Necroptosis is a form of programmed necrosis mediated by signaling complexes with receptor-interacting protein 1 (RIP1) and RIP3 kinases as the main mediators. However, the underlying execution ...pathways of this phenomenon have yet to be elucidated in detail. In this study, a RIP1/RIP3 complex was formed in 2-methoxy-6-acetyl-7-methyljuglone (MAM)-treated HCT116 and HT29 colon cancer cells. With this formation, mitochondrial reactive oxygen species (ROS) levels increased, mitochondrial depolarization occurred, and ATP concentrations decreased. This process was identified as necroptosis. This finding was confirmed by experiments showing that MAM-induced cell death was attenuated by the pharmacological or genetic blockage of necroptosis signaling, including RIP1 inhibitor necrostatin-1s (Nec-1s) and siRNA-mediated gene silencing of RIP1 and RIP3, but was unaffected by caspase inhibitor z-vad-fmk or necrosis inhibitor 2-(1H-Indol-3-yl)-3-pentylamino-maleimide (IM54). Transmission electron microscopy (TEM) analysis further revealed the ultrastructural features of MAM-induced necroptosis. MAM-induced RIP1/RIP3 complex triggered necroptosis through cytosolic calcium (Ca2+) accumulation and sustained c-Jun N-terminal kinase (JNK) activation. Both calcium chelator BAPTA-AM and JNK inhibitor SP600125 could attenuate necroptotic features, including mitochondrial ROS elevation, mitochondrial depolarization, and ATP depletion. 2-thenoyltrifluoroacetone (TTFA), which is a mitochondrial complex II inhibitor, was found to effectively reverse both MAM induced mitochondrial ROS generation and cell death, indicating the complex II was the ROS-producing site. The essential role of mitochondrial ROS was confirmed by the protective effect of overexpression of manganese superoxide dismutase (MnSOD). MAM-induced necroptosis was independent of TNFα, p53, MLKL, and lysosomal membrane permeabilization. In summary, our study demonstrated that RIP1/RIP3 complex-triggered cytosolic calcium accumulation is a critical mediator in MAM-induced necroptosis through sustained JNK activation and mitochondrial ROS production. Our study also provided new insights into the molecular regulation of necroptosis in human colon cancer cells.
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•MAM, a natural naphthoquinone, induces RIP1/RIP3 complex dependent necroptosis in human colon cancer cells.•Calcium accumulation and JNK activation function downstream of RIP1/RIP3 necrosome formation.•Mitochondrial ROS originated from complex II is playing an essential role in mediating MAM induced necroptosis.
Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on ...various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as anticancer agents is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made.
Drug resistance is a major challenge in cancer treatment. The substrates of NAD(P)H:quinone oxidoreductase 1 (NQO1) show a promising anticancer effect in clinical trials. We previously identified a ...natural NQO1 substrate 2-methoxy-6-acetyl-7-methyljuglone (MAM) with a potent anticancer effect. The present study was designed to explore the efficacy of MAM in fighting against drug-resistant non-small cell lung cancer (NSCLC). The anticancer effect of MAM was evaluated in cisplatin-resistant A549 and AZD9291-resistant H1975 cells. The interaction of MAM with NQO1 was measured by cellular thermal shift assay and drug affinity responsive target stability assay. The NQO1 activity and expression were measured using NQO1 recombinant protein, Western blotting, and immunofluorescence staining assay. The roles of NQO1 were examined by NQO1 inhibitor, small interfering RNA (siRNA), and short hairpin RNA (shRNA). The roles of reactive oxygen species (ROS), labile iron pool (LIP), and lipid peroxidation were determined. MAM induced significant cell death in drug-resistant cells with similar potency to that of parental cells, which were completely abolished by NQO1 inhibitor, NQO1 siRNA, and iron chelators. MAM activates and binds to NQO1, which triggers ROS generation, LIP increase, and lipid peroxidation. MAM significantly suppressed tumor growth in the tumor xenograft zebrafish model. These results showed that MAM induced ferroptosis by targeting NQO1 in drug-resistant NSCLC cells. Our findings provided a novel therapeutic strategy for fighting against drug resistance by induction of NQO1-mediated ferroptosis.
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•MAM showed significant anticancer effect in cisplatin and AZD9291 resistant NSCLC.•NQO1 mediated MAM’s anticancer effect both in vitro and in vivo.•MAM triggers NQO1 mediated ferroptosis in lung cancer cells.
CD47, a transmembrane protein, acts as a “do not eat me” signal that is overexpressed in many tumor cell types, thereby forming a signaling axis with its ligand signal regulatory protein alpha ...(SIRPα) and enabling the tumor cells to escape from macrophage-mediated phagocytosis. Several clinical trials with CD47 targeting agents are underway and have achieved impressive results preliminarily. However, hematotoxicity (particularly anemia) has emerged as the most common side effect that cannot be neglected. In the development of CD47 targeting agents, various methods have been used to mitigate this toxicity. In this review, we summarized five strategies used to alleviate CD47 blockade-induced hematotoxicity, as follows: change in the mode of administration; dual targeting bispecific antibodies of CD47; CD47 antibodies/SIRPα fusion proteins with negligible red blood cell binding; anti-SIRPα antibodies; and glutaminyl-peptide cyclotransferase like inhibitors. With these strategies, the development of CD47 targeting agents can be improved.
CD47 is overexpressed in various types of cancers and it can directly bind with SIRPα, which is mainly located on macrophages. The binding of CD47-SIRPα transmits a “don't eat me” signal, which can ...prevent cancer cells from immune clearance. Targeting the phagocytosis checkpoint of CD47-SIRPα axis has shown remarkable anticancer effect in preclinical and clinical research, which indicates the potential application of CD47-SIRPα blockade for cancer treatment. In this case, the comprehensive description of the regulation of CD47 in different types of cancer cells has significant implications for furthering our understanding of the role of CD47 in cancer. Based on the current reports, we summarized the regulatory factors, i.e., cytokines, oncogenes, microRNAs as well as enzymes, of CD47 expression in cancer cells. Accordingly, we also proposed several points needing further research, hoping to provide useful insights for the future investigation on the regulation of CD47 in cancers.
CD47 is overexpressed in various types of cancers and it can directly bind with SIRPα, which is mainly located on macrophages. The binding of CD47-SIRPα transmits a “don't eat me” signal, which can prevent cancer cells from immune clearance. In this case, the comprehensive understandings of the regulation of CD47 in cancer cells are essential for further developments. In this review, based on the current reports, we summarized that CD47 expression could be regulated by cytokines, oncogenes, microRNAs and enzymes in cancer cells. Likewise, CD47 expression could be regulated at the transcriptional level, post-transcriptional level, post-translational modification level, etc. However, further studies are required to determine other factors that regulate CD47 expression. Display omitted
•Cytokines, oncogenes, microRNAs and enzymes regulate CD47 expression in cancer.•CD47 expression could be regulated at the transcriptional, post-transcriptional and post-translational modification level.•Further studies are required to determine other factors that regulate CD47 expression.
Cell death plays a critical role in organism development and the pathogenesis of diseases. Necrosis is considered a non-programmed cell death in an extreme environment. Recent advances have provided ...solid evidence that necrosis could be programmed and quite a few types of programmed necrosis, such as necroptosis, ferroptosis, pyroptosis, paraptosis, mitochondrial permeability transition-driven necrosis, and oncosis, have been identified. The specific biomarkers, detailed signaling, and precise pathophysiological importance of programmed necrosis are yet to be clarified, but these forms of necrosis provide novel strategies for the treatment of various diseases, including cancer. Natural compounds are a unique source of lead compounds for the discovery of anti-cancer drugs. Natural compounds can induce both apoptosis and programmed necrosis. In this review, we summarized the recent progress of programmed necrosis and introduced their natural inducers. Noptosis, which is a novel type of programmed necrosis that is strictly dependent on NAD(P)H: quinone oxidoreductase 1-derived oxidative stress was proposed. Furthermore, the anti-cancer strategies that take advantage of programmed necrosis and the main concerns from the scientific community in this regard were discussed.
Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung ...cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-l-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells.
•Osimertinib induced the expressions of cytoplasmic vacuoles and autophagic markers in different cancer cells.•Osimertinib induced autophagic flux in NSCLC NCI-H1975 and HCC827 cell lines.•ROS generation contributed to osimertinib-induced cytoplasmic vacuoles, autophagy, cell viability decrease, and apoptosis.
Capacitive deionization (CDI) is a competent water desalination technique offering an appropriate route to obtain clean water. However, a rational designed structure of the electrode materials is ...essentially required for achieving high CDI performance. Here, a novel sponge‐templated strategy is developed for the first time to prepare graphene sheets with high specific surface area and suitable pore size distribution. Sponge is used as the support of graphene oxide to prevent the restack of graphene sheets, as well as to suppress the agglomerate during the annealing process. Importantly, the as‐fabricated graphene sheets possess high specific surface area of 305 m2 g−1 and wide pore size distribution. Ultrahigh CDI performance, a remarkable electrosorptive capacity of 4.95 mg g−1, and siginificant desorption rate of 25 min, is achieved with the sponge‐templated prepared graphene electrodes. This work provides an effective solution for the synthesis of rational graphene architectures for general applications in CDI, energy storage and conversion.
Sponge‐templated graphene sheets (STGS) with high specific surface area, wide pore size distribution, and low internal resistance are prepared through a simple annealing method. The as‐prepared STGS exhibits promising CDI performance with an ultrahigh electrosorptive capacity of 4.95 mg g−1 and fast desorption rate of 25 min.
•Platycodins represent the main bioactive components of Platycodonis Radix.•More than 70 platycodins have been identified from Platycodonis Radix.•The platycodins possess various pharmacological ...activities.•Toxicology and pharmacokinetics of the platycodins have been summarized.
Platycodonis Radix, the root of Platycodon grandiflorum (Jacq.) A. DC., is a well-known edible herbal medicine. It is a common vegetable used for the preparation of side dish, kimchi, dessert, and tea. Besides, it has been used to treat respiratory disease including cough, excessive phlegm, and sore throat for a long history. In the past decades, the bioactive components and the pharmacological activities of Platycodonis Radix have been widely investigated. Thereinto, platycodins, the oleanane-type triterpenoid saponins were demonstrated to be the main bioactive components in Platycodonis Radix, and more than 70 platycodins have been identified up to date. This paper mainly reviewed the phytochemistry, pharmacological activities (apophlegmatic, anti-tussive, anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, immunomodulatory, cardiovascular protective, and hepatoprotective activities, etc.), toxicology and pharmacokinetics of platycodins isolated from Platycodonis Radix, aiming to promote further investigation on therapeutic potential of these platycodins.
Programmed death ligand-1 (PD-L1) is an important immune checkpoint for cancer immunotherapy in clinic. In this study, we reported that platycodin D, a natural product isolated from an edible and ...medicinal plant Platycodon grandiflorus (Jacq.) A. DC., down-regulated the protein level of PD-L1 in lung cancer cells. Flow cytometry and immunofluorescence assay showed a weaker surface PD-L1 signal in NCI–H1975 cells after the incubation with platycodin D (10 μM) for 15 min compared to the control group. Jurkat T cells showed enhancive interleukin-2 secretion when co-cultured with platycodin D-treated NCI–H1975 cells, suggesting that platycodin D-induced PD-L1 reduction increases the activation of Jurkat T cells. An augmentation of PD-L1 protein was detected in the cell culture medium from platycodin D treatment group. Chlorpromazine (60 μM) almost abolished the platycodin D-mediated PD-L1 extracellular release and restored the membrane PD-L1. Finally, hemolysis assay exhibited that platycodin D-triggered PD-L1 extracellular release was independent of the hemolytic mechanism. Taken together, our study demonstrates that platycodin D reduces the protein level of PD-L1 in lung cancer cells via triggering its release into the cell culture medium, which sheds new light for the application of natural products in cancer immunotherapy.
•Platycodin D-triggered extracellular release of PD-L1 in lung cancer cells.•Jurkat T cells co-cultured with platycodin D-treated NCI–H1975 cells shows enhanced interleukin-2 secretion.•Chlorpromazine abolishes platycodin D-triggered extracellular release of PD-L1.
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