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Medical Hypotheses Mar 2020Cancer is one of the leading causes of death worldwide, and metastasis is the major cause of death in cancer, therefore, treatments to attenuate metastasis are urgently...
Cancer is one of the leading causes of death worldwide, and metastasis is the major cause of death in cancer, therefore, treatments to attenuate metastasis are urgently needed. Cell migration is indispensable in metastatic cascade, and aquaporins (AQPs) promote cell migration by facilitating water influx at cell front (lamellipodia). In fact, AQPs overexpressed widely among many cancer types. Accordingly, previous efforts of targeting AQPs as strategies of cancer treatments were based on AQP inhibitors, yet the efficacy of AQP inhibition was limited based on recent surveys. On the contrary, whether AQP agonist has role in cancer treatments has not been explored. AqF026, an AQP1 agonist, was initially applied to a mouse model of peritoneal dialysis. Herein, we aimed to apply AqF026 to magnify the water influx into lamellipodia of migrating cancer cells so as to induce oncosis by causing overloaded cancer cell swelling in advance of metastatic cascade. Cell swelling is a characteristic of oncosis. With impairment or insufficient regulatory volume decrease (RVD), cell swelling can lead to oncosis. Cancer cells with metastatic potentials shared the same population of cancer cells with multidrug resistance (MDR) lineage, and the impairment or insufficient RVD is shown in cancer cells with MDR. Taken together, the author hypothesized that given appropriate concentration or dose of AQP1 agonist AqF026, the AqF026 may induce oncosis of cancer cells preferentially rather than normal cells by causing overloaded water influx via AQP1 and consequent irreversible cell swelling.
PubMed: 32220711
DOI: 10.1016/j.mehy.2020.109685 -
Nanoscale Research Letters 2014Although much progress has been made in the illustration of the mechanism of aminophylline (AM) treating asthma, there is no data about its effect on the nanostructure...
Although much progress has been made in the illustration of the mechanism of aminophylline (AM) treating asthma, there is no data about its effect on the nanostructure and nanomechanics of T lymphocytes. Here, we presented atomic force spectroscopy (AFM)-based investigations at the nanoscale level to address the above fundamental biophysical questions. As increasing AM treatment time, T lymphocytes' volume nearly double increased and then decreased. The changes of nanostructural features of the cell membrane, i.e., mean height of particles, root-mean-square roughness (Rq), crack and fragment appearance, increased with AM treatment time. T lymphocytes were completely destroyed with 96-h treatment, and they existed in the form of small fragments. Analysis of force-distance curves showed that the adhesion force of cell surface decreased significantly with the increase of AM treatment time, while the cell stiffness increased firstly and then decreased. These changes were closely correlated to the characteristics and process of cell oncosis. In total, these quantitative and qualitative changes of T lymphocytes' structure and nanomechanical properties suggested that AM could induce T lymphocyte oncosis to exert anti-inflammatory effects for treating asthma. These findings provide new insights into the T lymphocyte oncosis and the anti-inflammatory mechanism and immune regulation actions of AM.
PubMed: 25258618
DOI: 10.1186/1556-276X-9-518 -
Journal of Enzyme Inhibition and... Dec 2019In this paper, a series of novel 1-dibenzo[,]carbazole derivatives of dehydroabietic acid bearing different -(piperazin-1-yl)alkyl side chains were designed, synthesised...
In this paper, a series of novel 1-dibenzo[,]carbazole derivatives of dehydroabietic acid bearing different -(piperazin-1-yl)alkyl side chains were designed, synthesised and evaluated for their anticancer activities against three human hepatocarcinoma cell lines (SMMC-7721, HepG2 and Hep3B). Among them, compound exhibited the most potent activity against three cancer cell lines with IC values of 1.39 ± 0.13, 0.51 ± 0.09 and 0.73 ± 0.08 µM, respectively. In the kinase inhibition assay, compound could significantly inhibit MEK1 kinase activity with IC of 0.11 ± 0.02 µM, which was confirmed by western blot analysis and molecular docking study. In addition, compound could elevate the intracellular ROS levels, decrease mitochondrial membrane potential, destroy the cell membrane integrity, and finally lead to the oncosis and apoptosis of HepG2 cells. Therefore, compound could be a potent MEK inhibitor and a promising anticancer agent worthy of further investigations.
Topics: Abietanes; Antineoplastic Agents; Carbazoles; Cell Cycle; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; MAP Kinase Kinase 1; Membrane Potential, Mitochondrial; Models, Molecular; Molecular Structure; Piperazine; Protein Kinase Inhibitors; Structure-Activity Relationship
PubMed: 31448648
DOI: 10.1080/14756366.2019.1655407 -
Cell Death & Disease Jan 2016The proinflammatory interleukin-33 (IL-33) binds to its receptor ST2L on the surface of immune cells and stimulates the production of Th2 cytokines; however, the effects...
The proinflammatory interleukin-33 (IL-33) binds to its receptor ST2L on the surface of immune cells and stimulates the production of Th2 cytokines; however, the effects of IL-33 on tumour cells are poorly understood. Here we show that ST2 was significantly downregulated in human lung cancer tissues and cells compared with normal lung tissues and cells. IL-33 expression was also inversely correlated with the stages of human lung cancers. In accordance with this finding, low-metastatic cells but not high-metastatic cells derived from Lewis lung carcinoma expressed functional ST2L. IL-33 was abundantly present in the tumours established by the low-metastatic cells compared with those formed by the high-metastatic cells. Although the low-metastatic cells scarcely expressed IL-33 in vitro, these cells did expry 6ess this molecule in vivo, likely due to stimulation by intratumoural IL-1β and IL-33. Importantly, IL-33 enhanced the cell death of ST2L-positive low-metastatic cells, but not of ST2L-negative high-metastatic cells, under glucose-depleted, glutamine-depleted and hypoxic conditions through p38 MAPK and mTOR activation, and in a mitochondria-dependent manner. The cell death was characterised by cytoplasmic blisters and karyolysis, which are unique morphological features of oncosis. Inevitably, the low-metastatic cells, but not of the high-metastatic cells, grew faster in IL-33(-/-) mice than in wild-type mice. Furthermore, IL-33 selected for the ST2L-positive, oncosis-resistant high-metastatic cells under conditions mimicking the tumour microenvironment. These data suggest that IL-33 enhances lung cancer progression by selecting for more malignant cells in the tumour microenvironment.
Topics: Animals; Humans; Interleukin-33; Lung Neoplasms; Mice; Neoplasm Metastasis; Transfection; Tumor Microenvironment
PubMed: 26775708
DOI: 10.1038/cddis.2015.418 -
Pharmaceutics Dec 2021Cancer has been identified as a leading cause of death worldwide, and the increasing number of cancer cases threatens to shorten the average life expectancy of people....
Cancer has been identified as a leading cause of death worldwide, and the increasing number of cancer cases threatens to shorten the average life expectancy of people. Recently, we reported a 3-azido-3-deoxythymidine (AZT)-based amphipathic small molecule, ADG-2e that revealed a notable potency against tumor metastasis. To evaluate the anticancer potential of ADG-2e, we assessed its anticancer potency in vitro and in vivo. Anticancer screening of ADG-2e against cervical cancer cells, HeLa CCL2, and BT549 mammary gland ductal carcinoma showed significant inhibition of cancer cell proliferation. Furthermore, mechanistic investigations revealed that cancer cell death presumably proceeded through an oncosis mechanistic pathway because ADG-2e treated cells showed severe damage on the plasma membrane, a loss of membrane integrity, and leakage of -tubulin and -actin. Finally, evaluation of the antitumorigenic potential of ADG-2e in mouse xenograft models revealed that this compound potentially inhibits cancer cell proliferation. Collectively, these findings suggest that ADG-2e can evolve as an anticancer agent, which may represent a model for nucleoside-based small molecule anticancer drug discovery.
PubMed: 34959352
DOI: 10.3390/pharmaceutics13122071 -
Acta Pharmacologica Sinica Dec 2014To investigate the role of extracellular signal-regulated kinases (ERKs) in sevoflurane post-conditioning induced cardioprotection in vitro.
AIM
To investigate the role of extracellular signal-regulated kinases (ERKs) in sevoflurane post-conditioning induced cardioprotection in vitro.
METHODS
Isolated rat hearts were subjected to 30 min ischemia followed by 120 min reperfusion (I/R). Sevoflurane post-conditioning was carried out by administration of O2-enriched gas mixture with 3% sevoflurane (SEVO) for 15 min from the onset of reperfusion. Cardiac functions, myocardial infarct size, myocardial ATP and NAD(+) contents, mitochondrial ultrastructure, and anti-apototic and anti-oncosis protein levels were measured.
RESULTS
Sevoflurane post-conditioning significantly improved the heart function, decreased infarct size and mitochondria damage, and increased myocardial ATP and NAD(+) content in the I/R hearts. Furthermore, sevoflurane post-conditioning significantly increased the levels of p-ERK and p-p70S6K, decreased the levels of porimin, caspase-8, cleaved caspase-3, and cytosolic cytochrome c in the I/R hearts. Co-administration of the ERK1/2 inhibitor PD98059 (20 μmol/L) abolished the sevoflurane-induced protective effects against myocardial I/R.
CONCLUSION
Sevoflurane post-conditioning protects isolated rat hearts against myocardial I/R injury and inhibits cell oncosis and apoptosis via activation of the ERK1/2 pathway.
Topics: Adenosine Triphosphate; Animals; Apoptosis; Apoptosis Regulatory Proteins; Cardiotonic Agents; Cytoprotection; Disease Models, Animal; Enzyme Activation; Heart Rate; MAP Kinase Signaling System; Male; Methyl Ethers; Mitochondria, Heart; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NAD; Perfusion; Phosphorylation; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Sevoflurane; Time Factors; Ventricular Function, Left
PubMed: 25345742
DOI: 10.1038/aps.2014.78 -
Cell Death and Differentiation Mar 2017Antibody-mediated cell killing has significantly facilitated the elimination of undesired cells in therapeutic applications. Besides the well-known Fc-dependent...
Antibody-mediated cell killing has significantly facilitated the elimination of undesired cells in therapeutic applications. Besides the well-known Fc-dependent mechanisms, pathways of antibody-induced apoptosis were also extensively studied. However, with fewer studies reporting the ability of antibodies to evoke an alternative form of programmed cell death, oncosis, the molecular mechanism of antibody-mediated oncosis remains underinvestigated. In this study, a monoclonal antibody (mAb), TAG-A1 (A1), was generated to selectively kill residual undifferentiated human embryonic stem cells (hESC) so as to prevent teratoma formation upon transplantation of hESC-derived products. We revealed that A1 induces hESC death via oncosis. Aided with high-resolution scanning electron microscopy (SEM), we uncovered nanoscale morphological changes in A1-induced hESC oncosis, as well as A1 distribution on hESC surface. A1 induces hESC oncosis via binding-initiated signaling cascade, most likely by ligating receptors on surface microvilli. The ability to evoke excess reactive oxygen species (ROS) production via the Nox2 isoform of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is critical in the cell death pathway. Excess ROS production occurs downstream of microvilli degradation and homotypic adhesion, but upstream of actin reorganization, plasma membrane damage and mitochondrial membrane permeabilization. To our knowledge, this is the first mechanistic model of mAb-induced oncosis on hESC revealing a previously unrecognized role for NAPDH oxidase-derived ROS in mediating oncotic hESC death. These findings in the cell death pathway may potentially be exploited to improve the efficiency of A1 in eliminating undifferentiated hESC and to provide insights into the study of other mAb-induced cell death.
Topics: Actins; Antibodies, Monoclonal; Apoptosis; Carbohydrate Sequence; Cell Line; Cell Membrane; Epitopes; Human Embryonic Stem Cells; Humans; Microscopy, Electron, Scanning; Mitochondrial Membranes; NADPH Oxidase 2; Permeability; Reactive Oxygen Species
PubMed: 28106884
DOI: 10.1038/cdd.2016.164 -
American Journal of Physiology.... Sep 2020How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies;...
How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies; however, findings are contradictory. We test whether low-level stress and Western diet (WD) feeding synergistically influence homeostasis, mood, and myocardial ischemic tolerance. Male C57BL6/J mice were fed a control diet or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wk, with subgroups restrained for 30 min/day over the final 3 wk. Metabolism, behavior, tolerance of perfused hearts to ischemia-reperfusion (I/R), and cardiac "death proteins" were assessed. The WD resulted in insignificant trends toward increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%), and cholesterol (+20%) and reduced leptin (-20%) while significantly reducing insulin sensitivity [100% rise in homeostasis model assessment of insulin resistance (HOMA-IR), < 0.05]. Restraint did not independently influence metabolism while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice ( < 0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was nonadditive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-α, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, whereas the combination worsened dysfunction and oncosis [lactate dehydrogenase (LDH) efflux]. Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3, and PARP) were unchanged. We conclude that mild, anxiogenic yet cardio-metabolically "benign" stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).
Topics: Animals; Diet, High-Fat; Energy Intake; Heart; Homeostasis; Insulin Resistance; Mice, Inbred C57BL; Myocardial Ischemia; Myocardium; Obesity
PubMed: 32755463
DOI: 10.1152/ajpregu.00322.2019 -
Nanoscale Research Letters Dec 2017Artemisinin and its derivatives were considered to exert a broad spectrum of anti-cancer activities, and they induced significant anti-cancer effects in tumor cells....
Artemisinin and its derivatives were considered to exert a broad spectrum of anti-cancer activities, and they induced significant anti-cancer effects in tumor cells. Artemisinin and its derivatives could be absorbed quickly, and they were widely distributed, selectively killing tumor cells. Since low concentrations of artesunate primarily depended on oncosis to induce cell death in tumor cells, its anti-tumor effects were undesirable and limited. To obtain better anti-tumor effects, in this study, we took advantage of a new nanotechnology to design novel artesunate-loaded bovine serum albumin nanoparticles to achieve the mitochondrial accumulation of artesunate and induce mitochondrial-mediated apoptosis. The results showed that when compared with free artesunate's reliance on oncotic death, artesunate-loaded bovine serum albumin nanoparticles showed higher cytotoxicity and their significant apoptotic effects were induced through the distribution of artesunate in the mitochondria. This finding indicated that artesunate-loaded bovine serum albumin nanoparticles damaged the mitochondrial integrity and activated mitochondrial-mediated cell apoptosis by upregulating apoptosis-related proteins and facilitating the rapid release of cytochrome C.
PubMed: 28610396
DOI: 10.1186/s11671-017-2169-7 -
Oncoscience 2016High frequency quantitative ultrasound techniques were investigated to characterize different forms of cell death . Suspension-grown acute myeloid leukemia cells were...
High frequency quantitative ultrasound techniques were investigated to characterize different forms of cell death . Suspension-grown acute myeloid leukemia cells were treated to cause apoptosis, oncosis, mitotic arrest, and heat-induced death. Samples were scanned with 20 and 40 MHz ultrasound and assessed histologically in terms of cellular structure. Frequency-domain analysis of 20 MHz ultrasound data demonstrated midband fit changes of 6.0 ± 0.7 dBr, 6.2 ± 1.8 dBr, 4.0 ± 1.0 dBr and -4.6 ± 1.7 dBr after 48-hour cisplatinum-induced apoptosis, 48-hour oncotic decay, 36-hour colchicine-induced mitotic arrest, and heat treatment compared to control, respectively. Trends from 40 MHz ultrasound were similar. Spectral slope changes obtained from 40 MHz ultrasound data were reflective of alterations in cell and nucleus size. Chromatin pyknosis or lysis trends suggested that the density of nuclear material may be responsible for observed changes in ultrasound backscatter. Flow cytometry analysis confirmed the modes of cell death and supported midband fit trends in ultrasound data. Scatterer-size and concentration estimates obtained from a fluid-filled sphere form factor model further corresponded with spectral analysis and histology. Results indicate quantitative ultrasound spectral analysis may be used for probing anti-cancer response and distinguishing various modes of cell death .
PubMed: 28050578
DOI: 10.18632/oncoscience.319