furthermore, treatment with a mixed lineage kinase domain-like psuedokinase (MLKL) inhibitor and partial knockout of MLKL resulted in reduced sensitivity to necroptosis in M6-1D4-treated HepG2 cells. Surprisingly however, the observed necroptotic signaling axis appeared to be non-canonical as it was independent of receptor-interacting serine/threonine-protein kinase (RIPK) phosphorylation. In addition, no cytotoxic effect on human dermal fibroblast (HDF) was observed after incubation with M6-1D4. Taken together, this study provides clues to target CD147 in HCC using mAbs, as well as sheds new light on a novel strategy to kill cancerous cells by the induction of necroptosis.
Topics: Antibodies, Monoclonal; Basigin; Carcinoma, Hepatocellular; Cell Line; Humans; Immunoglobulin M; Liver Neoplasms; Necroptosis
PubMed: 35598753
DOI: 10.1016/j.bbamcr.2022.119295 -
Phytomedicine : International Journal... Jul 2022Spiropachysine A is the extracted compound of traditional Chinese ethnic medicine Pachysandra axillaries Franch. var. styiosa (Dunn) M. Cheng. Spiropachysine A is the...
BACKGROUND
Spiropachysine A is the extracted compound of traditional Chinese ethnic medicine Pachysandra axillaries Franch. var. styiosa (Dunn) M. Cheng. Spiropachysine A is the primary active steroidal alkaloids (SAs) widely used to facilitate blood circulation and relieve pain and inflammation. Few previous studies have investigated the anti-cancer activity of Spiropachysine A to treat hepatocellular carcinoma (HCC), and its molecular mechanism remains unknown.
PURPOSE
This study aims to investigate the anti-cancer activity of Spiropachysine A and the underlying mechanisms by inducing methuosis in vitro and in vivo.
METHODS
Here, the activity of Spiropachysine A against cancer was evaluated by the experiments with MHCC-97H cells and the xenografted mice model. The cell proliferation was examined using MTT assay, and cell morphological characteristics were observed by microscope cellular imaging. The effects of autophagy, paraptosis, and oncosis on cytoplasmic vacuolisation were detected using immunofluorescence staining, transmission electron microscopy (TEM) and western blotting (WB). The cell cycle distribution and apoptosis were analysed by flow cytometry. Hematoxylin eosin (H & E) staining was used to observe the pathological changes of the tissues.
RESULTS
The in vitro and in vivo results indicated that Spiropachysine A could inhibit HCC cells proliferation (IC = 2.39 ± 0.21 μM against MHCC-97H cells) and tumor growth (TGI = 32.81 ± 0.23% at 25 mg/kg and 50.32 ± 0.26% at 50 mg/kg). The morphological changes of the treated cells showed that cell proliferation inhibition caused by Spiropachysine A was associated with numerous cytoplasmic vacuolization. Mechanistically, Spiropachysine A-induced methuosis rather than autophagy or arapaptic because the autophagy flux was blocked, leading to the increased LC3-II/I value and an accumulation of selective autophagy substrate p62. And, there was no activation of the regulatory parapaptic MAPK pathway. Additionally, the TEM and Lucifer yellow (LY) accumulation data confirmed that Spiropachysine A significantly triggered methuosis instead of oncosis. Further, the study indicated that the anti-proliferative activity of Spiropachysine A was independent of PCD since no alterations in apoptosis and cell cycle arrest-related proteins were observed after Spiropachysine A treatment. Impressively, the increased expression of Rac1 was observed in Spiropachysine A-treated MHCC-97H cells and its xenograft tumours, confirming that Spiropachysine A inhibited cell proliferation and induced methuosis through Ras/Rac1 signal pathways.
CONCLUSIONS
Spiropachysine A was collectively identified as a novel methuosis inducer that suppresses HCC in vitro and in vivo. The underlying mechanisms might be involved in the Ras/Rac1 pathway. Such data predict that Spiropachysine A is a promising candidate for developing novel chemotherapeutic agents as a methuosis inducer for cancer therapy.
Topics: Animals; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Liver Neoplasms; Mice; Necrosis
PubMed: 35584581
DOI: 10.1016/j.phymed.2022.154151 -
Journal of Clinical Laboratory Analysis Jun 2022As an important non-apoptotic cell death method, oncosis has been reported to be closely associated with tumors in recent years. However, few research reported the...
BACKGROUND
As an important non-apoptotic cell death method, oncosis has been reported to be closely associated with tumors in recent years. However, few research reported the relationship between oncosis and lung cancer.
METHODS
In this study, we established an oncosis-based algorithm comprised of cluster grouping and a risk assessment model to predict the survival outcomes and related tumor immunity of patients with lung adenocarcinomas (LUAD). We selected 11 oncosis-related lncRNAs associated with the prognosis (CARD8-AS1, LINC00941, LINC01137, LINC01116, AC010980.2, LINC00324, AL365203.2, AL606489.1, AC004687.1, HLA-DQB1-AS1, and AL590226.1) to divide the LUAD patients into different clusters and different risk groups. Compared with patients in clsuter1, patients in cluster2 had a survival advantage and had a relatively more active tumor immunity. Subsequently, we constructed a risk assessment model to distinguish between patients into different risk groups, in which low-risk patients tend to have a better prognosis. GO enrichment analysis revealed that the risk assessment model was closely related to immune activities. In addition, low-risk patients tended to have a higher content of immune cells and stromal cells in tumor microenvironment, higher expression of PD-1, CTLA-4, HAVCR2, and were more sensitive to immune checkpoint inhibitors (ICIs), including PD-1/CTLA-4 inhibitors. The risk score had a significantly positive correlation with tumor mutation burden (TMB). The survival curve of the novel oncosis-based algorithm suggested that low-risk patients in cluster2 have the most obvious survival advantage.
CONCLUSION
The novel oncosis-based algorithm investigated the prognosis and the related tumor immunity of patients with LUAD, which could provide theoretical support for customized individual treatment for LUAD patients.
Topics: Adenocarcinoma; Algorithms; CARD Signaling Adaptor Proteins; Humans; Lung; Lung Neoplasms; Neoplasm Proteins; Prognosis; Programmed Cell Death 1 Receptor; RNA, Long Noncoding; Risk Assessment; Tumor Microenvironment
PubMed: 35476781
DOI: 10.1002/jcla.24461 -
Georgian Medical News Mar 2022Objective - to establish the pathomorphological features of liver and lung tissue of patients with non-alcoholic steatohepatitis (NASH) and obesity depending on... (Randomized Controlled Trial)
Randomized Controlled Trial
HISTOLOGICAL AND HISTOCHEMICAL FEATURES OF LIVER AND LUNG TISSUE IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS AND OBESITY DEPENDING ON THE PRESENCE OF COMORBID CHRONIC OBSTRUCTIVE PULMONARY DISEASE.
Objective - to establish the pathomorphological features of liver and lung tissue of patients with non-alcoholic steatohepatitis (NASH) and obesity depending on comorbidity with chronic obstructive pulmonary disease (COPD). The study used autopsy material of 13 cases of NASH and class I obesity (Group 1), 14 cases of NASH, class I obesity with comorbid COPD of stage II-III (Group 2). For comparison, we used the autopsy material of 12 patients with isolated COPD of stage II-III (Group 3), as well as 11 practically healthy individuals (PHI), whose death was caused by polytrauma or traumatic brain injury or sudden coronary death. The groups were randomized by age, sex, and class of obesity. The average age of patients was 59.3±3.21. In Group 2 there was a maximum percentage of hepatocytes in the state of steatosis (1.9 times more than in Group 1, p<0.05), 1.6 times more hepatocytes in the state of fatty necrosis compared with NASH, p<0.05), oncosis (2.1 times, p<0.05), as well as lipofuscinosis (3.1 times more than in case of NASH with obesity, p<0.05). The combined course of obesity, NASH and COPD contributed to a significant increase in the number of lipocytes in the lungs (29.6 times, p<0.05) compared with isolated COPD, as well as a probable increase in their diameter (1.8 times, p<0.05). In the comorbid course of NASH, obesity and COPD, more intense histological and histochemical changes were observed, indicating more significant dysmetabolic disorders and the role of COPD in the activity of the inflammatory process in the liver, namely a higher % of steatosis in hepatocytes. Accumulation of adipocytes was observed in the lungs in this combined pathology, which probably indicates the aggravating effect of NASH and obesity on the course of COPD.
Topics: Comorbidity; Female; Humans; Lung; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Pulmonary Disease, Chronic Obstructive
PubMed: 35417873
DOI: No ID Found